Vitamin D Status and the Risk of Cardiovascular Disease Death

Vitamin D Status and the Risk of Cardiovascular Disease Death

 

  1. 1.    Annamari Kilkkinen,
  2. 2.    Paul Knekt,
  3. 3.    Antti Aro,
  4. 4.    Harri Rissanen,
  5. 5.    Jukka Marniemi,
  6. 6.    Markku Heliövaara,
  7. 7.    Olli Impivaara and
  8. 8.    Antti Reunanen
  9. Correspondence to Dr. Annamari Kilkkinen, National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland (e-mail: annamari.kilkkinen@thl.fi).

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Vitamin D Status and the Risk of Cardiovascular Disease Death

Annamari Kilkkinen,

Paul Knekt,

Antti Aro,

Harri Rissanen,

Jukka Marniemi,

Markku Heliövaara,

Olli Impivaara and

Antti Reunanen

Correspondence to Dr. Annamari Kilkkinen, National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland (e-mail: annamari.kilkkinen@thl.fi).

Received April 24, 2009.

Accepted July 1, 2009.

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ABSTRACT

Accumulating evidence suggests that inadequate vitamin D levels may predispose people to chronic diseases. The authors aimed to investigate whether serum 25-hydroxyvitamin D (25(OH)D) level predicts mortality from cardiovascular disease (CVD). The study was based on the Mini-Finland Health Survey and included 6,219 men and women aged ≥30 years who were free from CVD at baseline (1978–1980). During follow-up through 2006, 640 coronary disease deaths and 293 cerebrovascular disease deaths were identified. Levels of 25(OH)D were determined from serum collected at baseline. Cox’s proportional hazards model was used to assess the association between 25(OH)D and risk of CVD death. After adjustment for potential confounders, the hazard ratio for total CVD death was 0.76 (95% confidence interval (95% CI): 0.60, 0.95) for the highest quintile of 25(OH)D level versus the lowest. The association was evident for cerebrovascular death (hazard ratio = 0.48, 95% CI: 0.31, 0.75) but not coronary death (hazard ratio = 0.91, 95% CI: 0.70, 1.18). A low vitamin D level may be associated with higher risk of a fatal CVD event, particularly cerebrovascular death. These findings need to be replicated in other populations. To demonstrate a causal link between vitamin D and CVD, randomized controlled trials are required.

Key words

cardiovascular diseases

cohort studies

mortality

vitamin D

 

Interest in vitamin D has intensified lately, with a growing body of evidence suggesting that adequate vitamin D status is required for optimal health (1, 2). The importance of vitamin D for bone health has long been acknowledged. Recent evidence suggests that vitamin D can also play a role in reducing the risk of several other diseases, including cardiovascular disease (CVD).

Vitamin D, whether ingested or synthesized in the skin, is metabolized in the human body into 25-hydroxyvitamin D (25(OH)D) and further into the biologically active form, 1,25-dihydroxyvitamin D (1, 2). Receptors for vitamin D have been found in many different cells, including cardiomyocytes and vascular endothelial cells, giving it the potential to have wide-ranging vascular effects (36). Evidence from ecologic, animal, and clinical studies also supports a potential beneficial role for vitamin D in the development of CVD (3, 4, 710). Furthermore, vitamin D status has been demonstrated to be associated with several established risk factors for CVD (11) and prevalent CVD (12). Epidemiologic evidence, however, is limited and inconclusive; both inverse associations (1315) and no associations (16) between vitamin D status and CVD risk have been reported. In addition, vitamin D supplementation had no influence on CVD incidence and mortality in the Women’s Health Initiative trial (17, 18). In the present study, we extended previous research on vitamin D and CVD by evaluating whether serum 25(OH)D level predicts mortality from coronary and cerebrovascular diseases in a cohort of more than 6,000 Finnish men and women.

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MATERIALS AND METHODS

STUDY POPULATION

The Mini-Finland Health Survey was carried out in 1978–1980 in 40 areas of Finland (19). A 2-stage random sample (n = 8,000) was drawn from the population register to represent Finnish men and women aged 30 years or more. A total of 7,217 subjects (90% of the sample) participated in the survey, which included a health examination. Of these, 890 subjects who had a history of (or findings suggestive of) CVD at baseline and 108 subjects who did not have a serum sample available for 25(OH)D analysis were excluded. This resulted in a cohort of 6,219 subjects.

BASELINE MEASUREMENTS

Fasting blood samples were taken during a health examination and kept frozen at −20°C until 2003, when 25(OH)D levels were determined by radioimmunoassay (DiaSorin, Inc., Stillwater, Minnesota). The interassay coefficient of variation for 25(OH)D determination was 7.80% at the mean level of 47.3 nmol/L (n = 167) and 9.12% at the level of 131.3 nmol/L (n = 135). The proportion of quality-control samples was 13.5%.

Serum total and high density lipoprotein cholesterol levels were determined with a direct modification of the Liebermann–Burchard method (20) in 1978–1980. The level of high density lipoprotein cholesterol was analyzed from the supernatant of the serum after precipitation of low density lipoprotein cholesterol and very low density lipoprotein cholesterol with magnesium/dextran sulfate. Serum triglyceride levels were analyzed enzymatically (Boehringer Mannheim GmbH, Mannheim, Germany). Low density lipoprotein cholesterol level was calculated according to the Friedewald formula: total cholesterol − high density lipoprotein cholesterol − 0.45 × total triglyceride level. Plasma glucose level was measured using the glucose oxidase method (Boehringer Mannheim) in 1978–1980, and cotinine level was measured by radioimmunoassay (Diagnostic Products Corporation, Los Angeles, California) in 1999.

The health examination included electrocardiographic recordings and blood pressure measurements. Height and weight were measured, and body mass index (weight (kg)/height (m)2) was calculated. Subjects with chronic disease histories, symptoms, or findings suggestive of cardiovascular, respiratory, or musculoskeletal diseases were asked to participate in a standardized physical examination conducted by specially trained physicians. At the end of the examination, the physicians made diagnostic assessments on the basis of all available documents, self-reported disease histories, symptoms, and clinical signs and findings. Angina pectoris was defined as typical chest pain brought on by exertion and relieved by nitroglycerine or rest. Myocardial infarction was defined as a positive history in the medical records, old myocardial infarction found upon electrocardiography, or a typical self-reported history of myocardial infarction treated in a hospital. Stroke was defined as a positive history in the medical records or a typical self-reported history of stroke treated in a hospital.

Information on socioeconomic background, symptoms, diseases, medications, and lifestyle was collected via questionnaires and interviews. Educational level was categorized into 2 groups (low, 0–9 years; high, ≥10 years) and marital status into 4 groups (unmarried, married (including common-law marriage) or in a committed relationship, widowed, divorced). Leisure-time physical activity was assessed with a question about the duration, intensity, and frequency of physical activity, and subjects were classified as inactive, occasionally active, or regularly active. Categories of alcohol consumption (ethanol intake; 0, 1–14.9, or ≥15 g/week) were derived from responses to questionnaire items concerning average weekly consumption of beer, wine, and liquor during the preceding month. Both self-reported information on smoking habits and serum cotinine level were used to generate the smoking variable. Subjects who reported that they had never smoked or had quit smoking and had a serum cotinine level of 100 ng/mL or less were categorized as nonsmokers. The rest of the subjects were divided into tertiles (cutoff points, 405 ng/mL and 767 ng/mL) based on their serum cotinine level.

Definite hypertension was defined as systolic blood pressure ≥170 mm Hg and diastolic blood pressure ≥100 mm Hg or the use of antihypertensive medication. Of the remaining members of the study population, those with systolic blood pressure ≥160 mm Hg and diastolic blood pressure ≥95 mm Hg were considered to have mild hypertension and those with systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg were considered to be normotensive. All other subjects were considered to have borderline hypertension. Diabetes mellitus was defined as a self-reported history of diabetes that had been diagnosed and treated by a physician or a fasting plasma glucose level ≥6.7 mmol/L. In Finland, which is situated geographically between 60°N latitude and 70°N latitude, biologically effective ultraviolet B irradiation for production of vitamin D by the skin is provided by sunshine during the summer months only; therefore, serum 25(OH)D levels are higher between June and September than during the rest of the year. Because the baseline examinations were conducted in different seasons, the subjects were divided into 2 seasonal groups, winter (October–May) and summer (June–September).

FOLLOW-UP DATA

Incident cases of fatal CVD were identified through linkage with Statistics Finland, using the Finnish nationwide individual identification number as the identity link. The Eighth, Ninth, and Tenth revisions of the International Classification of Diseases (ICD-8, ICD-9, and ICD-10, respectively) were used for coding the causes of death. Deaths with ICD codes 410–414 (ICD-8 and ICD-9) and I20–I25 (ICD-10) were classified as coronary heart disease deaths. Cerebrovascular deaths included those due to subarachnoid hemorrhage (ICD-8 and ICD-9 code 430, ICD-10 code I60), hemorrhagic stroke (ICD-8 and ICD-9 code 431, ICD-10 code I61), ischemic stroke (ICD-8 and ICD-9 codes 433–434, ICD-10 code I63), or other unspecified cerebrovascular causes (ICD-8 codes 435–438, ICD-9 codes 432 and 435–438, ICD-10 codes I6 and I64–I69).

STATISTICAL ANALYSES

The Cox proportional hazards model was used to estimate hazard ratios and 95% confidence intervals for total CVD, coronary heart disease, and cerebrovascular deaths according to quintile of serum 25(OH)D level. The follow-up period was defined as the time from the baseline examination to the date of CVD death, death from other causes, or the end of follow-up (December 31, 2006)—whichever came first. All analyses were adjusted for age (in years, as a continuous variable) and sex (model 1). Multivariable analyses (model 2) also included adjustment for the following a priori potential confounders: marital status, educational level, body mass index, alcohol consumption, smoking, leisure-time physical activity, and season of baseline examination. We defined 2 additional models, one of which further included serum levels of high and low density lipoprotein cholesterol (model 3) and another that also included blood pressure and diabetes (model 4).

In secondary analyses, the subjects who died of CVD within the first 4 years of follow-up or were aged 70 years or older at baseline were excluded. In addition, interactions between vitamin D and the potential effect-modifying factors (blood pressure, smoking, age, sex, body mass index, season of baseline examination, serum total, high and low density lipoprotein cholesterol levels, leisure-time physical activity, alcohol consumption and diabetes) were assessed in the main multivariable model (model 2). Because the results of these secondary analyses were essentially similar for total CVD, coronary heart disease, and cerebrovascular mortality, only the results for total CVD are presented. The vitamin D–stroke association was also analyzed according to subtypes of stroke (hemorrhagic and ischemic); these analyses were conducted using tertiles of serum 25(OH)D because of the small number of cases. In addition, subjects were divided into 2 categories using commonly applied cutoff points for low (<50 nmol/L) and high (≥50 nmol/L) levels of vitamin D (1).

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RESULTS

The study population consisted of 2,817 men and 3,402 women with a mean age of 49.4 years (standard deviation (SD), 13.6) at baseline. The mean serum 25(OH)D level was 43.4 nmol/L (SD, 19.7) (45.7 nmol/L (SD, 20.3) in men and 41.5 nmol/L (SD, 18.9) in women), with 67.6% of the population having a level less than 50 nmol/L. Older and highly educated subjects were more likely to have a higher vitamin D status than younger and less-educated subjects, respectively (Table 1). Heavy smoking, high alcohol consumption, low leisure-time physical activity, high body mass index, diabetes, hypertension, and a poor serum lipid profile were also associated with low serum 25(OH)D level.

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Table 1.

Baseline Characteristics of Participants According to Quintile of Serum 25-Hydroxyvitamin D Level, Mini-Finland Health Survey, Finland, 1978–1980a

During a median follow-up period of 27.1 years (range, 9 days–28.9 years), 640 coronary heart disease deaths (358 in men and 282 in women) and 293 cerebrovascular disease deaths (122 in men and 171 in women) were identified. Cerebrovascular events included 175 ischemic strokes, 43 hemorrhagic strokes, 22 subarachnoid hemorrhages, and 53 other unspecified cerebrovascular events.

There was an inverse association between serum 25(OH)D level and total CVD mortality when results were adjusted for age and sex only (for the highest quintile in model 1 vs. the lowest, hazard ratio (HR) = 0.71, 95% confidence interval (CI): 0.58, 0.87; P for trend < 0.001 (Table 2)). Adjustment for potential confounders, including also marital status, educational level, body mass index, alcohol consumption, smoking, leisure-time physical activity, and season of baseline examination, only slightly attenuated the association (in model 2, HR = 0.76, 95% CI: 0.61, 0.95; P for trend = 0.005). Further adjustment for serum high and low density lipoprotein cholesterol levels (in model 3, HR = 0.75, 95% CI: 0.59, 0.94; P for trend = 0.004) and diabetes and blood pressure (in model 4, HR = 0.80, 95% CI: 0.64, 1.01; P for trend 0.012) did not notably change the results. Moreover, the results remained essentially similar after the exclusion of subjects who died of CVD during the first 4 years of follow-up (in model 2, HR = 0.76, 95% CI: 0.60, 0.96; P for trend = 0.008) or were 70 years of age or older at baseline (in model 2, HR = 0.79, 95% CI: 0.61, 1.03; P for trend = 0.029). No statistically significant interaction was observed between 25(OH)D level and age (P for interaction = 0.95), alcohol consumption (P = 0.53), body mass index (P = 0.49), diabetes (P = 0.32), blood pressure (P = 0.81), leisure-time physical activity (P = 0.30), season of baseline examination (P = 0.75), sex (P = 0.74), smoking (P = 0.24), or serum total (P = 0.12), high density lipoprotein (P = 0.23), or low density lipoprotein (P = 0.13) cholesterol level.

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Table 2.

Hazard Ratios for Cerebrovascular and Coronary Disease Mortality According to Quintile of Baseline Serum 25-Hydroxyvitamin D Level, Mini-Finland Health Survey, Finland, 1978–1980

An inverse association was found between serum 25(OH)D level and mortality from cerebrovascular disease (for the highest quintile in model 1 vs. the lowest, HR = 0.47, 95% CI: 0.31, 0.70; P for trend < 0.001 (Table 2)). Results from multivariable analyses were rather similar (in model 2, HR = 0.48, 95% CI: 0.31, 0.75; P for trend = 0.002), indicating that there was little confounding by the covariates. Further adjustment for serum high and low density lipoprotein cholesterol concentrations (in model 3, HR = 0.50, 95% CI: 0.32, 0.77; P for trend = 0.003) and diabetes and blood pressure (in model 4, HR = 0.52, 95% CI: 0.33, 0.80; P for trend = 0.004) did not change the results. In the analyses conducted according to subtype of stroke, the multivariable adjusted hazard ratios (for the highest tertile in model 2 vs. the lowest) for hemorrhagic and ischemic stroke were 0.61 (95% CI: 0.26, 1.46; P for trend = 0.29) and 0.60 (95% CI: 0.38, 0.93; P for trend = 0.050), respectively (Table 3).

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Table 3.

Hazard Ratios for Various Subtypes of Stroke According to Tertile of Baseline Serum 25-Hydroxyvitamin D Level, Mini-Finland Health Survey, Finland, 1978–1980

In model 1, with adjustment for age and sex only, an inverse association was found between serum 25(OH)D level and the risk of coronary heart disease death (for the highest quintile vs. the lowest, HR = 0.83, 95% CI: 0.65, 1.06; P for trend = 0.037 (Table 2)). After adjustment for potential confounders, the hazard ratios were no longer statistically significant (in model 2, HR = 0.91, 95% CI: 0.70, 1.18; P for trend = 0.20). No single risk factor was responsible for the attenuation. Further inclusion of serum high and low density lipoprotein cholesterol concentrations in the model did not change the results (in model 3, HR = 0.87, 95% CI: 0.67, 1.14; P for trend = 0.12). In the model 4 that also included diabetes and blood pressure, the hazard ratio for the highest quintile versus the lowest was 0.96 (95% CI: 0.73, 1.25; P for trend = 0.28).

In further analysis based on the cutoff value of 50 nmol/L for serum 25(OH)D level, the multivariable adjusted hazard ratio (for high vitamin D category in model 2 vs. low vitamin D category) for total CVD death was 0.88 (95% CI: 0.75, 1.03). For mortality from cerebrovascular disease and coronary heart disease, the corresponding hazard ratios were 0.58 (95% CI: 0.42, 0.79) and 1.04 (95% CI: 0.86, 1.25), respectively.

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DISCUSSION

This cohort study provided evidence that a low circulating level of vitamin D may predict a higher risk of CVD death. The observed association was particularly striking for mortality from cerebrovascular disease; subjects in the highest quintile of serum 25(OH)D level had less than half the risk of cerebrovascular death as those in the lowest quintile.

Epidemiologic evidence on the association between vitamin D and the risk of CVD is limited. In the Health Professionals Follow-up Study, men with a high circulating level of vitamin D had half the risk of myocardial infarction as men with vitamin D insufficiency (14). Similarly, a study of German adults who were undergoing elective cardiac catheterization showed a 2-fold risk of CVD death among persons in the lowest quartile of baseline vitamin D level compared with those in the highest quartile (13). In addition, among participants in the Framingham Offspring Study cohort, vitamin D deficiency was associated with an increased risk of CVD (relative risk = 1.62, 95% CI: 1.11, 2.36) (15). However, in contrast to our findings, the association was observed only in hypertensive subjects, not in those without hypertension (15). Moreover, in a recent cohort study based on data from the Third National Health and Nutrition Examination Survey, Melamed et al. (16) could not find a statistically significant association between vitamin D status and CVD mortality in the general population. Note, however, that data on coronary heart disease and cerebrovascular events were pooled in the Third National Health and Nutrition Examination Survey (16) and in most earlier studies (13, 15), whereas we analyzed deaths from coronary heart disease and cerebrovascular disease separately. Indeed, our findings suggest that vitamin D might have a more important role in the prevention of cerebrovascular disease, especially ischemic stroke, than in the etiology of coronary heart disease. There is no obvious explanation for this finding, and confirmation in other studies is required. However, although coronary heart disease and cerebrovascular disease share important risk factors, the impact of some risk factors (e.g., blood lipids and blood pressure) varies (21). This may imply different underlying mechanisms for these diseases and offers a possible explanation for the differences in our results for cerebrovascular disease and coronary heart disease.

Although the exact mechanisms by which an adequate vitamin D status may protect against CVD are not fully understood, experimental studies indicate that vitamin D is one of the most potent hormones for suppressing the renin-angiotensin system and thus for regulating blood pressure (4). The vascular effects of vitamin D also include inhibition of thrombosis (3) and arterial calcification (22). Furthermore, several types of cells, including vascular smooth muscle cells and lymphocytes, express receptors for vitamin D and have the ability to convert circulating 25(OH)D to 1,25-dihydroxyvitamin D, which in turn can reduce the proliferation of lymphocytes and the production of cytokines (5, 6). Because there is increasing evidence that systemic inflammation plays an important role in the development of atherosclerosis (23), the antiinflammatory properties of vitamin D warrant further exploration. Vitamin D deficiency, on the other hand, increases the secretion of parathyroid hormone, which has been shown to contribute to pathologic changes in the cardiovascular system (24). Further studies are required to clarify the vitamin D–CVD association and the mechanisms behind the association. Data from supplementation trials of the effects of vitamin D on bone health could provide useful information.

The mean serum 25(OH)D values in our study were approximately of the same order of magnitude as those previously found in Finland (25) but somewhat lower than those generally observed in other European (13, 26) and American (12) populations. There is no absolute consensus as to what the optimal range for serum 25(OH)D levels should be. However, relatively high concentrations of 25(OH)D (>75 nmol/L) are required to maintain normal parathyroid hormone levels, and even higher concentrations (≥83–121 nmol/L) are suggested to be desirable for cancer prevention (27). Although optimal levels for cardiovascular protection may differ from those, it is noteworthy that the values in our cohort were substantially lower than those previously thought to be sufficient (27).

The main strengths of the present study lay in the prospective design and the fairly large nationally representative population sample. In addition, information on CVD mortality was obtained from the nationwide mortality register, which is based on death certificates and has been shown to have reasonably good validity (28, 29). A further strength of the study was the information on CVD and its risk factors at baseline from the physician’s examination. However, while the detailed data on multiple CVD risk factors allowed adjustment for potential confounders, we cannot rule out the possibility of residual confounding. It can be speculated that persons with chronic illness may have reduced serum vitamin D levels because of their limited exposure to sunlight and inadequate dietary intake of vitamin D. This raises the possibility that low vitamin D status is only a nonspecific indicator of chronic illness rather than a direct contributor to disease pathogenesis. It is important to acknowledge potential confounding by dietary factors, as we did not have information on vitamin D intake from diet and supplements. The major dietary source of vitamin D is fatty fish, consumption of which is suggested to be protective against CVD because of its n-3 polyunsaturated fatty acid content (30). A recent meta-analysis, however, did not show a definite effect of omega-3 fatty acids on CVD events (31).

A further limitation of this study was the use of a single measurement of vitamin D. It can be questioned whether serum 25(OH)D level measured at a single point in time reflects only recent exposure rather than long-term exposure. Nevertheless, in 1 study, the correlation coefficient for correlation between 2 measurements of vitamin D taken 3 years apart appeared to be moderately high, 0.70 (32), suggesting that a single serum measurement of this compound could be a useful tool in epidemiologic studies. Such measurement, however, fails to take into account the intraindividual seasonal variation in serum 25(OH)D levels. Inclusion of the season of baseline examination as a potential confounder in the model or the use of it as an effect-modifying factor did not substantially change our results. Because serum samples were stored at −20°C up to 25 years before the determination of vitamin D level, a change in vitamin D concentrations during storage is a potential concern. However, vitamin D metabolites in blood stored at 24°C for up to 72 hours have been shown to remain intact (33), and only a minimal decline is observed for plasma 25(OH)D level for up to 4 years of storage at −20°C (34). Although the evidence suggests that 25(OH)D is a stable compound (3335), we cannot rule out the possibility that levels might have changed during storage at −20°C. Finally, the use of mortality rather than incidence data was a potential limitation of the study.

In conclusion, our results suggest that a low circulating level of vitamin D may be associated with a higher risk of fatal CVD events. Although a possible causal link between vitamin D and CVD is biologically plausible, further investigations from different populations with repeated measurements of vitamin D are warranted. To demonstrate a causal link between vitamin D status and the risk of CVD, randomized controlled clinical trials are required. Because CVD remains the leading cause of death in most developed countries, identification of new CVD risk factors (such as vitamin D) is an area of much interest, both scientifically and among the lay public. Our findings may have profound public health implications; while the prevalence of suboptimal vitamin D levels has been observed to be high worldwide, vitamin D status can be rather inexpensively and easily improved through supplementation or lifestyle measures.

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Acknowledgments

Author affiliation: National Institute for Health and Welfare, Helsinki, Finland.

This work was supported in part by the Social Insurance Institution of Finland.

Conflict of interest: none declared.

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Footnotes

Abbreviations:

Abbreviations

CI

confidence interval

CVD

cardiovascular disease

HR

hazard ratio

ICD

International Classification of Diseases

25(OH)D

25-hydroxyvitamin D

SD

standard deviation

American Journal of Epidemiology © The Author 2009. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

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****

Dra. Cristina Sales – «Saber comer é pura informação»

Dra . Cristina Sales –  «Saber comer é pura informação»

Por Célia Rosa. Fotografia de Pedro Granadeiro/GI

Cristina%20Sales

E se o seu organismo não reconhecer aquilo que você come como um alimento? Defende-se, inflama-se, fica doente. É o que fazem muitos dos produtos que levamos à boca. Cristina Sales, médica e especialista em alimentação, garante que na origem da maioria das doenças que afetam o homem do século XXI está o que comemos e o modo como o fazemos. É que os alimentos são veículos de comunicação: dizem às células como devem comportar-se.

Precisamos de mudar a forma como nos alimentamos?

_É obrigatório que o façamos porque a alimentação que a população dos países ocidentais, incluindo Portugal, passou a fazer nos últimos cinquenta anos é o que está na origem da maior parte das doenças endócrinas, metabólicas, autoimunes, degenerativas e alérgicas. As novas epidemias devem-se sobretudo aos estilos de vida e à alimentação que fazemos desde o pós-guerra.

A alimentação é decisiva para a saúde e o bem-estar mas está a provocar doenças e a aumentar a mortalidade precoce?

_A geração dos nossos filhos terá uma esperança de vida mais reduzida do que a nossa por causa dos estilos de vida e da alimentação. Primeiro, os produtos altamente processados pela indústria alimentar conduzem a uma desnutrição em nutrientes fundamentais e ingerimos uma grande quantidade de calorias vazias. Segundo, são muito diferentes dos alimentos originais e o organismo não sabe lidar com eles, não os reconhece como alimentos. Depois, há uma sobrecarga tóxica inerente à alimentação que provém dos agroquímicos (da produção), dos conservantes, corantes e adoçantes que são adicionados para preservar os produtos durante mais tempo e para os manter bonitinhos.

São alimentos para ver…

_Os produtos que nos chegam ao prato foram feitos para vender e não para comer. Não têm nada que ver com os alimentos que ingerimos e que nos fizeram viver e sobreviver ao longo de milhões de anos. Esta mudança ocorreu tão depressa que o organismo não está adaptado para gerir, digerir e assimilar estes produtos, pelo contrário, vê-os como substâncias estranhas e reage, inflamando-se.

Como é que podemos livrar-nos dessa teia?

_As escolhas alimentares são condicionadas pela publicidade, as pessoas não são ensinadas a escolher. Quem é que é ensinado a consumir maçãs ou laranjas? Ninguém. A informação que passa de forma subliminar através dos anúncios da TV e dos jornais é que se deve beber sumo de maçã e de laranja. Mas se alguém ler os rótulos das embalagens verifica que contém imenso açúcar, frutose, acidificantes, etc., e o que falta é a maçã e a laranja. É preciso informar, ensinar e consciencializar a população.

A atitude da indústria alimentar tem de mudar?

_No global sim, mas também depende do que a indústria faz. A conservação de alimentos através da congelação, por exemplo, é perfeita. Os legumes congelados são uma ótima opção, por vezes mais económica, e chegam ao consumidor mais frescos e com mais nutrientes do que os que são mantidos durante cinco ou seis dias nas cadeias de distribuição. Já quando falamos de alimentos que têm de levar uma quantidade enorme de aditivos para serem consumidos – é o caso das carnes de muito má qualidade e dos aproveitamentos que se fazem dos restos dos mariscos – é diferente. Sempre que tivermos de dobrar a língua muitas vezes para conseguir ler o que está escrito nos rótulos é porque não é comida. Não compre. Será qualquer coisa que do ponto de vista nutricional, químico e metabólico está muito longe do alimento original.

Está a falar de alimentos que duram ad eternum?

_Por exemplo. Como é que duram? Fizeram-se estudos com hambúrgueres e batatas fritas – uns feitos em casa, com carne picada, e batatas que foram descascadas, outros com produtos processados e embalados – e verificou-se que ao fim de trinta ou quarenta dias alguns hambúrgueres se mantinham iguaizinhos. Não se degradaram, ao contrário dos que foram feitos em casa, que estavam estragados três dias depois. Ora alguém acha que uma coisa daquelas pode ser comida?

Quando ingerimos produtos desse tipo como é que o organismo reage?

_Defende-se e inflama-se ou agarra naquelas coisas que não considera importantes e arruma-as nos depósitos de lixo, que são as células gordas. Estas, além de serem o nosso reservatório de energia, são também o depósito de substâncias tóxicas que o organismo não metaboliza ou não utiliza para impedir que entrem nos circuitos mais nobres. Esta acumulação de lixo cria bloqueios bioquímicos e alterações metabólicas que impedem as células de trabalhar em condições. Hoje ninguém sabe que consequências é que isto tem para o cérebro e o sistema imunitário e para o bom trabalho hepático e digestivo. Os circuitos da toxicidade são cruzados – se uma pessoa come de vez em quando um gelado, um iogurte, umas bolachas ou um sumo que tem um determinado corante é uma coisa, mas se o faz com regularidade, ao fim de seis meses já ultrapassou as doses suportáveis e entra em sobrecarga tóxica.

E o que é que acontece?

_Veja-se o ácido fosfórico, um aditivo que está presente em alimentos de consumo diário, como os cereais de pequeno-almoço e os refrigerantes. Quem ingere estes produtos todos os dias, além de ficar com o sistema acidificado e perder cálcio (uma compensação do organismo que depois predispõe à osteoporose), também fica numa excitação – o ácido fosfórico é um estimulante cerebral e é óbvio que uma criança que de manhã come um prato de cereais chega à escola e não para quieta. O ácido fosfórico altera o comportamento e em determinadas concentrações é neurotóxico.

Como é que os alimentos atuam no organismo?

_Os alimentos servem para construir tecido, osso, órgãos, etc., e para nos darem energia, mas o que as ciências da nutrição têm vindo a mostrar é que os alimentos são essencialmente moduladores do comportamento celular – são informadores das células, dizem-lhes como devem funcionar. Imagine que tem um prato com uma determinada quantidade de proteínas (peixe ou carne) e outra de hidratos de carbono. Só a proporção entre a quantidade de carne e batatas ingeridas vai informar o organismo da necessidade de produzir uma hormona ou outra, neste caso insulina (que é a hormona do armazenamento) ou glucagon (a hormona do desarmazenamento).

Explique lá melhor…

_Se comer mais proteínas do que hidratos de carbono vai produzir mais glucagon e induzir o metabolismo a ir buscar gordura acumulada para disponibilizar às células, ou seja, vai desarmazenar. Mas se comer mais arroz, massa ou batatas vai dar uma ordem em sentido contrário, vai dizer que é precisa mais insulina e vai acumular gordura.

Mas se as pessoas forem ativas podem queimar essa energia…

_Isso é outra coisa, o que importa reter é que na proporção hidratos de carbono/proteínas a quantidade de açúcar que chega aos sensores do tubo digestivo aciona imediatamente uma ordem de libertação de glucagon ou de insulina. Se a indicação é libertar glucagon, o organismo vai usar a gordura acumulada, se a ordem for para libertar insulina, o organismo vai armazenar gordura. Isto é pura informação.

Quem quer perder peso tem de saber isso, certo?

_Se a pessoa tiver consciência da informação que dá ao corpo tem muito mais capacidade para o modular. Outro exemplo. A leptina, a hormona que sinaliza o apetite, que depende sobretudo do ritmo solar. Ora, uma pessoa equilibrada, que durma de noite e trabalhe de dia, produz mais leptina de manhã (e tem apetite) e ao fim do dia produz menor quantidade (o apetite diminui). Se uma pessoa comer muito à noite estraga este equilíbrio e a certa altura está sempre com fome porque inutilizou os sensores da leptina. Nós somos mamíferos e de noite, quando dormimos, não precisamos de comer. O nosso corpo tem a sabedoria para sinalizar o apetite em função da hora do dia – comer muito à noite estraga essa sinalização, faz ter apetite a toda a hora.

A alimentação é bioquímica?

_Os alimentos são veículos de comunicação. Se fizer uma refeição de gordura saturada – uma sopa com um chouriço e depois um cozido à portuguesa – dá um sinal à cárdia (esfíncter entre o estômago e o esófago) para alargar e é assim que ocorrer o refluxo gastroesofágico e aparece a azia. A gordura saturada é um sinal que se dá à cárdia para se manter aberta. Se no dia seguinte a mesma pessoa só comer azeite ou gorduras de peixe não terá azia. Sabe porquê? É que o azeite ajuda a fechar a cárdia. Este é outro exemplo que ilustra a importância do conhecimento. Pessoas mais esclarecidas fazem escolhas mais acertadas.

A forma como nos alimentamos dita o comportamento das células?

_Quando ingeridas, as gorduras saturadas e as gorduras ómega 6 (provenientes essencialmente dos animais e dos cereais, sobretudo da soja) são a estrutura a partir da qual as células fazem substâncias pró-inflamatórias. As gorduras ómega 3 – provenientes das algas e dos peixes – são as que permitem que as células produzam substâncias anti-inflamatórias. Se uma pessoa tem uma doença inflamatória (por exemplo, uma alergia, artrite ou doença autoimune) e come muita gordura saturada, esta vai funcionar como substrato para a fogueira e agravar o processo inflamatório da doença que já tem. Ao contrário, se a pessoa ingerir gorduras ómega 3, vai ser capaz de construir extintores de incêndio para que as suas células produzam anti-inflamatórios.

Há outros exemplos?

_Se uma pessoa tem tendência depressiva porque não consegue produzir serotonina em quantidade suficiente, deve comer os alimentos que têm os aminoácidos precursores da serotonina – a carne de peru, por exemplo, é extremamente rica em triptofano, que é um precursor da serotonina. Se a pessoa souber isto, no outono, quando o tempo fica mais escuro, porque é que não há de comer mais carne de peru em vez de carne de vaca?

A alimentação e o processo digestivo podem agravar ou controlar certas doenças?

_Sim, se uma pessoa tem uma predisposição genética para a diabetes, Alzheimer, etc., a doença só vai manifestar-se se o gene for ativado. Mas o que as pessoas precisam de saber é que os genes também podem ser desativados – é a modulação genética através da nutrigenética. Como? O que ativa ou suprime a expressão dos genes é a presença de determinados fitoquímicos, substâncias que também se encontram nos alimentos.

Podemos dizer que há alimentos anti-inflamatórios?

_Claramente. Os que têm ómega 3 – sardinha, cavala e os peixes das águas frias do Norte. Algumas substâncias vegetais dos legumes (tomate), frutos (quivi) e especiarias (a curcuma, que confere a cor amarela ao caril) também têm efeito modulador de alguns genes pró-inflamatórios. Mas alimentos anti-inflamatórios devem ser consumidos, independentemente de se ter doença ou não. Hoje sabe-se que um cérebro com Alzheimer já está inflamado vinte anos antes da manifestação da doença. Todas as doenças degenerativas começam com processos inflamatórias, as autoimunes também. Não conhecemos é as causas.

Há substâncias que devem mesmo ser eliminadas da alimentação?

_Os aditivos químicos. Falo das substâncias químicas que não são alimentos, que são usadas pela indústria alimentar e podem ser geradoras de inflamação em contacto com o organismo. A vida corrente não nos permite evitar todos os aditivos, mas se estivermos despertos para esta realidade teremos mais atenção, faremos escolhas mais saudáveis e ingerimos menores quantidades.

E as gorduras?

_As gorduras ómega 6, que se encontram nas margarinas e nos óleos e que são provenientes da soja, do milho e do amendoim, são claramente pró-inflamatórias. Precisamos de ómega 6 no organismo, mas em quantidades muito reduzidas. O problema é que a cadeia alimentar atual é geradora de uma alimentação extraordinariamente rica em ómega 6 e pobre em ómega 3. Basta pensar que, dantes, as galinhas e as vacas comiam erva, agora comem rações provenientes da soja; os peixes comiam algas, agora comem rações também com soja. Os produtos alimentares que usamos são essencialmente da linha produtora de ómega 6.

Nos supermercados temos centenas de alimentos à escolha. Precisamos de tanta coisa?

_Não precisamos de tantos produtos alimentares, necessitamos é de maior diversidade alimentar. Essas centenas ou milhares de produtos que vemos nas prateleiras são provenientes de quatro ou cinco alimentos – cereais, lácteos, açúcares e gorduras – e da indústria de processamento. Se olharmos para a quantidade de legumes, frutos, oleaginosas e peixe que as pessoas comem no dia a dia verificamos que não há variedade alimentar, as pessoas comem quase sempre o mesmo. Já pensou na variedade de saladas que é possível fazer? Mas se perguntar a alguém qual é a que come diz-lhe alface e tomate.

No supermercado fazemos escolhas condicionadas pela publicidade e o marketing. Como podemos fugir a isso?

_Só vai mudar com a informação dos cidadãos. Nos países do Norte da Europa, onde a população é muito mais esclarecida, não encontramos nos supermercados esta quantidade enorme de alimentos-lixo – basta verificar que o espaço ocupado por refrigerantes, cereais de pequeno-almoço e óleos alimentares é muito reduzido. Exatamente o oposto do que se passa em Portugal.

A crise económica e as dificuldades das famílias podem piorar ainda mais a alimentação dos portugueses?

_Também pode acontecer o contrário. Numa altura em que todos sentimos uma necessidade absoluta de gerir muito bem os orçamentos familiares, devemos fazer listas de compras de forma racional. E antes de comprar certos produtos alimentares, é obrigatório perguntar: «Preciso mesmo disto? Vale a pena? Faz-me ficar mais forte, vital, inteligente? Tem mais nutrientes?» Ocasionalmente, podemos comprar os tais alimentos que não comportam nenhum valor acrescentado mas que agradam ao paladar, mas isso é num dia de festa.

De que produtos podemos e devemos mesmo prescindir quando vamos às compras?

_Devemos tirar os refrigerantes, cereais com açúcar, pastelaria, óleos e margarinas – para cozinhar devemos usar o azeite, só azeite. Todos os refrigerantes são um estrago de dinheiro – as pessoas devem beber água. Os cereais com açúcar (os de pequeno-almoço e as bolachas) também são prescindíveis – devemos escolher cereais completos, integrais, que até são mais baratos. Compare-se o preço de uma caixa de cereais de pequeno-almoço com o de um pacote de flocos de aveia, que são altamente nutritivos. A aveia é muito mais barata e muito nutritiva.

Mas comprar carne magra e peixe gordo, frutos e hortaliças é muito mais dispendioso…

_Mas há estratégias que podem ser implementadas. Uma é comprar carne de melhor qualidade e comer menos quantidade e menos vezes. É preferível comer carne três vezes por semana em vez de comer carne gorda todos os dias. Além disso, toda a gente ganha se fizer uma alimentação vegetariana dois dias da semana e em vez da carne comer, por exemplo, arroz de feijão ou grão-de-bico com massa. Se se acrescentar hortaliças, ervas aromáticas e azeite, podemos dizer que são refeições perfeitas. Menos carne, mas de melhor qualidade; mais peixe (incluindo cavala e sardinhas, frescas ou em conserva de azeite) e ovos (podem ser consumidos três ou quatro por semana) são opções a privilegiar.

Não retira massa, arroz ou batatas ao seu carrinho de compras?

_Não, mas reduzo as quantidades ingeridas. No prato devemos ter pequenas porções de massa, arroz ou batatas e maior quantidade de hortaliças, legumes e leguminosas.

Fala-se muito na responsabilidade social da indústria farmacêutica, que ganha dinheiro à custa do tratamento dos doentes. E quanto à responsabilidade social da indústria alimentar, que ganha dinheiro atirando-nos para a doença?

_A indústria alimentar está a fazer maus alimentos, mas a verdade é que as pessoas só compram o que querem. Sei que quanto menor é a informação maior é a permeabilidade ao marketing, mas o caminho também se faz através da informação dos cidadãos e da sua responsabilização. Custa-me imenso ver nas caixas de supermercado que as pessoas aparentemente mais pobres também são as que levam os carrinhos repletos de produtos inúteis e nefastos para a sua saúde. É preciso repensar a política alimentar e inovar.

BI

A medicina que Cristina Sales exerce dá pelo nome de medicina funcional integrativa – reúne diferentes disciplinas, profissionais e recursos terapêuticos, é centrada na pessoa e procura entender onde estão os desequilíbrios que desencadeiam a doença. Para uns, trata-se de uma abordagem vanguardista, mais adaptada aos pacientes, ao tratamento e controlo das chamadas doenças da civilização. Para outros, a prática médica de Cristina Sales ainda gera alguma desconfiança. Quem não receia são os doentes que a procuram – sobretudo pessoas que vivem com doenças crónicas (alergias, enxaquecas, fadiga crónica, doenças inflamatórias, endócrinas, metabólicas e autoimunes) e que não encontraram resposta satisfatória para os problemas que as afetam até chegarem ao seu consultório no Porto. Uma consulta com a médica dura hora e meia e não se marca de um dia para o outro. Porque os pacientes já são muitos e porque as palestras e conferências em que Cristina Sales é oradora convidada são frequentes.

http://www.jn.pt/revistas/nm/interior.aspx?content_id=2609289

– – –

A correcção terapêutica da deficiência em vitamina D3 nas doenças auto-imunes é uma opção terapêutica baseada em evidência científica

Segundo a experiência pioneira do Dr Cicero Coimbra, MD, PhD, Professor Associado de Neurologia e Neurociência da Universidade Federal de São Paulo, Brasil, a correcção terapêutica dos níveis sanguíneos de vitamina D3, pela toma continuada de doses elevadas, ou muito elevadas, de vitamina D3 sob controlo médico, pode reverter em parte ou na totalidade os sintomas da doença e mesmo fazer a doença entrar em remissão. (14)

 

A correcção terapêutica da deficiência em vitamina D3 nas doenças auto-imunes é uma opção terapêutica baseada em evidência científica

 

Por Dra Cristina Sales

 Cristina%20Sales

Dra Cristina Sales na revista Notícias Magazine

Foto e entrevista http://www.jn.pt/revistas/nm/interior.aspx?content_id=2609289 em Quarta-Feira, 20 Junho, 2012

Autoimunes e Vitamina D3

Doenças autoimunes e vitamina D3

Criamos uma consulta multidisciplinar para aplicação do protocolo de correcção terapêutica da deficiência em vitamina D3 nas doenças auto-imunes que segue a metodologia e tem o apoio do Dr Cícero Coimbra, seu autor.

A 1ª etapa do protocolo de correcção terapêutica da deficiência em vitamina D3 nas doenças auto-imunes, que é constituida por uma consulta médica e uma consulta de nutrição.


Ambas as consultas são agendadas para o mesmo dia.

As consultas médicas serão realizadas pela Dra Cristina Sales ou pela Dra Filomena Vieira.

As consultas de nutrição serão realizadas pela Dra Daniela Seabra ou pela Dra Helena Santos.

Para marcação de consulta queira informa-se clicando aqui .

Informação científica:

A correcção terapêutica da deficiência em vitamina D3 nas doenças autoimunes é uma opção terapêutica baseada em evidência científica

 

A investigação científica recente mostrou que a vitamina D3, para além do conhecido papel no metabolismo do cálcio e processo de ossificação, tem múltiplas acções no organismo, com relevância para uma importante intervenção no sistema imunitário.

A amplitude da sua acção e o facto de todas as células do organismo humano terem receptores para esta substância sugerem tratar-se não de uma vitamina mas de uma pró-hormona (1).

 

A síntese da vitamina D3, no organismo humano, é feita pela pele e depende totalmente da sua exposição solar. Para produzir a quantidade necessária de vitamina D3 é preciso expor ao sol as pernas, braços, pescoço e face durante, pelo menos, 15minutos, ao inicio da manhã ou ao fim da tarde quando a inclinação do sol provoca uma sombra do tamanho da pessoa.
A vida urbana moderna e o uso de protectores solares impossibilitam a produção de vitamina D3 na quantidade suficiente. O afastamento da zona geográfica onde se habita do equador representa mais um factor de risco.
Verifica-se, por outro lado, que a grande maioria da população dos países industrializados é deficitária em vitamina D3. O deficit de vitamina D3 promove a osteoporose e as patologias dentárias, aumenta a incidência dos cancros de mama, de próstata e de cólon e de doenças cardiovasculares.

 

Há pessoas cujo perfil genético interfere, de forma dramática, no metabolismo da vitamina D3, condicionando níveis sanguíneos muito baixos de vitamina D3 (2).
A grande maioria das pessoas com doenças auto-imunes pertence a este grupo populacional e apresenta uma grave deficiência em vitamina D3.

 

De entre as doenças auto-imunes, a esclerose múltipla é aquela em que a evidência científica é mais contundente. Existem mais de 3.600 (3) estudos científicos publicados que mostram a relação entre esclerose múltipla e deficiência em vitamina D3.

 

A alta frequência de surtos e elevada severidade das sequelas neurológicas (paraplegia, cegueira) correlaciona-se com níveis circulantes mais baixos de vitamina D tanto em adultos (4, 5) como em crianças (6).

 

Em 1986 um estudo mostrou que a vitamina D3, em doses modestas (5.000 UI por dia) foi capaz de reduzir em mais de 50% a frequência de surtos em portadores de esclerose múltipla (7).

 

Em 2007 um estudo envolvendo 12 doentes por um período de 28 semanas mostrou que a administração de doses progressivamente elevadas ao longo de 7 meses  (a partir da dose semanal de 28.000 UI = 4.000 UI por dia, até ser atingida a dose semanal de 280.000 UI = 40.000 UI por dia), levaram à redução das lesões activas em comparação com o número de lesões activas encontradas nos mesmos pacientes antes desses 7 meses, não sendo verificada a ocorrência de efeitos colaterais (8).

 

Um estudo “duplo-cego, randomizado” publicado em 2012, mostra a redução do número de lesões activas no grupo tratado com doses relativamente baixas de vitamina D (20.000 UI por semana) durante apenas 1 ano, além de diversas outras melhoras, sem efeitos colaterais verificados (9), em comparação com o grupo que recebeu apenas interferon + placebo.

 

Em Junho 2012, a publicação científica “Currente Opinion in Neurology” num artigo intitulado “Vitamin D and multiple sclerosis: epidemiology, immunology, and genetics” conclui “continuarem a acumular-se evidências em relação ao papel protector da vitamina D contra o risco da esclerose múltipla se desenvolver e contra a progressão da doença (10).
Um dado da maior relevância na abordagem terapêutica das doenças auto-imunes é que a acção imunitária da vitamina D3 diminui a resposta auto-imune ao mesmo tempo que mantém, ou mesmo aumenta, a capacidade de defesa face a doenças infecto-contagiosas.
De facto, na qualidade de potente pró-hormona imuno-reguladora, a vitamina D inibe a resposta imunológica direccionada contra o próprio organismo  (denominada pelos imunologistas como “TH17”), tanto em indivíduos saudáveis (11) como nos portadores de esclerose múltipla (12)  sem inibir a resposta direccionada contra infecções e pelo contrário, potencializando a resposta antimicrobiana, tal como se verifica, por exemplo, no tratamento da tuberculose pulmonar (13).

 

Se a evidência científica é especialmente bem suportada no caso da esclerose múltipla, a correcção terapêutica da deficiência em vitamina D3 assume-se como um dever ético e pode beneficiar igualmente os doentes com outras doenças auto-imunes – artrite reumatóide, lupus, diabetes tipo1, tiroidite de Hashimoto – que apresentem deficit de vitamina D3.
Segundo a experiência pioneira do Dr Cicero Coimbra, MD, PhD, Professor Associado de Neurologia e Neurociência da Universidade Federal de São Paulo, Brasil, a correcção terapêutica dos níveis sanguíneos de vitamina D3, pela toma continuada de doses elevadas, ou muito elevadas, de vitamina D3 sob controlo médico, pode reverter em parte ou na totalidade os sintomas da doença e mesmo fazer a doença entrar em remissão. (14)

 

As DDR – doses diárias recomendadas – de vitamina D3 que ao longo de décadas têm sido 200, 400 ou 600 UI, mostram-se totalmente desadequadas para repor o nível sérico nos doentes cujos perfis genéticos condicionam o normal metabolismo da vitamina D3, desde a sua absorção até ao seu efeito biológico.

 

As pessoas portadoras de EM são parcialmente resistentes à vitamina D em decorrência de polimorfismos genéticos (2)necessitando,  portanto, de doses muito maiores para obterem o mesmo efeito biológico dessa potente pró-hormona imuno-reguladora.

 
A administração diária de 1.000 UI eleva a concentração plasmática de vitamina D em cerca de 5 ng/mL(12.5 nmol/L); já a administração diária de 5.000 UI eleva a concentração plasmática de vitamina D em cerca de 36 ng/mL(90 nmol/L); a administração diária de 10.000 UI eleva a concentração plasmática de vitamina D em cerca de 64 ng/mL (160 nmol/L) (15).

 

A terapêutica com doses elevadas, ou muito elevadas, de vitamina D3 comporta alguns riscos. Por isso, este tratamento deve ser acompanhado por um regime alimentar específico e ser sujeito a uma monitorização médica e laboratorial regular para um ajuste adequado e personalizado das doses terapêuticas da vitamina D3.

 

Bibliografia:

(1) Norman AW. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. American Journal of Clinical Nutrition. August 2008. vol. 88 no. 2 491S-499S

(2) Sundqvist E, Bäärnhielm M, Alfredsson L,  Hillert J, Olsson T,  Kockum I. Confirmation of association between multiple sclerosis and CYP27B1. European Journal of Human Genetics. 2010 December; 18(12): 1349–1352.

(3) Scirus [homepage]. Acedido em Junho 2012. Disponível em: http://www.scirus.com/srsapp/search?sort=0&t=all&q=%22vitamin+D%22&cn=all&co=AND&t=all&q=%22multiple+sclerosis%22&cn=all&g=a&fdt=0&tdt=2013&dt=all&ff=all&ds=jnl&ds=nom&ds=web&sa=all(pesquisa feita por “vitamin D” (“multiple sclerosis”))

(4) Smolders J. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis. Multiple Sclerosis Journal. November 2008 vol. 14 no. 9 1220-1224.

(5) Weinstock-Guttman B, Zivadinov R, Qu J, Cookfair D, Duan X, Bang E, Bergsland N, Hussein S, Cherneva M, Willis L, Heininen-Brown M, Ramanathan M. Vitamin D metabolites are associated with clinical and MRI outcomes in multiple sclerosis patients. Journal of Neurology, Neurosurgery & Psychiatry. 2011 Feb;82(2):189-95.

(6) Mowry EM, Krupp LB, Milazzo M, Chabas D, Strober JB, Belman AL, McDonald JC, Oksenberg JR, Bacchetti P, Waubant E. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Annals of Neurology. 2010 May; 67(5):618-24.

(7) Goldberg P, Fleming MC, Picard EH. Multiple sclerosis: Decreased relapse rate through dietary supplementation with calcium, magnesium and vitamin D. Medical Hypotheses. Volume 21, Issue 2, October 1986, Pages 193–200.

(8) Kimball SM, Ursell MR, O’Connor P, Vieth R. Safety of vitamin D3 in adults with multiple sclerosis. American Journal of Clinical Nutrition. September 2007. vol. 86 no. 3 645-651.

(9) Soilu-Hänninen M,  Åivo J,  Lindström BM, et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon ß-1b in patients with multiple sclerosis. Journal of Neurology Neurosurgery and Psychiatry. 2012; 83:565-571.

(10) Simon, Kelly C.; Munger, Kassandra L.; Ascherio, Alberto. Vitamin D and multiple sclerosis: epidemiology, immunology, and genetics. Current Opinion in Neurology. June 2012 – Volume 25 – Issue 3 – p 246–251
(11) Aideen C Allen, Siobhan Kelly, Sharee A Basdeo, et al. A pilot study of the immunological effects of high-dose vitamin D in healthy volunteers. Multiple Sclerosis Journal. March 28, 2012.

(12) J.M. Burton, S. Kimball, R. Vieth, et al. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology. 2010 June 8; 74(23): 1852–1859.

(13) Martineau AR, Timms PM, Bothamley GH, et al. High-dose vitamin D3 during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial. The Lancet, Volume 377, Issue 9761, Pages 242 – 250, 15 January 2011.

(14) Vitamina D – Por uma outra terapia (Vitamin D – For an alternative therapy). Documentário online em:http://www.youtube.com/watch?v=erAgu1XcY-U

(15) Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. American Journal of  Clinical Nutrition. 2003 Jan;77(1):204-10.

 http://www.cristinasales.pt/Medicina-Integrada/Texts/Text.aspx?PageID=649&MVID=1000833

 

Australian and New Zealand Bone and Mineral Society and Osteoporosis Australia release new guidelines

1946_sunglasses_hat_in_sunVitamin D news

Australian and New Zealand Bone and Mineral Society and Osteoporosis Australia release new guidelines

18 February 2013

Sunshine is good, according to new guidelines set by the Australian and New Zealand Bone and Mineral Society and Osteoporosis Australia (ANZBMS).

ANZBMS put together a working group to reevaluate and redraft a position statement on vitamin D, specifically for adolescents and children. They previously released a statement in 2006. Their new guidelines were based on a systematic review of literature stored in the MEDLINE database between 1946 and July 2011.

In their position statement, ANZBMS recognized sunlight as “the most important source of vitamin D,” noting that it can provide up to 90% of vitamin D requirements if sought after adequately. They recommended that adults and pregnant women seek moderate sun exposure and be careful not to burn. They also encouraged general physical outdoor activity.

However, ANZBMS did not recommend moderate sun exposure for children and adolescents, carefully noting that those under 18 should avoid burning and use protective measures to do so, like use of clothing and shade.

For vitamin D levels, they recommended a level of over 20 ng/ml (50 nmol/l). Since levels drop in the wintertime, the working group recommended that levels may need to be at least as high as 24-28 ng/ml (60-70 nmol/l) in the summer to ensure levels over 20 ng/ml in the winter.

Have a child or adolescent with vitamin D deficiency? The ANZBMS also released treatment guidelines. For those aged 1-18 years old, the working group recommended deficiency be treated with 1,000-2,000 IU/day for 3-6 months. For those under 12 months old, they recommended the use of 1,000 IU/day for severe deficiency and 400 IU/day for mild deficiency for three months. They also recommended a “maintenance” dose of 400 IU for all ages under 18, for those that are not deficient.

The new position statement is intended for primary care providers and specialists involved in the care of children and pregnant women.

Source

Paxton GA et al. Vitamin D and health in pregnancy, infants, children and adolescents in Australia and New Zealand; a position statement. Medical Journal of Australia, 2013

Page last edited: 18 February 2013

http://www.vitamindcouncil.org/australian-and-new-zealand-bone-and-mineral-society-and-osteoporosis-australia-release-new-guidelines/

Vitamin D levels of professional ballet dancers: Winter vs. Summer

“Further studies on the impact of vitamin D3 supplementation on markers of bone metabolism, muscle function and injury profile would help to enhance our understanding of this important area of metabolism in athletes/dancers.”

Dancers

Vitamin D Council

Vitamin D news

Vitamin D levels of professional ballet dancers: Winter vs. Summer

19 February 2013

Professional ballerinas have a high incidence of vitamin D deficiency, improving slightly during summer months. Dancers also are more likely to get injured during the winter, according to research published in theJournal of Science and Medicine in Sport.

Roger Wolman, MD, of the Royal National Orthopaedic Hospital in Stanmore, UK, and colleagues recruited 18 ballet dancers from a single international touring dance company. The participants were professional Caucasian dancers who dance an average of 6-8 hours per day, 38 hours per week. A lifestyle questionnaire and blood samples were completed in February and August 2010. Company doctors kept track of any injuries that occurred during the study period.

Dr Wolman and colleagues found that during winter season, all dancers were either insufficient, characterized as 10-30 ng/ml, or deficient,< 10 ng/ml. During summer months the authors noted significant improvement, with 3 dancers with vitamin D levels >30 ng/ml, while 14 were insufficient and 2 deficient. The authors also found that serum parathyroid hormone (PTH) significantly decreased during this time. Chronically high PTH is associated with vitamin D deficiency and can lead to problems with the thyroid.

There was a significant decrease in incidence of injury between winter and summer months (p<0.05). Interestingly, the authors noticed that among female dancers, taking an oral contraceptive had a significant beneficial effect on vitamin D status, PTH, and markers of healthy bone. They conclude,

“Further studies on the impact of vitamin D3 supplementation on markers of bone metabolism, muscle function and injury profile would help to enhance our understanding of this important area of metabolism in athletes/dancers.”

Source

Wolman R, Wyon MA, Koutedakis Y, Nevill AM, Eastell R, Allen N. Vitamin D status in professional ballet dancers: Winter vs. summer. Journal of Science and Medicine in Sport. 2013.

Page last edited: 19 February 2013

Tratamento com a Vitamina D, Cura e Prevenção – Low vitamin D levels ‘linked to Parkinson’s disease’

Tratamento com a Vitamina D, Cura e Prevenção – Low vitamin D levels ‘linked to Parkinson’s disease’

30-year study

The researchers from Finland’s National Institute for Health and Welfare measured vitamin D levels from the study group between 1978 and 1980, using blood samples.

12 July 2010 Last updated at 23:24 GMT

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Sunlight on the skin helps generate vitamin D

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Having low vitamin D levels may increase a person’s risk of developing Parkinson’s disease later in life, say Finnish researchers.

Their study of 3,000 people, published in Archives of Neurology, found people with the lowest levels of the sunshine vitamin had a three-fold higher risk.

Vitamin D could be helping to protect the nerve cells gradually lost by people with the disease, experts say.

The charity Parkinson’s UK said further research was required.

Parkinson’s disease affects several parts of the brain, leading to symptoms like tremor and slow movements.

30-year study

The researchers from Finland’s National Institute for Health and Welfare measured vitamin D levels from the study group between 1978 and 1980, using blood samples.

They then followed these people over 30 years to see whether they developed Parkinson’s disease.

They found that people with the lowest levels of vitamin D were three times more likely to develop Parkinson’s, compared with the group with the highest levels of vitamin D.

Most vitamin D is made by the body when the skin is exposed to sunlight, although some comes from foods like oily fish, milk or cereals.

As people age, however, their skin becomes less able to produce vitamin D.

Doctors have known for many years that vitamin D helps calcium uptake and bone formation.

But research is now showing that it also plays a role in regulating the immune system, as well as in the development of the nervous system.

Vitamin target

Writing in an editorial in the US journal Archives of Neurology, Marian Evatt, assistant professor of neurology at Emory University School of Medicine, says that health authorities should consider raising the target vitamin D level.

“At this point, 30 nanograms per millilitre of blood or more appears optimal for bone health in humans.

“However, researchers don’t yet know what level is optimal for brain health or at what point vitamin D becomes toxic for humans, and this is a topic that deserves close examination.”

Dr Kieran Breen, director of research at Parkinson’s UK, said: “The study provides further clues about the potential environmental factors that may influence or protect against the progression of Parkinson’s.

“A balanced healthy diet should provide the recommended levels of vitamin D.

“Further research is required to find out whether taking a dietary supplement, or increased exposure to sunlight, may have an effect on Parkinson’s, and at what stage these would be most beneficial.”

More on This Story

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http://www.bbc.co.uk/news/10601091

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Tratamento com a Vitamina D, Cura e Prevenção – Role of Vitamin D in Parkinson’s Disease

parkinsonian-syndrome

VE
US National Library of Medicine
National Institutes of Health

http://www.ncbi.nlm.nih.gov/pmc/

Tratamento com a Vitamina D, Cura e Prevenção – Role of Vitamin D in Parkinson’s Disease

Parte superior do formulário

Role of Vitamin D in Parkinson’s Disease

ISRN Neurol. 2012; 2012: 134289.

Published online 2012 March 7. doi:  10.5402/2012/134289

PMCID: PMC3349248

Role of Vitamin D in Parkinson’s Disease

Khanh Lương * and Lan Nguyễn

Author information ► Article notes ► Copyright and License information ►Go to:

 

Abstract

Parkinson’s disease (PD) is the second most common form of neurodegeneration in the elderly population. Clinically, it is characterized by tremor, rigidity, slowness of movement, and postural imbalance. A significant association between low serum vitamin D and PD has been demonstrated, suggesting that elevated vitamin D levels might provide protection against PD. Genetic studies have helped identify a number of proteins linking vitamin D to PD pathology, including the major histocompatibility complex (MHC) class II, the vitamin D receptor (VDR), cytochrome P450 2D6 (CYP2D6), chromosome 22, the renin-angiotensin system (RAS), heme oxygenase-1 (HO-1), poly(ADP-ribose) polymerase-1 gene (PARP-1), neurotrophic factor (NTF), and Sp1 transcription factor. Vitamin D has also been implicated in PD through its effects on L-type voltage-sensitive calcium channels (L-VSCC), nerve growth factor (NGF), matrix metalloproteinases (MMPs), prostaglandins (PGs) and cyclooxygenase-2 (COX-2), reactive oxygen species (ROS), and nitric oxide synthase (NOS). A growing body of evidence suggests that vitamin D supplementation may be beneficial for PD patients. Among the different forms of vitamin D, calcitriol (1,25-dihydroxyvitamin D3) is best indicated for PD, because it is a highly active vitamin D3 metabolite with an appropriate receptor in the central nervous system (CNS).

 

Introduction

Parkinson’s disease (PD) is a movement disorder characterized by tremor, rigidity, slowness of movement, and postural imbalance. There is evidence of abnormalities in the vitamin D-endocrine system in PD patients, including low bone mineral density (BMD), decreased vitamin D levels, and increased bone turnover makers (bone alkaline phosphatase and urinary N-terminal telopeptide of type I collagen) compared to controls [1]. These factors, combined with balance problems, are the probable reasons for the high incidence of fractures, especially of the hip, reported in elderly women with PD [2]. Sunlight exposure can increase the BMD of PD by increasing serum 25-hydroxyvitamin D3 (25OHD) levels [3]. In another study, serum 25OHD and BMD were reported to be reduced in PD patients. The BMD Z-score of the trochanter was directly correlated to the degree of physical activity and total body BMD Z-score correlated to the degree of rigidity [4]. Osteoporosis and osteopenia are common findings in PD patients, affecting up to 91% of women and 61% of men [5]. Decreased BMD, low concentrations of serum ionized calcium, and compensatory hyperparathyroidism increase the risk of hip fracture in PD patients [1]. Despite an abundance of correlational studies, it is unknown whether vitamin D deficiency is a cause or consequence of PD. In the present paper, we review the hypothesized roles of vitamin D in PD pathogenesis.

 

2. Genomic Factors Associated with Vitamin D in Parkinson’s Disease

 

2.1. Major Histocompatibility Complex (MHC)

Studies have suggested that several genes in the MHC region promote susceptibility to PD. Significantly increased levels of MHC class II expressions were detected in the cerebrospinal fluid (CSF) monocytes of PD patients [6]. Human leukocyte antigen (HLA) genes have also been implicated in PD, and large numbers of HLA-DR-positive reactive microglia were detected in the substantia nigra (SN) and the nigrostriatal tract in PD patients [78]. HLA-DR-positive microglia have also been found in these regions in a case of Parkinson’s-associated dementia in Guam [8]. Conversely, calcitriol (1,25-dihydroxyvitamin D3) is known to stimulate phagocytosis but suppress MHC class II antigen expression in human mononuclear phagocytes [910]. Calcitriol also decreases interferon-gamma-induced HLA-DR antigen expression on normal and transformed human keratinocytes [1112]. These findings suggested that vitamin D may modulate MHC class II antigen expression in PD.

2.2. Vitamin D Receptor (VDR)

There is ample evidence for vitamin D involvement in mammalian brain function. VDR and 1α-hydroxylase, the enzyme responsible for the formation of active vitamin D in the human brain, are found in the large neurons of the SN, as well as in neurons and glial cells in the hypothalamus [13]. VDR, a nuclear receptor, is restricted to the nucleus but 1α-hydroxylase is distributed throughout the cytoplasm. The presence of these proteins in the CNS suggests that vitamin D is active within the brain. VDR knockout mice have muscular and motor impairment [14]. Genetic studies provide an opportunity to link molecular variations with epidemiological data, DNA sequence variations, such as polymorphisms, exert subtle biological effects on the expression and functionality of proteins. VDR mRNA was identified as a potential blood marker for PD [15]. In a Korean population, the VDR BsmI genotype is reported to be associated with PD [16]. Butler et al. [17] reported that the VDR gene is a potential susceptibility gene for PD in the Caucasian population. These reports suggested a role of vitamin D in PD.

2.3. The Cytochrome P450 (CYP)

CYP superfamily of enzymes is responsible for the oxidation, peroxidation, and/or reduction of vitamins, steroids, and xenobiotics, as well as the metabolism of drugs. CYP2D6, an important member of this superfamily, is expressed in neurons in the brain and gut and may be influenced by polymorphic expression. There is a higher prevalence of the poor-metabolizing CYP2D6*4 allele in PD patients compared with controls (20.7% versus 11.0%) [18]. In case-control and meta-analysis studies, the CYP2D polymorphism was found to be associated with PD [1920]. Other studies, however, did not find an association between the CYP2D6 polymorphism and PD in an Asian population [2122]. Although the poor metabolizer genotype has a small but highly significant association with PD, it would be easily missed in studies with modest numbers of subjects. CYP2D6 protein and enzymatic activity are completely absent in less than 1% of Asian people and in up to 10% of Caucasians with two null alleles [23]. Singh et al. reported the expression of CYP2D22, an ortholog of human CYP2D6, in mouse striatum and its modulation in MPTP-induced PD phenotype and nicotine-mediated neuroprotection [24]. CYP2D6 is a potential 25-hydroxylase, which converts vitamin D3 into 25OHD, and vitamin D 25-hydroxylase deficiency resulted in vitamin D deficiency [25]. Moreover, the CYP2D and PD loci are located on the same chromosome 22 [2627]. Deletion of chromosome 22q11 syndrome was reported to be associated with PD [2829]. Interestingly, patients with a deletion of chromosome 22q11 showed a reduced BMD, serum calcium, and PTH levels; 11% and 8% of these patients had serum 25OHD levels under 20ng/ml and abnormal serum 1,25OHD levels, respectively [30].

 

2.4. The Renin-Angiotensin System (RAS)

The primary function of the RAS is to maintain fluid homeostasis and regulate blood pressure. Several components of the RAS and its receptors are found in the CNS [3134], suggesting that RAS is important in the brain. CSF levels of angiotensin-converting enzyme (ACE) activity were reported to be decreased in PD patients and increased with dopaminergic treatment [3536]. In addition, the ACE inhibitor perindopril has been shown to exert beneficial effects on the dopaminergic system [3738]. After four weeks of treatment with perindopril, patients with PD had faster improvement in motor response after L-dopa and a reduction in “on phase” peak dyskinesia [39]. The frequency of the homozygous DD genotype of the ACE gene was significantly increased in patients with PD, and is also higher in PD patients with L-dopa-induced psychosis versus without psychosis [4041]. However, other studies did not reveal any associations between ACE polymorphisms, PD, and of L-dopa-induced adverse effects [4243]. The dissimilar findings may be attributable to differences between Chinese and Caucasian populations. Interestingly, there is also an interaction between vitamin D and the RAS. The use of ACE inhibitors by the ACE DD genotype has been shown to decrease the level of calcitriol [44]. In addition, genetic disruption of the VDR resulted in overstimulation of the RAS with increased production of renin and angiotensin II, thereby leading to high blood pressure and cardiac hypertrophy. Treatment with captopril reduced cardiac hypertrophy in VDR knockout mice [45], suggesting that calcitriol may function as an endocrine suppressor of renin biosynthesis. Vitamin D has also been reported to decrease ACE activity in bovine endothelial cells [46]. The findings suggested that vitamin D might affect ACE activity in PD.

2.5. Heme Oxygenase-1 (HO-1)

HO-1 is a stress protein that may confer cytoprotection by enhancing catabolism of pro-oxidant heme to the radical scavenging bile pigments, biliverdin, and bilirubin. The HO-1 gene can be upregulated by a host of noxious stimuli and is induced in CNS tissues affected by neurological diseases [47]. In the normal brain, basal HO-1 expression is low and restricted to small groups of scattered neurons and neuroglia [48]. In the brains of PD patients, the HO-1 is highly overexpressed in astrocytes within the SN and in Lewy bodies found in affected dopaminergic neurons [49]. Serum HO-1 levels are increased in PD patients but not in patients with Alzheimer’s disease (AD) [50], suggesting a systemic antioxidant reaction to a chronic oxidative stress state that is unique to PD. Similarly, calcitriol delayed of HO-1 immunoreactivity after the postlesional survival time of 12 hours concomitant with a reduction in glial fibrillary acidic protein immunoreactivity in remote cortical regions affected by a secondary spread of injury in glial cells of the focal cerebral ischemic [51], thereby supporting the protective role of calcitriol in postcellular injury.

2.6. Poly(ADP-Ribose) Polymerase-1 (PARP-1)

PARP-1 is a nuclear protein that can promote either neuronal death or survival under certain stress conditions. Overexpression of PARP-1 has been reported in the dopaminergic neurons of the SN in PD [52]. PARP-1 is also implicated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP-) induced neurotoxicity in vivo [53]. MPTP is a neurotoxin that induces parkinsonian symptoms in human and animals, but mice lacking PARP gene are spared from MPTP neurotoxicity [54]. Therefore, PARP inhibitors have proved to be valuable tools in PD model [5556]. PARP-1 variants are reported to be protective against PD [57]. In addition, increased levels of vitamin D seem to downregulate PARP-1 expression; PARP-1 levels decrease following calcitriol treatment in NB4 cells, which represent an acute promyelocytic leukemia cells [58]. Vitamin D exerts a concentration-dependent inhibitory effect on PARP-1 in the human keratinocyte cells [59]. Vitamin D-induced downregulation of PARP is further enhanced by nicotinamide in human myeloblastic leukemia cells [60]. Furthermore, PARP is attenuated in the hippocampus of rats that received dexamethasone and vitamin D [61], suggesting that the anti-inflammatory effects of dexamethasone and vitamin D derives from their ability to downregulate microglial activation. These findings suggested that vitamin D may have a protective role in PD by downregulating PARP.

2.7. Neurotrophic Factors (NTFs)

NTFs are keys to surviving various neuronal insults and promote neuronal regeneration following injury [62]. NTFs can exert protective or even restorative effects on PD animal models and dopaminergic cell cultures; key examples include brain-derived neurotrophic factor (BDNF) [63], glial-derived neurotrophic factor (GDNF) [64], mesencephalic-astrocyte-derived neurotrophic factor (MANF) [65], and cerebral dopamine neurotropic factor (CDNF) [66]. Receptors for these NTFs are expressed in the striatum and SN [6768]. NTF expression is reduced in the SN of patients with PD [6971]. Moreover, the C allele of an inotropic CDNF single nucleotide polymorphism (rs7094179) has been suggested to infer susceptibility to PD in a Korean population [72], and A allele of BDNF is associated with PD in a Chinese Han population [73]. Interestingly, calcitriol regulates the expression of the low-affinity neurotrophic receptor [74] and increases striatal GDNF mRNA and protein expression in adult rats [75]. In vivo, calcitriol is also a potent inducer of GDNF in rat glioma cells [76]. The brains of offspring from vitamin D-deficient dams are characterized by diminished expression of neurotrophic factors [77]. Furthermore, calcitriol protects against dopamine loss from 6-hydroxydopamine- (6-OHDA-) lesioned rats by increasing GDNF and partially restores tyrosine hydroxylase expression in SN and striatum [7879].

2.8. Sp1 Transcription Factor

 

 

Sp1 transcription factor is a member of an extended family of DNA-binding proteins that is acetylated in response to oxidative stress in neurons [80]. The Sp1 family of proteins plays an important role in controlling the expression of the dopamine transporter gene within dopaminergic neurons [81] and also regulates expression of rat dopamine receptor gene [82]. On the other hand, binding sites for the transcription factor Sp1 have been implicated in the transcription of several genes by hormones. In cultured human fibroblasts, the level of CYP24 (25-OHD 24-hydroxylase) mRNA plays a key role in the metabolism of 1,25OHD and increases up to 20,000-fold in response to calcitriol. Two vitamin D-responsive elements (VDREs) located upstream of the CYP24 gene are primarily responsible for the increased mRNA levels, and Sp1 acted synergistically with these VDREs for the induction [72]. The mVDR promoter is controlled by Sp1 sites [73] and functions as the transactivation component of the VDR/Sp1 complex to trigger gene expression [74]. Moreover, the genes encoding Sp1 and VDR were mapped to human chromosome 12q [7576].

 

3. Nongenomic Role of Vitamin D in Parkinson’s Disease

 

 

3.1. Diabetes Mellitus (DM)

Glucose is the molecule necessary to produce energy in the brain. A link between DM and PD has been suggested in several reports, but the results have been inconsistent. Insulin receptors and their mRNAs are localized in the SN [8384]. A high incidence of abnormal glucose tolerance has been reported in PD and seems to be exacerbated by L-dopa treatment [85]. DM has been associated with the risk of developing PD [8687] whereas others reported from protective to no associations with PD [8890]. Human and experimental animal studies, however, demonstrated neurodegeneration associated with peripheral insulin resistance [91]. In a 6-OHDA model of PD, striatal insulin resistance was observed in the striatum [92], and patients with PD exhibited increased autoimmune reactivity to insulin [93]. Individuals newly diagnosed with PD display reduced insulin-mediated glucose uptake [94], which is hypothesized to be due to inhibit early insulin secretion and hyperglycemia after glucose loading [95]. Furthermore, chronic hyperglycemia decreased limbic extracellular dopamine concentrations and striatal dopaminergic transmission in streptozotocin-induced diabetic rats [9697]. Vitamin D levels may provide a link between the diseases; serum 1,25OHD and 25OHD levels are low in diabetic patients [9899], and diabetic rats had an increased metabolic clearance rate of 1,25OHD [100]. Interestingly, a significant high prevalence of vitamin D insufficiency is reported in patients with PD [101102]. A significant inverse association between serum vitamin D and PD was demonstrated [103] and suggested that high vitamin D status might provide protection against PD. In diabetic-induced rats, vitamin D and insulin treatment markedly recovered the levels of altered gene (cholinergic, dopaminergic, and insulin receptors) expression and its binding parameters nearly to those of the control rats [104]. Maternal vitamin D deficiency was reported to alter the expression of genes involved in dopamine specification in the developing rat mesencephalon [105]. Calcitriol has been shown to protect dopamine neuronal toxicity induced by 6-OHDA and the combination of L-buthionine sulfoximine and MPTP, thereby restoring motor activity in the lesioned animals [106107]. Furthermore, vitamin D was reported to improve rigidity and akinesia and reduce levodopa dosage in a patient with PD [108].

3.2. L-Type Voltage-Sensitive Calcium Channels (L-VSCC)

Unlike most neurons in the brain, dopaminergic neurons function as autonomous pacemakers that rely on L-VSCC to generate action potentials at a clock-like 2–4Hz in the absence of synaptic input [109]. L-VSCC activity during autonomous pacemaking increased the sensitivity of dopaminergic neurons to mitochondrial toxins in an animal model of PD [110]. Epidemiological data supports a link between L-VSCC functioning and the risk of developing PD [111113]. Pretreatment with the calcium channel antagonist nimodipine has been shown to block the development of MPTP-induced neurotoxicity in animal models [114,115]. Israpidine, another L-VSCC antagonist, caused a dose-dependent reduction in L-dopa-induced rotational behavior and abnormal involuntary movements in the 6-OHDA-lesioned rat model of PD [116]. With respect to AD, amyloid-βprotein was reported to promote neurodegeneration by inducing L-VSCC expression and suppressing VDR expression; subsequent treatment with vitamin D protected neurons by preventing cytotoxicity and apoptosis, probably by downregulating L-VSCC and upregulating VDR [117]. Calcitriol decreased L-VSCC activity in aged rats and in neuronal vulnerability with particular impact on reducing age-related changes associated with Ca2+ dysregulation [118119]. Treatment with 24R, 25 dihydroxyvitamin D3 also reduced L-VSCC activity in vascular smooth muscle in rats [120].

3.3. Nerve Growth Factor (NGF)

NGF is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons. NGF has been implicated in maintaining and regulating the septohippocampal pathway, which is involved in learning and memory [121123]. NGF is also present in the human SN [124] and in the adrenal gland [125]. NGF concentrations are decreased in the SN of the PD and in a rat model of PD [69126]. NGF levels showed greater reductions in early states of the disease compared with advanced stages [126], implying that decreased NGF may be involved in the pathogenesis of PD. NGF is reported to protect dopamine neurotoxicity induced by MPTP, rotenone, and 6-OHDA via different pathways [127129]. The chronic infusion of NGF into the rat striatum resulted in cholinergic hyperinnervation and reduced spontaneous activity of striatal neurons [130]. Moreover, NGF increases survival of dopaminergic grafts, rescues nigral dopaminergic neurons, and restores motor dysfunction in a rat model of PD [131132]. In addition, the brains of newborn rats from vitamin D-deficient dams showed reduced expression of NGF [77]. In vitro, calcitriol regulated the expression of the VDR gene and stimulated the expression of the NGF gene in Schwann cells [133]. In mouse fibroblasts, calcitriol and vitamin D analogs are reported to enhance NGF induction by increasing AP-1 binding activity to the NGF promoter [134135]. These findings suggest a protective role for vitamin D in the CNS.

3.4. Matrix Metalloproteinases (MMPs)

MMPs are proteolytic enzymes responsible for extracellular matrix (ECM) remodeling and the regulation of leukocyte migration through the ECM, which is an important step for inflammatory processes. Neuroinflammation is known to contribute significantly to progressive dopaminergic neurodegeneration in PD. MMP involvement has been reported in the degeneration of dopaminergic neurons. MMP-3 expression is increased during lipopolysaccharide- (LPS-) induced dopamine neurotoxicity [136]. MMP-9 is also elevated in MPTP-induced parkinsonism in mice [137]. Application of dopaminergic neurotoxins to two human neuroblastoma cell lines downregulates the transcription and translation of tissue inhibitor of metalloproteinase- (TIMP-) 2 effectively enhancing MMP activity [138]. Exendin-4, which is an analogue of glucagon-like peptide 1 (GLP-1), significantly attenuates the loss of SN neurons and the striatal dopaminergic fibers in the MPTP-induced PD model, and inhibits the expression of MMP-3 [139]. Conversely, the VDR TaqI polymorphism is associated with decreased production of TIMP-1, a natural inhibitor of MMP-9 [140]. Calcitriol modulates tissue MMP expression under experimental conditions [141]. Calcitriol downregulates MMP-9 levels in keratinocytes and may attenuate deleterious effects due to excessive TNF-α-induced proteolytic activity associated with cutaneous inflammation [142]. In addition, a vitamin D analogue was reported to reduce the expression of MMP-2, MMP-9, VEGF, and parathyroid hormone-related protein in Lewis lung carcinoma cells [143]. These findings suggested that vitamin D plays a role in modulating MMP activation in PD.

 

3.5. Prostaglandins (PGs)

PGs play a role in inflammatory processes [144]. Cyclooxygenase (COX) participates in the conversion of arachidonic acid into PGs. PGE2 is a key product of COX-2 and is increased in the SN of patients with PD and MPTP-induced PD in an animal model [145146]. PGE2 is also directly and selectively toxic to dopaminergic neurons [147]. PGE2 receptors are found on dopaminergic neurons in the rat SN [147]. Overexpression of COX-2 is reported in PD and an MPTP-animal model [148149]. COX inhibitors provide neuroprotection in the MPTP-mouse model of PD [150]. Similarly, regular use of COX-2 inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, has been associated with a decreased incidence of PD [151]. Calcitriol, which reportedly regulates the expression of several key genes involved in PG pathways, decreases PG synthesis [152]. Calcitriol and its analogues have also been shown to inhibit selectively the activity of COX-2 [153]. These findings suggested that vitamin D has a role in anti-inflammatory processes in PD.

 

3.6. Oxidative Stress

Oxidative stress has been suggested to contribute to the pathogenesis of PD. Lymphocytes from untreated PD patients have increase oxidative stress [154]. Analyses of postmortembrains from PD reveal evidence of increased lipid peroxidation in PD SN [155156]. A selective superoxide dismutase (SOD) is also increased in the SN of PD patients [157]. Calcitriol administration has been reported to exert a receptor-mediated effect on the secretion of hydrogen peroxide by human monocytes [158]. In vitro, monocytes gradually lose their ability to produce superoxide when stimulated; the addition of calcitriol, lipopolysaccharide, or lipoteichoic acid (LTA) restored the ability of stimulated monocytes to produce superoxide and increases the oxidative capacity compared with unstimulated monocytes [159]. Calcitriol can also protect nonmalignant prostate cells from oxidative stress-induced cell death by preventing ROS-induced cellular injuries [160]. Vitamin D metabolites and analogues were reported to induce lipoxygenase mRNA expression, lipoxygenase activity, and ROS production in a human bone cell line [161]. Vitamin D can also reduce lipid peroxidation and induce SOD activity in the rat hepatic antioxidant system [162]. These findings suggested a role of vitamin D in oxidative stress in PD.

 

3.7. Nitric Oxide Synthase (NOS)

NOS is an enzyme involved in the synthesis of nitric oxide (NO), which has also been implicated in PD. In postmortem brains of PD, high levels of NOS expression were found in the nigrostriatal region and basal ganglia [163]. A significant increase in the nitrite content was reported in polymorphonuclear leukocytes of PD patients [164]. Inducible and neuronal NO are increased in both 6-OHDA and MPTP animal models [165166]. Moreover, studies with NOS inhibitors and NOS knock-out animals have also confirmed the role of NOS in neurodegeneration [167168]. Reduced and oxidized glutathione (GSH) were demonstrated in the SN of patients with PD [169]. Conversely, the activation of 1α-hydroxylase in macrophages increases in 1,25OHD, which inhibits inducible NOS (iNOS) expression and reduces NO production by lipopolysaccharide- (LPS-) stimulated macrophages [170]. Thus, calcitriol production by macrophages may provide protection against oxidative injuries caused by the NO burst. Calcitriol is known to inhibit LPS-induced immune activation in human endothelial cells [171]. In experimental allergic encephalomyelitis, calcitriol inhibits the expression of iNOS in the rat CNS [172]. Astrocytes play a pivotal role in CNS detoxification pathways where glutathione (GSH) is involved in the elimination of oxygen and nitrogen reactive species, such as nitric oxide. Calcitriol affects this pathway by enhancing intracellular GSH pools and significantly reduces nitrite production induced by LPS [173].

 

4. Conclusion

Recent studies have highlighted a possible relationship between vitamin D and PD. Vitamin D may be beneficial in PD patients, as one patient showed improved rigidity and akinesia and was able to decrease their levodopa dosage after vitamin D therapy. Genetic studies have provided opportunities to determine what proteins may link vitamin D to PD pathology. Vitamin D can also act through a number of nongenomic mechanisms, including effects on protein expression, oxidative stress, inflammation, and cellular metabolism. Among the many forms of vitamin D, calcitriol (1,25-dihydroxyvitamin D3) is an attractive therapeutic candidate, because it is a particularly active metabolite, and its receptor is expressed in the CNS.

 

Conflict of Interests

The authors declare that they have no conflict of interests.

 

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