Parkinson’s diseaseHow does vitamin D work?

The observations discussed on previous pages in this section suggest a link between low serum 25(OH)D level and risk of Parkinson’s disease (PD).

The following hypothesis has been proposed relating chronic inadequacy of vitamin D to chronic and continued loss of dopaminergic neurons in the substantia nigra of the brain, leading to PD1:

  1. Normal function of brain cells depends, in part, on absorption of 25-OH Vit D from the circulation (i.e., serum) and internal cellular activation to calcitriol (1,25-(OH)2 Vit D) by local cytosolic 1 -OHase (cytochrome P-450-27B-1). The calcitriol is utilized to activate nuclear VDRs in normal cell function.
  2. The substantia nigra of the brain appears especially rich in, and likely dependent on, this system2.
  3. Inadequate levels of circulating 25-OH Vit D may lead to abnormal function of the cells of the substantia nigra.
  4. Chronic inadequacy of 25-OH Vit D may lead to cellular damage or degeneration and potential death of neurons, a  stress  reaction leading to abnormal cell function, including greater sensitivity to irreversible or nonrepairable damage, leading to degeneration of the substantia nigra neurons and greater sensitivity to moderate or low levels of toxins, viruses, psychotic drugs, reserpine, etc., that are more readily resisted by fully healthy cells.
  5. Intake of vitamin D in the United States, especially in northern states, and particularly in the elderly, is currently inadequate to maintain desired recommended levels of the circulating biochemical intermediate 25-OH Vit D, which is used for production of the active metabolite calcitriol in specific local cell cytosol, such as the neurons of the substatia nigra. 

Support for this hypothesis was available before, such as from animal studies prior34 and subsequently5.

A recent study added further support:

The underlying factor in the neurological disorders is increased oxidative stress substantiated by the findings that the protein side-chains are modified either directly by reactive oxygen species (ROS) or reactive nitrogen species (RNS), or indirectly, by the products of lipid peroxidation. … The oxidative stress linked with PD is supported by both postmortem studies and by studies showing the increased level of oxidative stress in the substantia nigra pars compacta, demonstrating thus the capacity of oxidative stress to induce nigral cell degeneration. Markers of lipid peroxidation include 4-hydroxy-trans-2-nonenal (HNE), 4-oxo-trans-2-nonenal (4-ONE), acrolein, and 4-oxo-trans-2-hexenal, all of which are well recognized neurotoxic agents. In addition, other important factors, involving inflammation, toxic action of nitric oxide (NO.), defects in protein clearance, and mitochondrial dysfunction all contribute to the etiology of PD….The role of redox metals iron and copper and non-redox metal zinc in oxidative stress-related etiology of AD and PD6.

Vitamin D increases absorption of calcium, which can counter the buildup of metal ions such as copper and iron. 

In addition, vitamin D can reduce inflammation in the brain in combination with such other compounds as progesterone:

Administration of the neurosteroid progesterone (PROG) has been shown to be beneficial in a number of brain injury models and in two recent clinical trials. Given widespread vitamin D deficiency and increasing traumatic brain injuries (TBIs) in the elderly, we investigated the interaction of vitamin D deficiency and PROG with cortical contusion injury in aged rats. Vitamin D deficient (VitD-deficient) animals showed elevated inflammatory proteins (TNFalpha, IL-1beta, IL-6, NFkappaB p65) in the brain even without injury. VitD-deficient rats with TBI, whether given PROG or vehicle, showed increased inflammation and greater open-field behavioral deficits compared to VitD-normal animals. Although PROG was beneficial in injured VitD-normal animals, in VitD-deficient subjects, neurosteroid treatment conferred no improvement over vehicle. A supplemental dose of 1,25-dihydroxyvitamin D(3) (VDH) given with the first PROG treatment dramatically improved results in VitD-deficient rats, but treatment with VDH alone did not. Our results suggest that VitD-deficiency can increase baseline brain inflammation, exacerbate the effects of TBI, and attenuate the benefits of PROG treatment; these effects may be reversed if the deficiency is corrected7

There is also evidence that vitamin D receptors, which are activated by 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] and modulate gene expression, are also involved in the pathology of PD:
1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3], which is the biologically active form of vitamin D, has anti-inflammatory effects and can prevent experimental Parkinson’s disease (PD). 1,25(OH)2D3 exerts most of its actions only after it binds to its specific nuclear receptors. Eighty-five Korean patients with PD and 231 unrelated healthy individuals were evaluated to determine if vitamin D receptor gene (VDRG) BsmI polymorphisms were markers for the susceptibility to PD in Korean patients. Each polymorphism was detected using polymerase chain reaction (PCR)-based restriction analysis. In addition, the relationship between the BsmI polymorphisms and the clinical manifestations of PD was evaluated. Overexpression of the b allele (91.2 vs. 85.7%; p=0.069) and homozygote bb (84.7 vs. 72.7%; p=0.043) was found in the PD patients compared with the controls8

Page last edited: 03 May 2011

References

  1. Newmark, H. L. Newmark, J. Vitamin D and Parkinson’s disease–a hypothesis. Mov Disord. 2007 Mar 15; 22 (4): 461-8.
  2. Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat. 2005 Jan; 29 (1): 21-30.
  3. Smith, M. P. Fletcher-Turner, A. Yurek, D. M. Cass, W. A. Calcitriol protection against dopamine loss induced by intracerebroventricular administration of 6-hydroxydopamine. Neurochem Res. 2006 Apr; 31 (4): 533-9.
  4. Wang, J. Y. Wu, J. N. Cherng, T. L. Hoffer, B. J. Chen, H. H. Borlongan, C. V. Wang, Y. Vitamin D(3) attenuates 6-hydroxydopamine-induced neurotoxicity in rats. Brain Res. 2001 Jun 15; 904 (1): 67-75.
  5. Sanchez, B. Relova, J. L. Gallego, R. Ben-Batalla, I. Perez-Fernandez, R. 1,25-Dihydroxyvitamin D3 administration to 6-hydroxydopamine-lesioned rats increases glial cell line-derived neurotrophic factor and partially restores tyrosine hydroxylase expression in substantia nigra and striatum. J Neurosci Res. 2009 Feb 15; 87 (3): 723-32.
  6. Jomova, K. Vondrakova, D. Lawson, M. Valko, M. Metals, oxidative stress and neurodegenerative disorders. Mol Cell Biochem. 2010 Aug 22;
  7. Cekic, M. Cutler, S. M. Vanlandingham, J. W. Stein, D. G. Vitamin D deficiency reduces the benefits of progesterone treatment after brain injury in aged rats. Neurobiol Aging. 2009 May 29;
  8. Kim, J. S. Kim, Y. I. Song, C. Yoon, I. Park, J. W. Choi, Y. B. Kim, H. T. Lee, K. S. Association of vitamin D receptor gene polymorphism and Parkinson’s disease in Koreans. J Korean Med Sci. 2005 Jun; 20 (3): 495-8.