We are excited to observe significant differences in the GPR109A levels in the white blood cells (macrophages) of Parkinson's disease (PD) patients and control individuals. Moreover, we observed similar changes in the GPR109A expressions in the substantia nigra regions that co-localize with the microglia of the PD patients and age-matched controls. We are the first lab to denote these changes. GPR109A is an anti- inflammatory receptor and niacin acts on it. Niacin is an anti-inflammatory agent and it is known to halt inflammation via GPR109A and nuclear factor-B (NFkB) pathway. Niacin is known to block the translocation of NFKB to nucleus and thus reduce the production of pro-inflammatory cytokines. We will study these effects of niacin in PD patients by analyzing inflammatory cytokines in the cerebrospinal fluid (CSF) of PD patients. It has been documented that PD patients who are on carbidopa treatment have decreased levels of niacin. We have found significant reduction in the niacin index (NAD/NADP ratio) in PD patients compared to age- matched controls, denoting reduced NAD levels and increased oxidative stress. We propose a novel hypothesis that by reducing inflammation, niacin treatment will restore niacin levels along with GPR109A levels and will help improve motor coordination and cognition performances in the PD patients.
Specific Aims : The two specific aims of the current proposal are as follows:
Aim 1 A: To determine whether niacin supplementation will improve the symptoms of PD patients as correlated by performances in motor coordination and cognitive tests.
Aim 1 B: To determine whether up-regulation of GPR109A in PD patients will respond to niacin therapy in reducing inflammatory markers in the CSF.
Aim 2 : To study the molecular mechanisms related to GPR109A as an anti-inflammatory therapeutic target in in-vitro models.

Public Health Relevance

Parkinson's disease (PD) is a devastating progressive neurological condition. The cost of management of VA population suffering from PD is phenomenal. Neuroinflammation is central in PD pathology. GPR109A is an anti-inflammatory receptor which is present everywhere in the body especially in the immune cells. We have observed up-regulation of this receptor in the substantia nigra and white blood cells (WBCs) of the PD patients. Niacin (Vitamin B3) acts as an agonist to this receptor and our preliminary findings in PD patients demonstrates its regulatory effects on GPR109A levels in WBCs. We propose to use niacin to facilitate rehabilitation of VA PD patients. Also we will study the mechanisms involved in the anti-inflammatory role of niacin via GPR109A in in-vitro models. Our goal is to ameliorate motor, coordination and cognitive symptoms of PD patients and find new avenues in treating our Veteran suffering from PD.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Charlie Norwood VA Medical Center
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Wakade, Chandramohan; Giri, Banabihari; Malik, Aneeq et al. (2018) Niacin modulates macrophage polarization in Parkinson's disease. J Neuroimmunol 320:76-79
Chong, Raymond; Albor, Lauren; Wakade, Chandramohan et al. (2018) The dimensionality of fatigue in Parkinson's disease. J Transl Med 16:192
Sharma, Amol; Kurek, Julie; Morgan, John C et al. (2018) Constipation in Parkinson's Disease: a Nuisance or Nuanced Answer to the Pathophysiological Puzzle? Curr Gastroenterol Rep 20:1