Transient receptor potential vanilloid subtype 1 contributes to mesencephalic dopaminergic neuronal survival by inhibiting microglia-originated oxidative stress.
The present study examined whether capsaicin (CAP), an agonist of transient receptor potential vanilloid subtype 1 (TRPV1) can prevent 1-methyl-4-phenylpyridinium (MPP(+))-induced dopaminergic (DA) neuronal death in the substantia nigra (SN). Unilateral injection of MPP(+) into the median forebrain bundle of rat brain resulted in a significant loss of nigral DA neurons, assessed by tyrosine hydroxylase (TH) immunostaining. In parallel, activation of microglia, visualized by OX-42 and OX-6 immunostaining were also observed in the SN, where degeneration of nigral neurons was found. By contrast, MPP(+) neurotoxicity was partially inhibited by co-treatment with MPP(+) and CAP. Interestingly, CAP significantly decreased not only immunoreactivity of OX-42 and OX-6 but also production of microglia-derived reactive oxygen species (ROS) in the SN of MPP(+)-treated rats. In experiments designed to further verify effectiveness of CAP against microglia-derived neurotoxicity, CAP inhibited ROS production and blocked MPP(+)-induced death of DA neurons in co-cultures of mesencephalic neurons and microglia, but not in microglia-free, neuron-enriched mesencephalic cultures. This beneficial effect was reversed by capsazepine, an antagonist of TRPV1, expressed in microglia, indicating TRPV1 involvement. Our data demonstrate for the first time that CAP may inhibit microglial activation-mediated oxidative stress via TRPV1, suggesting that CAP and its analogs may have therapeutic value by inhibiting microglial activation and/or ROS generation that occurs in Parkinson's disease.
Department of Biochemistry & Molecular Biology, Department of Neuroscience, Neurodegeneration Control Research Center, School of Medicine Kyung Hee University, Seoul 130-701, South Korea.
Eun S
ES
Park
Sang R
SR
Kim
Byung K
BK
Jin
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002211:Capsaicin / Q000627:therapeutic use; D002452:Cell Count; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects*; D004347:Drug Interactions; D005260:Female; D007839:Functional Laterality; D008636:Mesencephalon / Q000166:cytology*; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D009498:Neurotoxins / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D018689:Sensory System Agents / Q000627:therapeutic use; D013378:Substantia Nigra / Q000187:drug effects; D050916:TRPV Cation Channels / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015703:Antigens, CD; D017077:Culture Media, Conditioned; D009498:Neurotoxins; D017382:Reactive Oxygen Species; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D010751:Phosphopyruvate Hydratase; D002211:Capsaicin