Nimodipine protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation.
Nimodipine, a calcium channel blocker, has been used mainly in the therapy of cardiovascular diseases. Recently, its indications have been extended experimentally to a wider range of disorders especially some central nervous system (CNS) disorders. In this study, we investigated whether nimodipine is neuroprotective to inflammation-mediated neurodegenerative diseases. Pretreatment with nimodipine reduced the degeneration of dopaminergic (DA) neurons induced by LPS in mesencephalic neuron-glia cultures in a dose-dependent manner. The neuroprotective effect of nimodipine was attributed to the inhibition of microglial activation, since nimodipine significantly inhibited the production of nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and prostaglandin E(2) (PGE(2)) from LPS-stimulated microglia. Moreover, nimodipine was not neuroprotective to 1-methyi-4-phenylpyridinium (MPP(+))-induced DA neurotoxicity in the absence of microglia. Mechanistic study showed that nimodipine failed to protect the degeneration of neurons in neuron-glia cultures from mice lacking functional NADPH oxidase (PHOX), a key enzyme for extracellular superoxide production in immune cells. Taken together these results suggest that nimodipine is protective to DA neurodegeneration via inhibiting the microglial-mediated oxidative stress and inflammatory response. Thus, nimodipine may be a potential therapeutic agent for the treatment of inflammation-related neurodegenerative disorders such as Parkinson's disease.
Li
Yachen
Y
School of Environmental and Biological Science and Technology, Dalian University of Technology, No. 2 Linggong Road, Dalian, Liaoning 116024, China.
Hu
Xiaoming
X
Liu
Yuxin
Y
Bao
Yongming
Y
An
Lijia
L
D000818:Animals; D018929:Cell Culture Techniques; D004298:Dopamine / Q000378:metabolism; D007249:Inflammation / Q000150:complications / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D019255:NADPH Oxidases / Q000096:biosynthesis; D009410:Nerve Degeneration / Q000139:chemically induced / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009553:Nimodipine / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats
D008070:Lipopolysaccharides; C440499:lipopolysaccharide, Escherichia coli O111 B4; D009553:Nimodipine; D019255:NADPH Oxidases; D004298:Dopamine