Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia.
Parkinson's disease is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic (DA) neurons in the substantia nigra. Accumulating evidence supports the notion that neuroinflammation is involved in the pathogenesis of this disease. Valproate (VPA) has long been used for the treatment of seizures and bipolar mood disorder. In vivo and in vitro studies have demonstrated that VPA has neuroprotective and neurotrophic actions. In this study, using primary neuron-glia cultures from rat midbrain, we demonstrated that VPA is a potent neuroprotective agent against lipopolysaccharide (LPS)-induced neurotoxicity. Results showed that pretreatment with 0.6 mM VPA for 48 h robustly attenuated LPS-induced degeneration of dopaminergic neurons as determined by [(3)H] dopamine uptake and counting of the number of TH-ir neurons. The neuroprotective effect of VPA was concentration-dependent and was mediated, at least in part, through a decrease in levels of pro-inflammatory factors released from activated microglia. Specifically, LPS-induced increase in the release of TNFa, NO, and intracellular reactive oxygen species was markedly reduced in cultures pretreated with VPA. These anti-inflammatory effects of VPA were time and concentration-dependent correlated with a decrease in the number of microglia. Thus, our results demonstrate that protracted VPA pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity through a reduction in levels of released pro-inflammatory factors, and further suggest that these anti-inflammatory effects may be contributed by VPA-induced reduction of microglia cell number. Taken together, our study reinforces the view that VPA may have utility in treating Parkinson's disease.
Peng
Giia-Sheun
GS
Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Li
Guorong
G
Tzeng
Nian-Sheng
NS
Chen
Po-See
PS
Chuang
De-Maw
DM
Hsu
Yaw-Don
YD
Yang
Sufen
S
Hong
Jau-Shyong
JS
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D039481:CD11b Antigen / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004625:Embryo, Nonmammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D007150:Immunohistochemistry / Q000379:methods; D008070:Lipopolysaccharides / Q000633:toxicity; D008636:Mesencephalon / Q000166:cytology*; D017628:Microglia / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000517:prevention & control*; D009573:Nitrites / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014319:Triturus / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use
D039481:CD11b Antigen; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009573:Nitrites; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D014635:Valproic Acid; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine