title: Simvastatin prevents dopaminergic neurodegeneration in experimental parkinsonian models: the association with anti-inflammatory responses.
abstract: BACKGROUND
  In addition to their original applications to lowering cholesterol, statins display multiple neuroprotective effects. N-methyl-D-aspartate (NMDA) receptors interact closely with the dopaminergic system and are strongly implicated in therapeutic paradigms of Parkinson's disease (PD). This study aims to investigate how simvastatin impacts on experimental parkinsonian models via regulating NMDA receptors.
  
  
  RESULTS
  Regional changes in NMDA receptors in the rat brain and anxiolytic-like activity were examined after unilateral medial forebrain bundle lesion by 6-hydroxydopamine via a 3-week administration of simvastatin. NMDA receptor alterations in the post-mortem rat brain were detected by [³H]MK-801(Dizocilpine) binding autoradiography. 6-hydroxydopamine treated PC12 was applied to investigate the neuroprotection of simvastatin, the association with NMDA receptors, and the anti-inflammation. 6-hydroxydopamine induced anxiety and the downregulation of NMDA receptors in the hippocampus, CA1(Cornu Ammonis 1 Area), amygdala and caudate putamen was observed in 6-OHDA(6-hydroxydopamine) lesioned rats whereas simvastatin significantly ameliorated the anxiety-like activity and restored the expression of NMDA receptors in examined brain regions. Significant positive correlations were identified between anxiolytic-like activity and the restoration of expression of NMDA receptors in the hippocampus, amygdala and CA1 following simvastatin administration. Simvastatin exerted neuroprotection in 6-hydroxydopamine-lesioned rat brain and 6-hydroxydopamine treated PC12, partially by regulating NMDA receptors, MMP9 (matrix metalloproteinase-9), and TNF-a (tumour necrosis factor-alpha).
  
  
  CONCLUSIONS
  Our results provide strong evidence that NMDA receptor modulation after simvastatin treatment could partially explain its anxiolytic-like activity and anti-inflammatory mechanisms in experimental parkinsonian models. These findings contribute to a better understanding of the critical roles of simvastatin in treating PD via NMDA receptors.
authors: Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.
authors: Junqiang
authors: J
authors: Yan
authors: Yunqi
authors: Y
authors: Xu
authors: Cansheng
authors: C
authors: Zhu
authors: Limin
authors: L
authors: Zhang
authors: Aimin
authors: A
authors: Wu
authors: Yu
authors: Y
authors: Yang
authors: Zhaojun
authors: Z
authors: Xiong
authors: Chao
authors: C
authors: Deng
authors: Xu-Feng
authors: XF
authors: Huang
authors: Midori A
authors: MA
authors: Yenari
authors: Yuan-Guo
authors: YG
authors: Yang
authors: Weihai
authors: W
authors: Ying
authors: Qing
authors: Q
authors: Wang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001007:Anxiety / Q000150:complications / Q000188:drug therapy; D017209:Apoptosis / Q000187:drug effects; D001345:Autoradiography; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D007150:Immunohistochemistry; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009410:Nerve Degeneration / Q000150:complications / Q000188:drug therapy* / Q000517:prevention & control*; D016627:Oxidopamine; D016716:PC12 Cells; D010300:Parkinson Disease / Q000150:complications* / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014316:Tritium / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016194:Receptors, N-Methyl-D-Aspartate; D014409:Tumor Necrosis Factor-alpha; D014316:Tritium; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D016627:Oxidopamine; D019821:Simvastatin; D007770:L-Lactate Dehydrogenase; D014446:Tyrosine 3-Monooxygenase; D020780:Matrix Metalloproteinase 9; D004298:Dopamine