Simvastatin Prevents Dopaminergic Neurodegeneration in Experimental Parkinsonian Models: The Association with Anti-Inflammatory Responses

Abstract

BackgroundIn 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.Methodology/Principal FindingsRegional 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/SignificanceOur 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.

Simvastatin reverses the downregulation of M1/4 receptor binding in 6-hydroxydopamine-induced parkinsonian rats: The association with improvements in long-term memory

“…Our studies and Selley (Selley, 2005;Wang et al, 2005) have shown that simvastatin regulated dopaminergic systems including receptors and transmission in the brain. Also, our study found the alterations of NMDA and M1/4 receptors in the brains following simvastatin treatment Wang et al, 2009b;Yan et al, 2011). Whether the application of simvastatin in Parkinsonian rats also influences the expression of M1 receptors raises an interesting question.…”

“…TH staining was performed as described in Yuan's study (Yuan et al, 2005;Yan et al, 2011). Briefly, distilled water was used to wash the brain sections for three times (5 min/per time), and the sections were immerged in citrate buffer for 20 minutes.…”

“…GmbH & Co KG) were mounted with the brain sections cut at 14 μm thickness (Li et al, 2010;Yan et al, 2011). Rat brain atlas was used to identify standard brain structures (Paxinos & Watson, 1997).…”

“…Beta Imager (BioSpace, Paris, France) was applied to quantify the M1/4 receptor binding sites as described in our previous studies (Wang et al, 2009b;Yan et al, 2011). Briefly, brain sections were put in the chamber of Beta Imager followed by 3.5 h scanning.…”

Simvastatin treatment reduces the cholesterol content of membrane/lipid rafts, implicating the N -methyl-D-aspartate receptor in anxiety: a literature review

“…It is well documented that NMDA receptors in the brain have a close correlation with anxiety-like activity (Bergink, van Megen, Westenberg, 2004;ChojnackaWójcik, Kłodzinska, Pilc, 2001). Modulation of NMDA receptors activity after SIM treatment could explain the drug's anxiolytic-like effects (Camargo et al, 2013;Carrocini et al, 2012;Cruz et al, 2011;Kilic et al, 2012;Pauleti et al, 2013;Santos et al, 2012;Wang et al, 2009;Yan et al, 2011). This hypothesis could be supported by the fact that altered levels of NMDA receptors in the hippocampus and amygdala directly influence anxiety behaviors (Barkus et al, 2010;Blundell, Adamec, 2007;Masneuf et al, 2014).…”