HMG-CoA reductase inhibitor simvastatin ameliorates trimethyltin neurotoxicity and cognitive impairment through reversal of Alzheimer's-associated markers.

Abstract

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder in elderly. The neurotoxicant trimethyltin (TMT) induces neurodegenerative changes, as observed in AD. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin (SV) has shown protective and promising therapeutic effects in neurological disorders such as AD and Parkinson's disease. The present study aimed to assess neuroprotective effect of simvastatin (SV) against trimethyltin (TMT) memory decline and hippocampal neurodegeneration. For inducing AD-like phenotype, rats were i.p. injected with TMT at 8 mg/kg and were treated with simvastatin daily for 3 weeks at 10 or 30 mg/kg. Our analysis of data indicated that simvastatin-treated TMT group has lower learning and memory deficits in behavioral tasks comprising Barnes maze, Y maze, and novel object discrimination (NOD). In addition, hippocampal inflammatory, oxidative, and apoptotic factors were attenuated besides reduction of acetylcholinesterase (AChE) activity and Alzheimer's pathology factors including presenilin-1 and hyperphorphorylated Tau (p-Tau) upon simvastatin. Moreover, simvastatin treatment of TMT group inverted hippocampal changes of Wnt, β-catenin, ERK, and Akt, ameliorated astrocytic and microglial reactivity, and also prevented injury of CA1 neurons. This study unraveled that simvastatin is capable to prevent TMT-induced Alzheimer's-like phenotype in association with Wnt/β-catenin/ERK/Akt as well as restraining hippocampal neurodegeneration.