Gemfibrozil pretreatment proved protection against acute restraint stress-induced changes in the male rats' hippocampus

highlights•Gemfibrozil protected rat hippocampus against the restraint stress dose-dependently.•Highest antioxidant activity of gemfibrozil was achieved at 90 mg/kg.•Gemfibrozil (90 mg/kg) induced HO-1, NQO-1, PGC-1α, and NRF-1 protein levels.•Gemfibrozil (90 mg/kg) reduced neuronal damage, AIF and cleaved caspase-3 levels.

Stress predisposes the brain to various neuropathological disorders. Fibrates like gemfibrozil, commonly used for hyperlipidemia, have not yet been examined for their protective/deteriorative potential against restraint stress-induced disturbances. Pretreatment of rats with a range of gemfibrozil concentrations showed significant protection against stress consequences at 90 mg/kg of gemfibrozil, as it resulted in the highest level of antioxidant defense system potentiation among other doses. It also reduced plasma corticosterone compared with the stressed animals. Administration of gemfibrozil (90 mg/kg) before stress induction was able to significantly induce the protein levels of some protective factors including hemeoxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone-1 (NQO-1) in the antioxidant nuclear factor erythroid-derived 2-like 2 (Nrf-2) pathway, as well as mitochondrial pro-survival proteins, including peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and nuclear respiratory factor 1 (NRF-1). In parallel, the level of cleaved caspase-3 and apoptosis-inducing factor (AIF), two proteins involved in apoptotic cell death, and the number of damaged neurons detected in hematoxylin–eosin (H&E) stained hippocampus sections were suppressed in the presence of gemfibrozil. Herein, although gemfibrozil demonstrated protection against the restraint stress, considering its dose and context-dependent effects reported in the previous studies, as well as its common application in clinic, further investigations are essential to unravel its exact beneficial/deleterious effects in various neuronal contexts.

Graphical abstractMajor changes of the studied molecules affected by restraint-induced stress and gemfibrozil pretreatment in the hippocampus of male rats are summarized in graphical abstract.Figure optionsDownload full-size imageDownload high-quality image (149 K)Download as PowerPoint slide