title: Gemfibrozil pretreatment affecting antioxidant defense system and inflammatory, but not Nrf-2 signaling pathways resulted in female neuroprotection and male neurotoxicity in the rat models of global cerebral ischemia-reperfusion.
abstract: Two important pathophysiological mechanisms involved during cerebral ischemia are oxidative stress and inflammation. In pathological conditions such as brain ischemia the ability of free radicals production is greater than that of elimination by endogenous antioxidative systems, so brain is highly injured due to oxidation and neuroinflammation. Fibrates as peroxisome proliferator-activated receptor (PPAR)-α ligands, are reported to have antioxidant and anti-inflammatory actions. In this study, gemfibrozil, a fibrate is investigated for its therapeutic potential against global cerebral ischemia-reperfusion (I/R) injury of male and female rats. This study particularly has focused on inflammatory and antioxidant signaling pathways, such as nuclear factor erythroid-related factor (Nrf)-2, as well as the activity of some endogenous antioxidant agents. It was found that pretreatment of animals with gemfibrozil prior to I/R resulted in a sexually dimorphic outcome. Within females it proved to be protective, modulating inflammatory factors and inducing antioxidant defense system including superoxide dismutase (SOD), catalase, as well as glutathione level. However, Nrf-2 signaling pathway was not affected. It also decreased malondialdehyde level as an index of lipid peroxidation. In contrast, gemfibrozil pretreatment was toxic to males, enhancing the expression of inflammatory factors such as tumor necrosis factor-α, nuclear factor-κB, and cyclooxygenase-2, and decreasing Nrf-2 expression and SOD activity, leading to hippocampal neurodegeneration. Considering that gemfibrozil is a commonly used anti-hyperlipidemic agent in clinic, undoubtedly more investigations are crucial to exactly unravel its sex-dependent neuroprotective/neurodegenerative potential.
authors: Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors: Fatemeh
authors: F
authors: Mohagheghi
authors: Leila
authors: L
authors: Khalaj
authors: Abolhassan
authors: A
authors: Ahmadiani
authors: Behrouz
authors: B
authors: Rahmani
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D005260:Female; D015248:Gemfibrozil / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000032:analysis; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D011292:Premedication; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C495637:Nfe2l2 protein, rat; D005978:Glutathione; D015248:Gemfibrozil