ABSTRACT
Tramadol (TRA) causes neurotoxicity whereas trimetazidine (TMZ) is neuroprotective. The potential involvement of the PI3K/Akt/mTOR signaling pathway in the neuroprotection of TMZ against TRA-induced neurotoxicity was evaluated. Seventy male Wistar rats were divided into groups. Groups 1 and 2 received saline or TRA (50 mg/kg). Groups 3, 4, and 5 received TRA (50 mg/kg) and TMZ (40, 80, or 160 mg/kg) for 14 days. Group 6 received TMZ (160 mg/kg). Hippocampal neurodegenerative, mitochondrial quadruple complex enzymes, phosphatidylinositol-3-kinases (PI3Ks)/protein kinase B levels, oxidative stress, inflammatory, apoptosis, autophagy, and histopathology were evaluated. TMZ decreased anxiety and depressive-like behavior induced by TRA. TMZ in tramadol-treated animals inhibited lipid peroxidation, GSSG, TNF-α, and IL-1ß while increasing GSH, SOD, GPx, GR, and mitochondrial quadruple complex enzymes in the hippocampus. TRA inhibited Glial fibrillary acidic protein expression and increased pyruvate dehydrogenase levels. TMZ reduced these changes. TRA decreased the level of JNK and increased Beclin-1 and Bax. TMZ decreased phosphorylated Bcl-2 while increasing the unphosphorylated form in tramadol-treated rats. TMZ activated phosphorylated PI3Ks, Akt, and mTOR proteins. TMZ inhibited tramadol-induced neurotoxicity by modulating the PI3K/Akt/mTOR signaling pathways and its downstream inflammatory, apoptosis, and autophagy-related cascades.
Subject(s)
Neuroprotective Agents , Neurotoxicity Syndromes , Tramadol , Trimetazidine , Male , Rats , Animals , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol 3-Kinases/pharmacology , Trimetazidine/pharmacology , Tramadol/toxicity , Neuroprotection , Rats, Wistar , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/pharmacology , Apoptosis , Neurotoxicity Syndromes/etiology , Neurotoxicity Syndromes/prevention & control , Autophagy , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic useABSTRACT
BACKGROUND: A number of studies have explored the issue of sex differences in stroke from biomedical perspective; however, there are still large gaps in the existing knowledge. The purpose of this study was to assess whether the differences in socioeconomic status and living conditions between men and women may explain the part of the sex differences in incidence and outcomes of stroke. METHODS: All stroke participants aged ≥60 years admitted in Vaseie Hospital in Sabzevar, Iran, from March 21, 2013, until March 20, 2014, were included in this study. Computerized tomography and magnetic resonance imaging were used to confirm stroke. A series of χ2 tests were performed and Statistical Program for Social Sciences, Version 21.0, was used to investigate the potential differences between older men and women in stroke incidence and outcomes. RESULTS: A total of 159 incident stroke cases were documented during 1 year. The annual rate of stroke was statistically significantly higher in elderly women than in elderly men (401 vs 357 per 100,000; P<0.001). Female elderly participants had significantly lower socioeconomic status, poorer living conditions, and higher lifetime history of depression, hypertension, and diabetes mellitus than their male counterparts. CONCLUSION: The findings from this study showed that elderly women are more adversely affected by stroke in terms of incidence and outcomes of stroke than elderly men. The most noticeable result is that sex differences in socioeconomic status and living conditions may result in increased incidence of stroke and poorer outcomes in elderly women. Therefore, it is imperative to identify vulnerable elderly women and provide them appropriate treatment and services.
