Evaluating the protective role of trimetazidine versus nano-trimetazidine in amelioration of bilateral renal ischemia/reperfusion induced neuro-degeneration: Implications of ERK1/2, JNK and Galectin-3 /NF-κB/TNF-α/HMGB-1 signaling.

BACKGROUND: Renal ischemia/reperfusion (I/R) is a primary culprit of acute kidney injury. Neurodegeneration can result from I/R, but the mechanisms are still challenging. We studied the implications of bilateral renal I/R on brain and potential involvement of the oxidative stress (OS) driven extracellular signal-regulated kinase1/2, c-Jun N-terminal kinase (ERK1/2, JNK) and Galectin-3 (Gal-3)/nuclear factor Kappa B (NF-қB)/tumor necrosis factor-alpha (TNF-α), high mobility group box-1 (HMGB-1), and caspase-3 paths upregulation. We tested the impact of Nano-trimetazidine (Nano-TMZ) on these pathways being a target of its neuroprotective effects. METHODS: Study groups; Sham, I/R, TMZ+I/R, and Nano-TMZ+I/R. Kidney functions, cognition, hippocampal OS markers, Gal-3, NF-қB, p65 and HMGB-1 gene expression, TNF-α level, t-JNK/p-JNK and t-ERK/p-ERK proteins, caspase-3, glial fibrillary acidic protein (GFAP) and ionized calcium binding protein-1 (Iba-1) were assessed. RESULTS: Nano-TMZ averted renal I/R-induced hippocampal impairment by virtue of its anti: oxidative, inflammatory, and apoptotic properties. CONCLUSION: Nano-TMZ is more than anti-ischemic.

Protective effect of apelin preconditioning in a rat model of hepatic ischemia reperfusion injury; possible interaction between the apelin/APJ system, Ang II/AT1R system and eNOS.

Introduction: Hepatic ischemic reperfusion injury occurs in multiple clinical settings. Novel potential protective agents are still needed to attenuate this injury. Apelin preconditioning protects against ischemic reperfusion injury in different organs. However, the protective mechanism of apelin on hepatic ischemic reperfusion injury is not yet clear. Aim: Evaluate the effect of apelin-13 preconditioning on hepatic ischemic reperfusion injury and clarify possible interactions between apelinergic, renin-angiotensin systems and endothelial nitric oxide synthase. Methods: In total, 60 rats were assigned to four groups: control sham-operated, ischemic reperfusion, apelin-treated ischemic reperfusion and apelin + N-nitro-L-arginine methyl ester-treated ischemic reperfusion. Apelin 2 µg/kg/day and N-nitro-L-arginine methyl ester 10 mg/kg/day were injected intraperitoneally daily for 3 days and 2 weeks respectively before hepatic ischemic reperfusion. Serum aminotransferase, aspartate aminotransferase, hepatic malondialdehyde, apelin, gene expression of caspase-3, endothelial nitric oxide synthase and angiotensin type 1 receptor and liver histopathology were compared between groups. Results: Apelin significantly reduced serum aminotransferase, aspartate aminotransferase, hepatic malondialdehyde, caspase-3 and angiotensin type 1 receptor expression, whereas hepatic apelin and endothelial nitric oxide synthase expression were significantly increased with improved hepatic histopathology. N-nitro-L-arginine methyl ester co-administration partially reversed this hepatoprotective effect. Conclusion: Apelin-13 reduced hepatic ischemic reperfusion injury. This protection could be related to the suppression of hepatic angiotensin type 1 receptor expression and elevation of hepatic apelin level and endothelial nitric oxide synthase expression, which counteracts the pathologic effects of Ang II/angiotensin type 1 receptor. An interaction exists between apelinergic, renin-angiotensin systems and endothelial nitric oxide synthase in hepatic ischemic reperfusion pathophysiology.