GPER1 Mediates Hippocampal Therapeutic Effect of Prunetin in Uremic Encephalopathy: Modulation of the RUNX2 Axis, TLR4 Cascade, Necroptosis, and Mitochondrial Dysfunction
Ahmed B. Hamed, Iten M. Fawzy, Dalaal M. Abdallah, Yasmin S. Abulfadl, Kawkab A. Ahmed, Hanan S. El-Abhar
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引用次数: 0
Abstract
Renal ischemia/reoxygenation triggers uremic encephalopathy (UE), culminating in cognitive and neural derangements. Despite its neuroprotective functions, the hippocampal repercussion of the estrogen receptor G protein-coupled estrogen receptor 1 (GPER1) in UE remains uncharted, alongside the prospective involvement of RUNX2. In Silico virtual screening suggested that prunetin (PRU) may activate GPER1 and inhibit RUNX2. To validate these findings in vivo, male Sprague Dawley rats were allocated into five groups: placebo-surgery (PS), PRU-treated PS, untreated UE, PRU-treated UE, and UE pretreated with G-15 (a selective GPER1 blocker) before PRU. Biochemically, PRU significantly restored hippocampal structure and behavioral functions impaired by UE, reduced serum IS levels, and replenished GPER1 expression. Additionally, it suppressed p-AKT, p-GSK3β, RUNX2, TLR4, and NF-κB, while enhancing cell survival by silencing the necroptotic signal (TICAM1/RIPK1/RIPK3/MLKL) and restoring caspase-8. PRU also counteracted mitochondrial dysfunction by downregulating PGAM5 and p-DRP-1. Crucially, these beneficial effects were nullified by G-15, confirming the role of activated GPER1 in mediating PRU's therapeutic effects. Collectively, PRU-induced GPER1 orchestrated neural integrity signal UE/AKT/GSK-3β/RUNX2, inflammatory axis UE/TLR-4/NF-κB, necroptosis pathway (TICAM1/RIPK1/RIPK3/MLKL), preventing mitochondrial dysfunction by suppressing the PGAM5/DRP-1 cue. These findings highlight the therapeutic potential of PRU in treating UE-related hippocampal damage through GPER1 activation.
期刊介绍:
Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.