Effects of dexmedetomidine treatment after cerebral ischemia/reperfusion on apoptosis and oxidative stress: a rat model

Abstract

Objectives: Cerebral ischemia/reperfusion (IR) injury is characterized by excessive oxidative stress and activation of apoptotic pathways, which play a central role in neuronal loss and poor neurological outcomes. Modulation of these mechanisms represents a clinically relevant strategy for neuroprotection. This study aimed to investigate the neuroprotective effects of dexmedetomidine (Dex) on oxidative stress, apoptotic signaling, and neuronal integrity in an experimental rat model of cerebral IR injury. Materials and Methods: Female Wistar rats were assigned to control, IR, and IR+Dex groups. Transient cerebral ischemia was induced for 45 min followed by 2 h of reperfusion. Oxidative stress was evaluated using serum antioxidant enzyme activities (superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GSH-Px]), total oxidant and antioxidant status (TOS, TAS), and lipid peroxidation levels (malondialdehyde [MDA]). Apoptotic signaling was assessed by histopathological examination, transmission electron microscopy, and immunohistochemical analysis of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax) and apoptotic peptidase activating factor-1 (APAF-1) expression, quantitatively evaluated using QuPath with statistical comparison between groups. Bioinformatic network analysis and molecular docking were performed to explore predicted interactions between Dex and apoptosis-related proteins. Results: Cerebral IR induced a marked oxidative imbalance, characterized by reduced antioxidant enzyme activities and increased lipid peroxidation. Dex treatment partially improved antioxidant capacity and reduced oxidative stress parameters. Histopathological and ultrastructural analyses demonstrated severe neuronal degeneration following IR, whereas Dex-treated rats exhibited attenuated neuronal damage and improved ultrastructural preservation. Immunohistochemical analysis showed increased Bax and APAF-1 expression and reduced Bcl-2 expression after IR; these alterations were significantly modulated toward control levels in the IR+Dex group. Bioinformatic analysis identified apoptosis-related pathways, including apoptosis, p53 signaling, and necroptosis, as significantly enriched, while molecular docking suggested stable predicted interactions between Dex and key apoptotic regulators. Conclusions: In this experimental rat cerebral IR model, Dex exerted partial but significant neuroprotective effects by attenuating oxidative stress, modulating apoptotic marker expression, and preserving neuronal morphology. These findings support the potential role of Dex as a neuroprotective agent in ischemia-related brain injury, warranting further translational investigation.