Kirenol alleviates cerebral ischemia-reperfusion injury by reducing oxidative stress and ameliorating mitochondrial dysfunction via activating the CK2/AKT pathway.

Abstract

Ischemic stroke represents a predominant cause of morbidity and mortality globally, resulting from abrupt vascular occlusion or rupture, which precipitates considerable neuronal damage. This study aims to shed more light on the specific neuroprotective mechanisms of Kirenol, a bioactive diterpene derived from traditional herbal medicine, with a particular focus on its regulation of mitochondrial dynamics via the CK2/AKT signalling pathway and its impact on the mitochondrial fusion protein Optic atrophy 1 (Opa1). The effects of Kirenol on neuronal viability, mitochondrial function, and pertinent signalling pathways were evaluated by employing a middle cerebral artery occlusion (MCAO) model in rats and subjecting HT22 neuronal cells to oxidative stress. Treatment with Kirenol significantly improved neurological outcomes, augmented Opa1 expression, and restored apoptotic-related protein markers, antioxidative factors, mitochondrial membrane potential, and adenosine triphosphate (ATP) levels (P < 0.01). Mechanistically, Kirenol elevated CK2 levels and phosphorylated AKT while inhibiting CK2/AKT signalling attenuated Kirenol's protective effects on Opa1 expression. Furthermore, silencing Opa1 using siRNA diminished the neuroprotective effects of Kirenol on oxidative stress and apoptosis-related markers, underscoring the critical role of Opa1. In vitro assessments demonstrated that Kirenol effectively mitigated oxidative stress-induced neuronal damage, restoring cell morphology and viability. Kirenol exhibited dose-dependent neuroprotective effects in the MCAO model (P < 0.01). These findings elucidate the neuroprotective role of Kirenol in ischemic stroke through Opa1-mediated mitochondrial fusion and highlight the CK2/AKT pathway as a promising therapeutic target.