Cornin protects against cerebral ischemia/reperfusion injury by preventing autophagy via the PI3K/Akt/mTOR pathway

Abstract

Background Ischemia stroke is the leading cause of disability, which is a consequence of vascular occlusion. The purpose of this study is to investigate the effect of cornin which is isolated from the fruit of Verbena officinalis L, against astrocytes autophagy induced by cerebral ischemia/reperfusion (CI/R) injury in vitro and in vivo and its potential mechanism. Methods Cornin at dose of 2.5, 5 and 10 mg/kg were intravenously injected to MCAO rats at 15 min after reperfusion. The infarction volume, blood–brain barrier (BBB), neurological severity score (mNSS), and autophagy related protein were used to evaluated the protective effects and potential mechanism of cornin in autophagy with or without phosphoinositide-3 kinase (PI3K)inhibitor LY294002 and mammalian target of rapamycin (mTOR) small interfering RNA (siRNA) at 24 h after CI/R injury. The potential protective effects and mechanism of cornin at concention of 10 ~ 1000 nM were also evaluated in oxygen glucose deprivation/reperfusion (OGD/R) in U87 cells. Results The results suggest that cornin at dose of 5 or 10 mg/kg significantly reduce the cerebral infarction volume and blood–brain barrier (BBB) leakage, and improve neurological recovery in MCAO rats. Cleaved caspase-3 and Bax levels were significantly decreased, while B-cell lymphoma-2 (Bcl-2) and the apoptosis regulator ratio (Bcl-2/Bax) were markedly increased when treated with 2.5–10 mg/kg cornin. The obvious decreased expressions of glial fibrillary acidic protein (GFAP), myosin-like BCL2 interacting protein (Beclin-1) and microtubule-associated protein light chain 3 II (LC3-II) and increased of neuronal nuclei (NeuN), sequestosome-1 (p62), phosphorylated mTOR (p-mTOR), and phosphorylated Akt (p-Akt) were observed in MCAO rats treated with 10 mg/kg cornin, which was counteracted by LY294002. The expression of autophagy-related proteins with or without LY294002 and mTOR siRNA presented the similar results as in vitro in OGD/R in U87 cells. Conclusions These results indicate that cornin improved neurological recovery after cerebral ischemia injury by preventing astrocytes autophagy induced by CI/R via the PI3K/Akt/mTOR signaling pathway.

Therapeutic Potential of Natural Compounds from Herbs and Nutraceuticals in Alleviating Neurological Disorders: Targeting the Wnt Signaling Pathway

“…119 Cornin is an iridoid glycoside isolated from the fruit of Verbena of ficinalis L. Recent studies have found that cornin can induce angiogenesis through a variety of mechanisms and plays a therapeutic role in cerebral ischemic injury. 120 Xu et al showed that intravenous injection of cornin improved the sensorimotor function of MCAO rats, increased microvessel density, and upregulated the expression of vascular endothelial growth factor (VEGF) and angiopoietin (Ang1)/Tie2. In addition, cornin reduced the BBB permeability.…”

Cognitive Impairment in Multiple Sclerosis

“…However, the loss of membrane PS asymmetry is reversible, and if membrane asymmetry is restored, injured cells are then given the ability to recover, and not be engulfed by inflammatory cells [197,[270][271][272]. With the later phase that involves deoxyribonucleic acid (DNA) degradation in the cell [34,40,77,226,[273][274][275], caspase activation plays a prominent role [15,77,194,206,210,273,[276][277][278]. This process of caspase activation and DNA destruction is irreversible [259].…”

“…This process of caspase activation and DNA destruction is irreversible [259]. Limiting apoptotic cell death may minimize memory loss and cognition during both acute and chronic insults [34,93,96,169,172,185,276,279]. This may occur during measures that reduce inflammatory pathways and affect neuronal and oligodendrocyte survival [9,108,132,187,252,276,[279][280][281][282], as well as cognitive performance [25,[283][284][285].…”

“…mTOR can influence programmed cell death pathways through multiple mechanisms. mTOR activity can block apoptotic cell death in the nervous system [15,69,71,73,85,115,172,276,407], prevent oxidative stress injury [399,[408][409][410], modulate the progression of infectious agents [85,[411][412][413][414][415][416], and oversee metabolic homeostasis [72,115,417,418]. In the presence of mTOR activity, Aβ toxicity can be blocked [154,172,399,409,[419][420][421], vascular cell death is prevented [105,422], and neonatal and adult central nervous system hypoxic injury is prevented [276,423].…”

A bibliometric analysis of research foci and trends in cerebral ischemia-reperfusion injury involving autophagy during 2008 to 2022

“…For instance, selenium can inhibit autophagy by modulating the PI3K/AKT/mTOR signaling pathway, effectively preventing BBB injury following CIRI, particularly under hyperglycemic conditions. [55] Curcumin, [56] Cornin, [57] and Cyclo-(Phe-Tyr) [58] also inhibit excessive autophagy through this pathway to offer neuroprotection and maintain BBB integrity. Additionally, (-)-Epigallocatechin-3-gallate (EGCG), a bioactive component found in green tea, can inhibit autophagy via the AKT/AMPK/mTOR phosphorylation pathway, thus preventing further reperfusion injury in the mouse brain.…”