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Published on: July 13, 2018
Phelligridimer A enhances the expression of mitofusin 2 and protects against cerebral ischemia/reperfusion injury
Xing Li1, Bingtian Xu1, Lu Long1
1NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Abstract:
Mitochondrial dysfunction and endoplasmic reticulum (ER) stress play pivotal roles in the pathology of cerebral ischemia. In this study, we investigated whether phelligridimer A (PA), an active compound isolated from the medicinal and edible fungus Phellinus igniarius, ameliorates ischemic cerebral injury by restoring mitochondrial function and restricting ER stress. An in vitro cellular model of ischemic stroke-induced neuronal damage was established by exposing HT-22 neuronal cells to oxygen-glucose deprivation/reoxygenation (OGD/R). An in vivo animal model was established in rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R). The results showed that PA (1-10 μM) dose-dependently increased HT-22 cell viability, reduced OGD/R-induced lactate dehydrogenase release, and reversed OGD/R-induced apoptosis. PA reduced OGD/R-induced accumulation of reactive oxygen species, restored mitochondrial membrane potential, and increased ATP levels. Additionally, PA reduced the expression of the 78-kDa glucose-regulated protein (GRP78) and the phosphorylation of inositol-requiring enzyme-1α (p-IRE1α) and eukaryotic translation-initiation factor 2α (p-eIF2α). PA also inhibited the activation of the mitogen-activated protein kinase (MAPK) pathway in the OGD/R model. Moreover, treatment with PA restored the expression of mitofusin 2 (Mfn-2), a protein linking mitochondria and ER. The silencing of Mfn-2 abolished the protective effects of PA. The results from the animal study showed that PA (3-10 mg/kg) significantly reduced the volume of cerebral infarction and neurological deficits, which were accompanied by an increased level of Mfn-2, and decreased activation of the ER stress in the penumbra of the ipsilateral side after MCAO/R in rats. Taken together, these results indicate that PA counteracts cerebral ischemia-induced injury by restoring mitochondrial function and reducing ER stress. Therefore, PA might be a novel protective agent to prevent ischemia stroke-induced neuronal injury.
Insights
Phelligridimer A (PA) protects brain cells from stroke injury by improving mitochondrial function and reducing endoplasmic reticulum (ER) stress. This compound shows promise as a novel therapeutic agent for ischemic stroke.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are key factors in cerebral ischemia pathology.
- Cerebral ischemia, or stroke, leads to significant neuronal damage and neurological deficits.
- Identifying novel therapeutic agents to mitigate ischemic brain injury is crucial.
Purpose of the Study:
- To investigate the neuroprotective effects of phelligridimer A (PA) against ischemic cerebral injury.
- To determine if PA restores mitochondrial function and reduces ER stress in models of cerebral ischemia.
- To elucidate the role of mitofusin 2 (Mfn-2) in PA's protective mechanism.
Main Methods:
- Established in vitro (HT-22 cells) and in vivo (MCAO/R rats) models of ischemic stroke.
- Assessed cell viability, lactate dehydrogenase release, apoptosis, reactive oxygen species, mitochondrial membrane potential, and ATP levels.
- Analyzed the expression of ER stress markers (GRP78, p-IRE1α, p-eIF2α), MAPK pathway, and Mfn-2.
Main Results:
- PA dose-dependently increased neuronal cell viability and reduced cell death in vitro.
- PA restored mitochondrial function, decreased oxidative stress, and inhibited ER stress markers and MAPK activation.
- PA treatment increased Mfn-2 expression, which was essential for its neuroprotective effects in both cellular and animal models.
Conclusions:
- Phelligridimer A (PA) effectively ameliorates ischemic cerebral injury by enhancing mitochondrial function and alleviating ER stress.
- PA's protective mechanism involves the restoration of Mfn-2 expression, linking mitochondrial and ER integrity.
- PA represents a potential novel therapeutic agent for preventing and treating ischemic stroke.
