Neuroprotective effects of metformin on cerebral ischemia‐reperfusion injury by regulating PI3K/Akt pathway

Abstract

Metformin (Met) is a commonly used drug in the treatment of type 2 diabetes. Currently, it has been found that Met can effectively reduce the incidence of stroke and exert anti-inflammatory effects. However, its role in ischemia-reperfusion (I/R)induced nerve injury remains unclear. This study aims to investigate the neuroprotective effects of Met in I/R-induced neuron injury as well as the underlying mechanism.A middle cerebral artery occlusion (MCAO) model was established in Sprague Dawley (SD) rats, which were then treated with different doses of Met. Neurological deficits of rats were measured at different times post-surgery. TTC staining was done to observe the volume of cerebral infarction. HE staining was performed to observe pathological changes of brain tissues. Immunohistochemistry was performed to observe the expression of inflammatory factors in the cerebral tissues. qRT-PCR method was used to detect the relative expression of PI3K, Akt mRNA in cells after 24 h of drug action.Western blot method was used to detect the expression of PI3K, p-PI3K, Akt, and p-Akt in hippocampus. What is more, in vitro experiments were performed on BV2 microglia to verify the role of Met against oxygen-glucose deprivation (OGD). As a result, Met dose-dependently attenuated neurological deficits and neuronal apoptosis. Besides, Met administration also significantly reduced BV2 cells apoptosis and inflammatory response. Mechanistically, Met inactivated PI3K/Akt pathway induced by I/R and OGD, while it upregulated PI3K. In conclusion, Met protected rats from cerebral I/R injury via reducing neuronal apoptosis and microglial inflammation through PI3K/Akt pathway.

Identification of Parkinson PACE subtypes and repurposing treatments through integrative analyses of multimodal clinical progression, neuroimaging, genetic, and transcriptomic data

“…70,71 In addition, metformin has been found to modulate PI3K/AKT activity. 72,73 Enhanced activations of AMPK and PI3K/AKT can amplify autophagy, which aids in the removal of toxic proteins like α -synuclein, thereby preventing dopaminergic neuronal death. 72,73 Finally, animal model studies have found that metformin may induce both angiogenesis and neurogenesis in the brain under different experimental conditions.…”

“…72,73 Enhanced activations of AMPK and PI3K/AKT can amplify autophagy, which aids in the removal of toxic proteins like 𝛼 -synuclein, thereby preventing dopaminergic neuronal death. 72,73 Finally, animal model studies have found that metformin may induce both angiogenesis and neurogenesis in the brain under different experimental conditions. [74][75][76] In conclusion, the neuroprotective effect of metformin against the PD-R subtype (rapid PD progression) could be attributed to its ability to inhibit neuroinflammation, enhance PI3K/AKT activity for efficient 𝛼synuclein clearance, and stimulate angiogenesis.…”

Exploring the active components and mechanism of modified bazhen decoction in treatment of chronic cerebral circulation insufficiency based on network pharmacology and molecular docking

“…[40] Studies have confirmed that the PI3K/Akt pathway is progressively inhibited during the pathological injury of cerebral ischemia-reperfusion, and by intervening to trigger and activate this pathway, the trend of excessive apoptosis can be reversed, thus reducing the extent of cerebral ischemia-reperfusion injury. [41] In order to verify the speculation of network pharmacology, this study selected the essential potent substance of MBZD and the core target for molecular docking verification, and the results showed that the critical potent substance of MBZD and the core target protein could bind stably, which verified the prediction of network pharmacology about the mechanism of action of MBZD. However, there are certain limitations to the present study.…”

Dysregulation of mTOR Signaling after Brain Ischemia

“…The direct inhibition of mTORC1, using pharmacological (sirolimus and everolimus treatment for 6 h after tMCAo induction) and genetic (Raptor-KO mice) approaches, leads to a reduction in pro-inflammatory cytokine expression, in parallel to an increase in the M2 phenotype [ 164 ]. Indeed, recent studies show similar results using different approaches to reduce mTORC1 activity, including the downregulation of some upstream players of the PI3K/mTORC1 pathway [ 165 , 166 , 167 , 168 ]. The mTOR activity regulates the synthesis of pro-inflammatory cytokines ( Figure 6 ) through the mTOR/STAT3 pathway but also enhances autophagy in microglia [ 166 , 169 ].…”