Evaluation of the Effectiveness of Post-Stroke Metformin Treatment Using Permanent Middle Cerebral Artery Occlusion in Rats

Abstract

Stroke is the second leading cause of death worldwide. Treatment options for ischemic stroke are limited, and the development of new therapeutic agents or combined therapies is imperative. Growing evidence suggests that metformin treatment, due to its anti-inflammatory action, exerts a neuroprotective effect against ischemia/reperfusion-induced brain damage. Experimental assessment has typically been performed in models of cerebral transient ischemia followed by long-term reperfusion. The aim of this study was to evaluate the neuroprotective effect of metformin treatment after permanent middle cerebral artery occlusion (pMCAO) without reperfusion in rats. Neurological deficits were assessed using the Longa scale, which offers a graded scale on body movement following pMCAO. Both infarct size and brain oedema area were measured by staining with 2,3,5-triphenyltetrazolium chloride. The number of neurons and total and activated microglia, as well as interleukin 10 (IL-10) production, in brain sections were evaluated by immunohistochemical staining. Our results show that metformin treatment improves the neurological state and reduces infarct size after 120 h of pMCAO. Metformin also prevents neuronal loss in the ischemic cortex but not in the striatum after 48 h of pMCAO. Moreover, post-stroke treatment with metformin significantly decreases the number of total and activated microglia at 48 h. The anti-inflammatory effect of metformin is associated with increased IL-10 production at 48 h after pMCAO. The results of the present study suggest that post-stroke treatment with metformin exerts anti-inflammatory and neuroprotective effects in a pMCAO model.

Metformin Alleviates Neuroinflammation Following Intracerebral Hemorrhage in Mice by Regulating Microglia/Macrophage Phenotype in a Gut Microbiota-Dependent Manner

“…Met is the most commonly used therapeutic agent for diabetes mellitus, and many studies have indicated that Met also exerts a treatment effect on CNS diseases. Treatment with Met exerted anti-inflammatory effects and prevented brain injury after IS (Liu et al, 2014 ; Zemgulyte et al, 2021 ). In Parkinson’s disease (PD) mice models, Met reduced mitochondrial respiration and inhibited neuroinflammation, which significantly improved motor function and neuronal viability (Mor et al, 2020 ; Ryu et al, 2020 ).…”

Metformin Intervention—A Panacea for Cancer Treatment?

“…While multiple reports based on in vivo and in vitro studies provide evidence that oxidative-stress markers unequivocally decrease in metformin-treated individuals, the details of the mechanisms responsible for these changes are not thoroughly understood [81][82][83][84][85][86].…”

“…While multiple reports based on in vivo and in vitro studies provide evidence that oxidative-stress markers unequivocally decrease in metformin-treated individuals, the details of the mechanisms responsible for these changes are not thoroughly understood [ 81 , 82 , 83 , 84 , 85 , 86 ]. The in vitro study performed by Javadipour et al, which focused on the antioxidant effects associated with metformin, revealed that metformin protected against increased oxidative stress via the nicotinamide adenine dinucleotide (NAD)-dependent protein deacylase sirtuin-3 ( SIRT3 )-related pathway [ 86 , 87 ].…”

The Development of Novel Drug Treatments for Stroke Patients: A Review

“…The opening of the pores causes depolarization of mitochondria. Some studies have suggested that the anti-diabetic medication metformin can demonstrate neuroprotective characteristics by hindering mitochondrial respiratory-chain-complex 1, enhancing the mitochondrial capacity for calcium and preventing the opening of its permeability pore [ 25 ]. Additionally, mitochondrial NCX facilitates calcium extrusion to the cytoplasm from the mitochondria, partially contributing to the deferred loading of cytoplasmic calcium during excitotoxicity.…”