Neuroprotective Effects of Long-Term Metformin Preconditioning on Rats with Ischemic Brain Injuries

Abstract

<b><i>Introduction:</i></b> This study is to analyze the neuroprotective effects of long-term metformin (Met) preconditioning on rats with ischemic brain injuries and the related mechanisms. <b><i>Methods:</i></b> Twenty-five Sprague-Dawley rats were randomly divided into 5 groups: sham group, middle cerebral artery occlusion (MCAO) group, normal saline + MCAO group, pre- Met + MCAO group, and 3-MA + Met + MCAO group. Pathological changes of brain were observed by hematoxylin-eosin staining. Neurobehavior scores were calculated. Infarct area was assessed by 2,3,5-triphenyltetrazolium chloride staining. Apoptosis of neurons was detected by TdT-mediated dUTP Nick-End Labeling (TUNEL). Western blot tested the expression of LC3 (microtubule-associated protein 1 light chain 3), Beclin-1, adenosine 5′-monophosphate ([AMP]-activated protein kinase [AMPK]), and p-AMPK in hippocampal CA1 region. <b><i>Results:</i></b> Compared with the sham group, the MCAO group induced severe pathological changes in the brain. The neurobehavior scores and infarct area in the brain were increased in the MCAO group than in the sham group. The apoptosis level in the MCAO group was also higher than in the sham group. However, after pretreatment with Met, the pathological changes in the brain were attenuated. Compared with the MCAO group, the pre-Met + MCAO group also had decreased neurobehavior scores and infarct area in the brain. Additionally, the apoptosis level in the pre-Met + MCAO group was lower than in the MCAO group. Moreover, the MCAO group had increased levels of LC3 and Beclin-1 than in the sham group. In the pre-Met + MCAO group, their levels were decreased than in the MCAO group. The p-AMPK level in the pre-Met + MCAO group was also increased than in the MCAO group, suggesting activation of p-AMPK by Met. <b><i>Conclusion:</i></b> Long-term Met pretreatment has neuroprotective effect on ischemic brain injury, which may be related to the regulation of autophagy-related protein expression and apoptosis.

Effects of Tolerance-Induced Preconditioning on Mitochondrial Biogenesis in Undifferentiated and Differentiated Neuronal Cells

“…To our knowledge, no such direct comparison was previously reported and the data presented here bears relevance to the mechanisms controlling mitochondrial biogenesis and its role in neuroprotection. The preconditioning paradigms, hypoxia and NO treatments, have been extensively tested both in vitro and in vivo studies and induced tolerance in a variety of cells and tissues [28][29][30][31][32]. In this study, we applied the preconditioning methods that were suitable for in vitro treatments of all neuronal cells.…”

The role of AMPK-dependent pathways in cellular and molecular mechanisms of metformin: a new perspective for treatment and prevention of diseases

“…However, treatment with AMPK activators could attenuate these behavioral and molecular changes in the pathophysiological profile of metabolic dysfunction (Wang et al 2018 ). Various studies have shown that treatment with metformin is effective in neurological diseases, including high MPTP and increased BDNF (Patil et al 2014 , Lu et al 2016 ), Parkinson’s disease (Choi et al 2010 ; Arbeláez-Quintero and Palacios 2017 ; Lu et al 2020 , Paudel et al 2020 ), epilepsy (H S, Paudel et al 2019 , Demaré et al 2021 ; Sanz et al 2021 , Salvati et al 2022 ), traumatic brain injury (Tao et al 2018 ; Taheri et al 2019 ; Fan et al 2020 ; Rahimi et al 2020 ), neuroprotection of the heart (Zhu et al 2018 , Benjanuwattra et al 2020 , Leech et al 2020 ), and preconditioning in ischemic brain injury (Wang et al 2021a , b , c ). Various studies have shown that BDNF can affect the structure of the anal sphincter (Singh and Rattan 2021 , Singh, Singh et al 2021 ).…”

“…Indeed, metformin administration in STZ-diabetic rats resulted in improved testosterone, LH and FSH hormones levels (Nasrolahi et al 2013 ). Various studies have shown that treatment with metformin is effective in reproductive system diseases, including female and male reproduction in endocrine pathologies (Lee et al 2019 ; Shpakov 2021 , ul haq Shah, Shrivastava et al 2022 ), endometriosis (Zhao et al 2018 , Mu et al 2020 , Stochino-Loi et al 2021 , Kimber-Trojnar et al 2022 ), polycystic ovary syndrome (Chen et al 2019 ; Fornes et al 2022 , Xu et al 2022 ) and prostate (Sun et al 2018 , Chen, Wang et al 2021a , b , c , Aydın et al 2022 , Morale et al 2022 ).…”

“…Furthermore, another investigation revealed that inhibiting the activation of the two pathways of STAT3 and NF-βB by AMPK has been effective in inhibiting the growth of pancreatic tumours (Tan et al 2015 ). In addition, various studies have shown that treatment with metformin is effective in digestive system diseases, including colitis (El-Mahdy et al 2021 , Liu, Liao et al 2021, El-Ghannam et al 2022 ), Pancreatitis (He et al 2021 , Wang et al 2021a , b , c , Wang, Yu et al 2021), Liver Disease (Saeedi Saravi et al 2016 , Pinyopornpanish et al 2021 , Xie, Wang et al 2021a , b , c ) and Gut Microbiota (Lee, Chae et al 2021b , a , Lee, Kim et al 2021, Liu, Liao et al 2021).…”

Lycium barbarum polysaccharide mitigated methamphetamine addiction and altered methamphetamine‐induced gut microbiota dysbiosis

“…LBP protects the hippocampal neuron model of ischemic brain injury in vivo [11]. It also studied the protective effect of LBP in the middle cerebral artery occlusion model in vivo [12]. Recently, it has been reported that LBP could effectively alleviate the degeneration of the nigrostriatal system induced by methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine treatment, which might be a potential candidate drug for Parkinson's disease (PD) treatment [13].…”