RETRACTED ARTICLE: Metformin Attenuates Cognitive Impairments in Hypoxia–Ischemia Neonatal Rats via Improving Remyelination

Abstract

Perinatal hypoxia-ischemia (H/I) causes brain injury and myelination damage. Finding efficient methods to restore myelination is critical for the recovery of brain impairments. By applying an H/I rat model, we demonstrate that metformin (Met) treatment significantly ameliorates the loss of locomotor activity and cognition of H/I rat in the Morris water maze and open field task tests. After administration of Met to H/I rat, the proliferation of Olig2+ oligodendrocyte progenitor cells and the expression of myelin basic protein are obviously increased in the corpus callosum. Additionally, the myelin sheaths are more compact and the impairments are evidently attenuated. These data indicate that Met is beneficial for the amelioration of H/I-induced myelination and behavior deficits.

Metformin Administration During Early Postnatal Life Rescues Autistic-Like Behaviors in the BTBR T+ Itpr3tf/J Mouse Model of Autism

“…It has been inferred that early intervention is important to prevent and correct the pathological phenotypes of neurodevelopmental disorders, thereby reversing behavioral and functional deficits in adults (Cioni et al, 2016 ). Treatment with Metformin significantly improved deficits of locomotor activity and cognition in rats subjected to perinatal hypoxia-ischemia (Qi et al, 2017 ). Another study indicated that metformin administration during the neonatal period could alleviate a contextual fear memory deficit in a fetal alcohol spectrum disorder model (Tunc-Ozcan et al, 2018 ).…”

Metformin treatment after the hypoxia-ischemia attenuates brain injury in newborn rats

“…Furthermore, it has been illustrated that metformin can promote neurogenesis and protect BBB integrity in experimental stroke [ 26 , 27 ]. Additionally, metformin has been identified to ameliorate cognitive impairments via improve remyelination in a neonatal white matter injury paradigm [ 28 ]. However, to the best of our knowledge, few studies have reported that treatment with metformin is able to promote neurogenesis and preserve BBB integrity in an animal model of neonatal HI brain injury.…”

Neuroprotective Effects of Diabetes Drugs for the Treatment of Neonatal Hypoxia-Ischemia Encephalopathy

“…Drug delivery properties, dosage and use can also be complex to translate from a adult to neonatal setting. Several proof-of-concept studies with different classes of diabetes drugs as a treatment in neonatal HIE have been identified with glibenclamide (Zhou et al, 2009), metformin (Dadwal et al, 2015;Fang et al, 2017;Qi et al, 2017) and exendin-4 (Rocha-Ferreira et al, 2018). These diabetes drugs act on a plethora of biological pathways (Rosa et al, 2008;Zhang et al, 2016;Zhu et al, 2016) and the precise mechanisms of action of diabetes drugs for neuroprotection are still not fully understood.…”

“…In addition to its neuroprotective effects, metformin has been shown to promote neurogenesis by enhancing neural precursor selfrenewal, proliferation, and differentiation (Potts and Lim, 2012;Wang J. et al, 2012). Increased neurogenesis upon metformin treatment resulted in improved memory formation in multiple experimental models of brain injury (Jin et al, 2014;Liu et al, 2014;Dadwal et al, 2015;Ge et al, 2017;Qi et al, 2017). In vitro studies using the OGD model demonstrated that metformin improves neuronal viability and regulates programmed cell death in a caspase-independent manner, thereby reducing ischemic reperfusion injuries (Mielke et al, 2006;Meng et al, 2016;Gabryel and Liber, 2018;Mohammad Alizadeh et al, 2018).…”

“…In vitro studies using the OGD model demonstrated that metformin improves neuronal viability and regulates programmed cell death in a caspase-independent manner, thereby reducing ischemic reperfusion injuries (Mielke et al, 2006;Meng et al, 2016;Gabryel and Liber, 2018;Mohammad Alizadeh et al, 2018). Metformin treatment remarkably attenuated brain infarct volumes, brain oedema and restored behavior deficits in a neonatal rat model of HI (Qi et al, 2017). It also induced activation of endogenous neural precursor cells (NPCs) (Dadwal et al, 2015).…”