Hypoglycemia causes dysregulation of Neuregulin 1, ErbB receptors, Ki67 in cerebellum and brainstem during diabetes: Implications in motor function复制标题

低血糖导致糖尿病期间小脑和脑干中神经调节蛋白1、ErbB受体、Ki67的失调: 运动功能的意义

Adult neurogenesis has added newer dimension to brain plasticity. Previously, regeneration in adult mammalian brain was considered rather unsuccessful due to several intrinsic and extrinsic factors. Neuregulin 1 (NRG1), the major signaling protein of neuregulin family, is implicated in migration, proliferation and differentiation of both neuronal and glial cells by binding to ErbB receptors including ErbB2, ErbB3 and ErbB4 via endocrine or juxtacrine signaling. Brain injury evokes NRG1-ErbB signals to trigger regeneration and replacement of the affected cells during adulthood and developmental stages. It is responsible for survival of newly formed neural cells in adult injured tissues by reducing oxidative stress and accelerating glucose transport via translocation of GLUT to meet the energy demand during cellular restoration. ErbB2 shows reduced rate of ligand dissociation and high activation of MAP-kinase; this significantly increases its receptor strength. Since it lacks a ligand binding domain, it requires hetero-dimerization with ErbB3 or ErbB4 for signal transduction. ErbB3, in turn, is a functional receptor possessing weak kinase activity. Re-expression of ErbB2 in adult brain is necessary for radial glia formation and loss of its activity disturbs neuronal migration. While ErbB3 is associated with proliferating cells, ErbB4 expression has been correlated with the appearance of a differentiated phenotype. Discrepancies in glucose metabolism and elevated oxidative stress are the major culprits of brain damage during diabetes. Excess extracellular glucose leads to activation of the polyol pathway, the hexosamine pathway and accumulation of advanced glycated end products which ultimately generates free radicals. Persistent oxidative stress disrupts cellular homeostasis and microenvironment needed for regeneration in brain. Furthermore, tight glycemic regulation by insulin treatment often leads to iatrotrogenic hypoglycemia in diabetic patients as a result of therapeutic insulin excess and compromised glucose counter-regulation. Such recurrent incidents amplify reactive oxygen species (ROS) generation, lipid peroxidation and cellular inflammation in already vulnerable brain cells leading to irreversible damage despite glucose normalization later.

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