Livingston Jessica M, Syeda Tasfia, Christie Taryn, Gilbert Emily A B, Morshead Cindi M
Division of Anatomy, Department of Surgery, University of Toronto, Toronto, M5S1A8, Canada.
Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, M5S3E, Canada.
Brain Behav Immun Health. 2020 Jul 25;7:100119. doi: 10.1016/j.bbih.2020.100119. eCollection 2020 Aug.
Hypoxia-ischemia (HI) injury is a leading cause of neonatal death and long-term disability, and existing treatment options for HI offer only modest benefit. Early intervention with the drug metformin has been shown to promote functional improvement in numerous rodent models of injury and has pleiotropic cellular effects in the brain. We have previously shown that 1 week of metformin treatment initiated 24 h after HI in neonatal mice resulted in improved motor and cognitive performance, activation of endogenous neural precursor cells (NPCs), and increased oligodendrogenesis. While promising, a limitation to this work is that immediate pharmacological intervention is not always possible in the clinic. Herein, we investigated whether delaying metformin treatment to begin in the subacute phase post-HI would still effectively promote recovery. Male and female C57/BL6 mice received HI injury postnatally, and metformin treatment began 7 days post-HI for up to 4 weeks. Motor and cognitive performance was assessed across time using behavioural tests (cylinder, foot fault, puzzle box). We found that metformin improved motor and cognitive behaviour, decreased inflammation, and increased oligodendrocytes in the motor cortex. Our present findings demonstrate that a clinically relevant subacute metformin treatment paradigm affords the potential to treat neonatal HI, and that improved outcomes occur through modulation of the inflammatory response and oligodendrogenesis.
缺氧缺血性（HI）损伤是新生儿死亡和长期残疾的主要原因，现有的HI治疗方案效果有限。早期使用二甲双胍药物干预已被证明可促进多种损伤啮齿动物模型的功能改善，并对大脑具有多效性细胞作用。我们之前已经表明，在新生小鼠HI后24小时开始为期1周的二甲双胍治疗可改善运动和认知能力，激活内源性神经前体细胞（NPC），并增加少突胶质细胞生成。尽管前景乐观，但这项研究的一个局限性在于临床中并非总是能够立即进行药物干预。在此，我们研究了将二甲双胍治疗推迟至HI后亚急性期开始是否仍能有效促进恢复。雄性和雌性C57/BL6小鼠在出生后接受HI损伤，并在HI后7天开始进行为期4周的二甲双胍治疗。通过行为测试（圆筒试验、足误试验、拼图盒试验）对运动和认知能力进行长期评估。我们发现二甲双胍改善了运动和认知行为，减轻了炎症，并增加了运动皮层中的少突胶质细胞。我们目前的研究结果表明，一种与临床相关的亚急性二甲双胍治疗模式具有治疗新生儿HI的潜力，并且通过调节炎症反应和少突胶质细胞生成可实现更好的治疗效果。
