Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, China; Department of Pharmacology, Shanxi Medical University, Taiyuan, 030001, China.
Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, China; Department of Pharmacology, Shanxi Medical University, Taiyuan, 030001, China.
Brain Res Bull. 2020 Nov;164:146-156. doi: 10.1016/j.brainresbull.2020.08.021. Epub 2020 Aug 26.
Accumulating evidence suggests that chronic metformin posttreatment offers potent neuroreparative effects against acute brain injury. However, in previous studies, metformin was not initially administered beyond 24 h postinjury, and the effects of delayed metformin treatment in traumatic brain injury (TBI) and other types of acute brain injury and the related mechanisms are unclear. To test this, male C57BL/6 mice received once daily metformin treatment (20, 50 or 100 mg/kg/d, i.p.) at day 1-14, day 1-2, day 1-10, day 3-10, day 5-12 or day 5-28 after cryogenic TBI (cTBI). The results showed that 100 mg/kg/d metformin administered at day 1-14 postinjury significantly promoted motor functional recovery in the beam walking and gait tests and reduced the infarct volume. Metformin (100 mg/kg/d) administered at day 1-10 or day 3-10 but not day 1-2 or day 5-12 after cTBI significantly improved motor functional outcomes at day 7 and 14, and reduced the infarct volume at day 14. Interestingly, the therapeutic time window was further expanded when the duration of metformin treatment starting at day 5 postinjury was extended to 2 weeks. Furthermore, compared with cTBI, the administration of metformin at day 3-10 or day 5-28 after cTBI significantly elevated the expression of phosphorylated adenosine monophosphate-activated protein kinase (AMPK) and growth associated protein 43 (an axonal regeneration marker) and the number of vascular branch points and decreased the area of glial scar and the number of amoeboid microglia in the peri-infarct area at day 14 or 28 postinjury. The above beneficial effects of metformin were blocked by the intracerebroventricular injection of the AMPK inhibitor compound C (40 μg/mouse/d). Our data provide the first evidence that metformin has a wide therapeutic time window for at least 5 days after cTBI, during which it can improve functional recovery by promoting tissue repair and inhibiting glial scar formation and microglial activation in a central AMPK-dependent manner.
越来越多的证据表明，慢性二甲双胍治疗后对急性脑损伤具有强大的神经修复作用。然而，在以前的研究中，二甲双胍在损伤后 24 小时内没有开始初始给药，并且延迟给予二甲双胍治疗创伤性脑损伤（TBI）和其他类型的急性脑损伤的效果及其相关机制尚不清楚。为了验证这一点，雄性 C57BL/6 小鼠在低温 TBI（cTBI）后第 1-14 天、第 1-2 天、第 1-10 天、第 3-10 天、第 5-12 天或第 5-28 天每天接受一次腹腔注射 20、50 或 100mg/kg/d 的二甲双胍治疗。结果表明，损伤后第 1-14 天给予 100mg/kg/d 的二甲双胍可显著促进在束行走和步态测试中的运动功能恢复，并减少梗死体积。在 cTBI 后第 1-10 天或第 3-10 天给予二甲双胍（100mg/kg/d）而不是第 1-2 天或第 5-12 天可显著改善第 7 天和第 14 天的运动功能结果，并减少第 14 天的梗死体积。有趣的是，当损伤后第 5 天开始的二甲双胍治疗持续时间延长至 2 周时，治疗时间窗进一步扩大。此外，与 cTBI 相比，在 cTBI 后第 3-10 天或第 5-28 天给予二甲双胍可显著提高磷酸化腺苷单磷酸激活蛋白激酶（AMPK）和生长相关蛋白 43（轴突再生标志物）的表达以及血管分支点的数量，并减少梗死区周围的神经胶质瘢痕面积和阿米巴样小胶质细胞的数量在第 14 天或第 28 天。在损伤后第 14 天或第 28 天，脑室注射 AMPK 抑制剂化合物 C（40μg/只/天）可阻断二甲双胍的上述有益作用。我们的数据首次提供了证据，表明二甲双胍在 cTBI 后至少 5 天内具有广泛的治疗时间窗，在此期间，它可以通过促进组织修复和抑制神经胶质瘢痕形成和小胶质细胞激活来改善功能恢复，这是一种中枢 AMPK 依赖性方式。
