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，慢性二甲双胍后治疗对急性脑损伤具有有效的神经修复作用。然而，在以往的研究中，二甲双胍最初并未在伤后 24 小时后给药，并且延迟二甲双胍治疗对创伤性脑损伤 (TBI) 和其他类型的急性脑损伤的影响及其相关机制尚不清楚。为了测试这一点，雄性 C57BL/6 小鼠在第 1-14 天、第 1-2 天、第 1-10 天、第 3-10 天每天接受一次二甲双胍治疗（20、50 或 100 mg/kg/d，ip）低温 TBI (cTBI) 后 5-12 天或第 5-28 天。结果表明，在伤后第 1-14 天服用 100 mg/kg/d 二甲双胍可显着促进横梁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 天但不是第 1-2 天或第 5-12 天施用二甲双胍（100 mg/kg/d）可显着改善第 7 天和第 14 天的运动功能结果，并减少梗死体积第 14 天。有趣的是，当从受伤后第 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 天使用二甲双胍显着提高磷酸化单磷酸腺苷活化蛋白激酶 (AMPK) 和生长相关蛋白 43（轴突再生标志物）和损伤后第 14 天或第 28 天，血管分支点的数量减少，并减少了梗死周围区域的胶质瘢痕面积和变形虫小胶质细胞的数量。二甲双胍的上述有益作用被AMPK抑制剂化合物C（40μg/小鼠/天）的脑室内注射阻断。我们的数据提供了第一个证据，即二甲双胍在 cTBI 后至少 5 天内具有广泛的治疗时间窗口，在此期间，它可以通过促进组织修复和抑制胶质瘢痕形成和小胶质细胞活化以中枢 AMPK 依赖性方式改善功能恢复。