Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA.
Discovery Theme on Chronic Brain Injury, The Ohio State University, Columbus, OH 43210, USA.
Brain. 2022 Jul 29;145(7):2378-2393. doi: 10.1093/brain/awac103.
Stroke causes devastating sensory-motor deficits and long-term disability due to disruption of descending motor pathways. Restoration of these functions enables independent living and therefore represents a high priority for those afflicted by stroke. Here, we report that daily administration of gabapentin, a clinically approved drug already used to treat various neurological disorders, promotes structural and functional plasticity of the corticospinal pathway after photothrombotic cortical stroke in adult mice. We found that gabapentin administration had no effects on vascular occlusion, haemodynamic changes nor survival of corticospinal neurons within the ipsilateral sensory-motor cortex in the acute stages of stroke. Instead, using a combination of tract tracing, electrical stimulation and functional connectivity mapping, we demonstrated that corticospinal axons originating from the contralateral side of the brain in mice administered gabapentin extend numerous collaterals, form new synaptic contacts and better integrate within spinal circuits that control forelimb muscles. Not only does gabapentin daily administration promote neuroplasticity, but it also dampens maladaptive plasticity by reducing the excitability of spinal motor circuitry. In turn, mice administered gabapentin starting 1 h or 1 day after stroke recovered skilled upper extremity function. Functional recovery persists even after stopping the treatment at 6 weeks following a stroke. Finally, chemogenetic silencing of cortical projections originating from the contralateral side of the brain transiently abrogated recovery in mice administered gabapentin, further supporting the conclusion that gabapentin-dependent reorganization of spared cortical pathways drives functional recovery after stroke. These observations highlight the strong potential for repurposing gabapentinoids as a promising treatment strategy for stroke repair.
中风会破坏下行运动通路，导致毁灭性的感觉运动功能障碍和长期残疾。这些功能的恢复使患者能够独立生活，因此是中风患者的首要治疗目标。在这里，我们报告称，每日给予加巴喷丁（一种已被临床批准用于治疗各种神经疾病的药物）可促进成年小鼠光血栓性皮质中风后皮质脊髓通路的结构和功能重塑。我们发现，加巴喷丁给药对血管闭塞、血液动力学变化以及同侧感觉运动皮层内皮质脊髓神经元的存活没有影响在中风的急性阶段。相反，我们使用示踪、电刺激和功能连接图相结合的方法，证明了给予加巴喷丁的小鼠大脑对侧起源的皮质脊髓轴突延伸出许多侧支，形成新的突触接触，并更好地整合控制前肢肌肉的脊髓回路。加巴喷丁的每日给药不仅促进了神经可塑性，而且通过降低脊髓运动回路的兴奋性来抑制适应不良的可塑性。反过来，给予加巴喷丁的小鼠在中风后 1 小时或 1 天开始治疗，上肢功能得到了恢复。即使在中风后 6 周停止治疗后，功能恢复仍然持续。最后，皮质投射起源于大脑对侧的化学遗传沉默短暂地阻断了给予加巴喷丁的小鼠的恢复，进一步支持了加巴喷丁依赖性的未受损皮质通路的重组驱动中风后的功能恢复的结论。这些观察结果强调了将加巴喷丁类药物重新用于治疗中风修复的巨大潜力。
