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.

中文翻译：

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通过加巴喷丁类给药利用皮质可塑性促进中风后的恢复。

由于下行运动通路的破坏，中风会导致毁灭性的感觉运动缺陷和长期残疾。恢复这些功能可以独立生活，因此对中风患者来说是当务之急。在这里，我们报告每天服用加巴喷丁（一种已获临床批准用于治疗各种神经系统疾病的药物）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可塑性。我们发现加巴喷丁给药对中风急性期同侧感觉运动皮层内的血管闭塞、血流动力学变化和皮质脊髓神经元的存活没有影响。相反，结合使用束追踪、电刺激和功能连接映射，我们证明，在给予加巴喷丁的小鼠中，起源于大脑对侧的皮质脊髓轴突延伸了许多侧枝，形成新的突触接触，并更好地整合到控制前肢肌肉的脊髓回路中。每天服用加巴喷丁不仅能促进神经可塑性，还能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，在中风后 1 小时或 1 天开始给予加巴喷丁的小鼠恢复了熟练的上肢功能。即使在中风后 6 周停止治疗后，功能恢复仍然存在。最后，来自大脑对侧的皮层投射的化学遗传学沉默暂时消除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的备用皮质通路重组驱动中风后功能恢复的结论。这些观察结果突出了将加巴喷丁类重新用作中风修复的有前途的治疗策略的巨大潜力。