Following stroke, the survival of neurons and their ability to reestablish connections is critical to functional recovery. This is strongly influenced by the balance between neuronal excitation and inhibition. In the acute phase of experimental stroke, lethal hyperexcitability can be attenuated by positive allosteric modulation of GABA_A receptors (GABA_ARs). Conversely, in the late phase, negative allosteric modulation of GABA_AR can correct the suboptimal excitability and improves both sensory and motor recovery. Here, we hypothesized that octadecaneuropeptide (ODN), an endogenous allosteric modulator of the GABA_AR synthesized by astrocytes, influences the outcome of ischemic brain tissue and subsequent functional recovery. We show that ODN boosts the excitability of cortical neurons, which makes it deleterious in the acute phase of stroke. However, if delivered after day 3, ODN is safe and improves motor recovery over the following month in two different paradigms of experimental stroke in mice. Furthermore, we bring evidence that, during the subacute period after stroke, the repairing cortex can be treated with ODN by means of a single hydrogel deposit into the stroke cavity.

SIGNIFICANCE STATEMENT Stroke remains a devastating clinical challenge because there is no efficient therapy to either minimize neuronal death with neuroprotective drugs or to enhance spontaneous recovery with neurorepair drugs. Around the brain damage, the peri-infarct cortex can be viewed as a reservoir of plasticity. However, the potential of wiring new circuits in these areas is restrained by a chronic excess of GABAergic inhibition. Here we show that an astrocyte-derived peptide, can be used as a delayed treatment, to safely correct cortical excitability and facilitate sensorimotor recovery after stroke.

中风后，神经元的存活及其重建连接的能力对于功能恢复至关重要。这受到神经元兴奋和抑制之间平衡的强烈影响。在实验性中风的急性期，致命的过度兴奋可以通过 GABA _A受体 (GABA _A Rs) 的正变构调节来减弱。相反，在后期，GABA _A R 的负变构调节可以纠正次优的兴奋性并改善感觉和运动恢复。在这里，我们假设十八烷神经肽 (ODN)，一种 GABA _{A的内源性变构调节剂}R 由星形胶质细胞合成，影响缺血性脑组织的结果和随后的功能恢复。我们表明 ODN 增强了皮质神经元的兴奋性，这使其在中风的急性期有害。然而，如果在第 3 天后交付，ODN 是安全的，并且在小鼠实验性中风的两种不同范例中，在接下来的一个月内可以改善运动恢复。此外，我们提供的证据表明，在中风后的亚急性期，可以通过将单个水凝胶沉积到中风腔中来用 ODN 治疗修复皮层。

意义声明中风仍然是一个毁灭性的临床挑战，因为没有有效的治疗方法可以通过神经保护药物最大限度地减少神经元死亡或通过神经修复药物促进自发恢复。在脑损伤周围，梗塞周围皮层可以被视为可塑性的储存库。然而，在这些区域连接新电路的潜力受到长期过量的 GABA 能抑制的限制。在这里，我们展示了一种星形胶质细胞衍生肽，可用作延迟治疗，以安全地纠正皮质兴奋性并促进中风后的感觉运动恢复。