Extracellular glutamate contributes to brain damage in ischemia. Under physiological conditions, glutamate transporters are responsible for regulating its intracellular/extracellular concentrations in the brain. However, how the extracellular glutamate is regulated in ischemia remains unclear. Here, we showed that the sonic hedgehog (SHH)–Smoothened (SMO)–GLT-1 pathway controlled extracellular glutamate and blocking SMO reduced ischemic brain damage in rodents. SHH was quickly released in a rodent model of ischemia, and activation of its pathway was associated with neuronal damage. Inhibiting SMO, the mediator of SHH signaling, maintained GLT-1 membrane expression, lowered extracellular glutamate, reduced infarct volume, and improved neurological functions in mice. Mechanistically, SHH suppressed GLT-1 membrane expression via PKCα phosphorylation of serine-562 on GLT-1. Last, administration of NVP-LDE225, an FDA-approved SMO antagonist used for cancer treatment in clinic, had protective effects in mice and cynomolgus monkeys subjected to ischemia. Together, these results suggest that SMO could be targeted for treating glutamate toxicity in ischemia.

中文翻译：

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Smoothened是减少缺血性中风谷氨酸毒性的治疗靶点

细胞外谷氨酸有助于缺血时的脑损伤。在生理条件下，谷氨酸转运蛋白负责调节其在大脑中的细胞内/细胞外浓度。然而，细胞外谷氨酸如何在缺血中被调节仍不清楚。在这里，我们发现声波刺猬 (SHH)-Smoothened (SMO)-GLT-1 通路控制细胞外谷氨酸并阻断 SMO 可减少啮齿动物的缺血性脑损伤。SHH 在缺血的啮齿动物模型中迅速释放，其通路的激活与神经元损伤有关。抑制 SMO（SHH 信号传导的介质）可维持 GLT-1 膜表达、降低细胞外谷氨酸、减少梗塞体积并改善小鼠的神经功能。机械地，SHH 通过 GLT-1 上丝氨酸 562 的 PKCα 磷酸化抑制 GLT-1 膜表达。最后，NVP-LDE225（一种 FDA 批准的用于临床癌症治疗的 SMO 拮抗剂）的给药对缺血的小鼠和食蟹猴具有保护作用。总之，这些结果表明 SMO 可以作为治疗缺血谷氨酸毒性的靶点。