Stroke is one of the leading causes of long-term disability. During ischemic stroke, glutamate is released, reuptake processes are impaired, and glutamate promotes excitotoxic neuronal death. Astrocytic glutamate transporter 1 (GLT-1) is the major transporter responsible for removing excess glutamate from the extracellular space. A translational activator of GLT-1, LDN/OSU 0212320 (LDN) has been previously developed with beneficial outcomes in epileptic animal models but has never been tested as a potential therapeutic for ischemic strokes. The present study evaluated the effects of LDN on stroke-associated brain injury. Male and female mice received LDN or vehicle 24 h before or 2 h after focal ischemia was induced in the sensorimotor cortex. Sensorimotor performance was determined using the Rung Ladder Walk and infarct area was assessed using triphenyltetrazolium chloride staining. Males treated with LDN exhibited upregulated GLT-1 protein levels, significantly smaller infarct size, and displayed better sensorimotor performance in comparison to those treated with vehicle only. In contrast, there was no upregulation of GLT-1 protein levels and no difference in infarct size or sensorimotor performance between vehicle- and LDN-treated females. Taken together, our results indicate that the GLT-1 translational activator LDN improved stroke outcomes in young adult male, but not female mice.

中文翻译：

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谷氨酸转运蛋白-1 (GLT-1) 的激活赋予脑缺血中的性别依赖性神经保护

中风是导致长期残疾的主要原因之一。在缺血性中风期间，谷氨酸被释放，再摄取过程受损，谷氨酸促进兴奋性毒性神经元死亡。星形胶质细胞谷氨酸转运蛋白 1 (GLT-1) 是负责从细胞外空间去除多余谷氨酸的主要转运蛋白。GLT-1 的翻译激活剂 LDN/OSU 0212320 (LDN) 先前已在癫痫动物模型中开发出有益结果，但从未被测试为缺血性中风的潜在治疗剂。本研究评估了 LDN 对中风相关脑损伤的影响。雄性和雌性小鼠在感觉运动皮层诱导局灶性缺血前 24 小时或后 2 小时接受 LDN 或载体。使用 Rung Ladder Walk 确定感觉运动性能，并使用氯化三苯基四唑染色评估梗塞面积。与仅用载体治疗的男性相比，用 LDN 治疗的男性表现出上调的 GLT-1 蛋白水平、明显更小的梗塞面积，并显示出更好的感觉运动性能。相比之下，载体和 LDN 治疗的女性之间没有 GLT-1 蛋白水平的上调，梗塞面积或感觉运动性能没有差异。总之，我们的结果表明 GLT-1 翻译激活剂 LDN 改善了年轻成年雄性小鼠的中风结果，但不能改善雌性小鼠的中风结果。与仅用车辆处理的那些相比，表现出更好的感觉运动性能。相比之下，GLT-1 蛋白水平没有上调，并且在媒介物和 LDN 治疗的雌性之间梗塞面积或感觉运动性能没有差异。总之，我们的结果表明 GLT-1 翻译激活剂 LDN 改善了年轻成年雄性小鼠的中风结果，但不能改善雌性小鼠的中风结果。与仅用车辆处理的那些相比，表现出更好的感觉运动性能。相比之下，载体和 LDN 治疗的女性之间没有 GLT-1 蛋白水平的上调，梗塞面积或感觉运动性能没有差异。总之，我们的结果表明 GLT-1 翻译激活剂 LDN 改善了年轻成年雄性小鼠的中风结果，但不能改善雌性小鼠的中风结果。