One important function of GABA B receptors is the control of neuronal activity to prevent overexcitation and thereby excitotoxic death, which is a hallmark of cerebral ischemia. Consequently, sustained activation of GABA B receptors with the selective agonist baclofen provides neuroprotection in in vitro and in vivo models of cerebral ischemia. However, excitotoxic conditions severely downregulate the receptors, which would compromise the neuroprotective effectiveness of baclofen. On the other hand, recent work suggests that sustained activation of GABA B receptors stabilizes receptor expression. Therefore, we addressed the question whether sustained activation of GABA B receptors reduces downregulation of the receptor under excitotoxic conditions and thereby preserves GABA B receptor-mediated inhibition. In cultured neurons subjected to oxygen and glucose deprivation (OGD), to mimic cerebral ischemia, GABA B receptors were severely downregulated. Treatment of the cultures with baclofen after OGD restored GABA B receptor expression and reduced loss of neurons. Restoration of GABA B receptors was due to enhanced fast recycling of the receptors, which reduced OGD-induced sorting of the receptors to lysosomal degradation. Utilizing the middle cerebral artery occlusion (MCAO) mouse model of cerebral ischemia, we verified the severe downregulation of GABA B receptors in the affected cortex and a partial restoration of the receptors after systemic injection of baclofen. Restored receptor expression recovered GABA B receptor-mediated currents, normalized the enhanced neuronal excitability observed after MCAO and limited progressive loss of neurons. These results suggest that baclofen-induced restoration of GABA B receptors provides the basis for the neuroprotective activity of baclofen after an ischemic insult. Since GABA B receptors regulate multiple beneficial pathways, they are promising targets for a neuroprotective strategy in acute cerebral ischemia.

中文翻译：

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脑缺血后巴氯芬诱导的 GABA B 受体的持续激活恢复受体表达和功能并限制神经元的进行性丢失。

GABA B 受体的一个重要功能是控制神经元活动以防止过度兴奋，从而防止兴奋性中毒死亡，这是脑缺血的标志。因此，用选择性激动剂巴氯芬持续激活 GABA B 受体可在脑缺血的体外和体内模型中提供神经保护。然而，兴奋毒性条件会严重下调受体，这会损害巴氯芬的神经保护效果。另一方面，最近的工作表明 GABA B 受体的持续激活可以稳定受体表达。因此，我们解决了 GABA B 受体的持续激活是否会降低兴奋性毒性条件下受体的下调，从而保持 GABA B 受体介导的抑制的问题。在经历氧和葡萄糖剥夺 (OGD) 的培养神经元中，为了模拟脑缺血，GABA B 受体被严重下调。OGD 后用巴氯芬处理培养物可恢复 GABA B 受体表达并减少神经元的损失。GABA B 受体的恢复是由于受体的快速循环增强，这减少了 OGD 诱导的受体分类到溶酶体降解。利用大脑缺血的大脑中动脉闭塞 (MCAO) 小鼠模型，我们验证了受累皮层中 GABA B 受体的严重下调和巴氯芬全身注射后受体的部分恢复。恢复的受体表达恢复了 GABA B 受体介导的电流，使 MCAO 后观察到的增强的神经元兴奋性正常化，并限制了神经元的渐进性损失。这些结果表明巴氯芬诱导的 GABA B 受体恢复为巴氯芬在缺血性损伤后的神经保护活性提供了基础。由于 GABA B 受体调节多种有益途径，它们是急性脑缺血神经保护策略的有希望的目标。