The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA; Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Exp Neurol. 2021 Oct;344:113792. doi: 10.1016/j.expneurol.2021.113792. Epub 2021 Jun 25.
Subarachnoid hemorrhage (SAH) results in severe neuronal dysfunction and degeneration. Since the nicotinic acetylcholine α receptors (α-AChR) are involved in neuronal function and survival, we investigated if stimulation of α-AChR would promote neuronal survival and improve behavioral outcome following SAH in mice. Male mice subjected to SAH were treated with either galantamine (α-AChR agonist) or vehicle. Neurobehavioral testing was performed 24 h after SAH, and mice were euthanized for analysis of neuronal cell death or a cell survival (PI3K/Akt) signaling pathway. Neuron cell cultures were subjected to hemoglobin toxicity to assess the direct effects of α-AChR agonism independent of other cells. Treatment with the α-AChR agonist promoted neuronal survival and improved functional outcomes 24 h post-SAH. The improved outcomes corresponded with increased PI3K/Akt activity. Antagonism of α-AChR or PI3K effectively reversed galantamine's beneficial effects. Tissue from α-AChR knockout mice confirmed α-AChR's role in neuronal survival after SAH. Data from the neuronal cell culture experiment supported a direct effect of α-AChR agonism in promoting cell survival. Our findings indicate that α-AChR is a therapeutic target following SAH which can promote neuronal survival, thereby improving neurobehavioral outcome. Thus, the clinically relevant α-AChR agonist, galantamine, might be a potential candidate for human use to improve outcome after SAH.
蛛网膜下腔出血 (SAH) 可导致严重的神经元功能障碍和退化。由于烟碱型乙酰胆碱α受体 (α-AChR) 参与神经元功能和存活，我们研究了刺激α-AChR 是否会促进 SAH 后小鼠的神经元存活和改善行为结果。接受 SAH 的雄性小鼠用加兰他敏（α-AChR 激动剂）或载体处理。在 SAH 后 24 小时进行神经行为测试，然后处死小鼠分析神经元细胞死亡或细胞存活（PI3K/Akt）信号通路。将神经元细胞培养物暴露于血红蛋白毒性下，以评估α-AChR 激动剂的直接作用，而不依赖于其他细胞。α-AChR 激动剂的治疗促进了 SAH 后 24 小时神经元的存活和功能结果的改善。改善的结果与 PI3K/Akt 活性的增加相对应。α-AChR 拮抗剂或 PI3K 的拮抗作用有效地逆转了加兰他敏的有益作用。来自α-AChR 敲除小鼠的组织证实了α-AChR 在 SAH 后神经元存活中的作用。神经元细胞培养实验的数据支持α-AChR 激动剂在促进细胞存活中的直接作用。我们的研究结果表明，α-AChR 是 SAH 后的治疗靶点，可促进神经元存活，从而改善神经行为结果。因此，临床上相关的α-AChR 激动剂加兰他敏可能是一种潜在的候选药物，可用于改善 SAH 后的结果。
