Center for Translational Neuromedicine, University of Rochester, Rochester, NY, USA.
Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
Nat Commun. 2024 Nov 6;15(1):9600. doi: 10.1038/s41467-024-53430-y.
Epileptogenesis is the process whereby the previously normally functioning brain begins to generate spontaneous, unprovoked seizures. Status epilepticus (SE), which entails a massive release of neuronal glutamate and other neuroactive substances, is one of the best-known triggers of epileptogenesis. We here asked whether pharmacologically promoting glymphatic clearance during or after SE is beneficial and able to attenuate the subsequent epileptogenesis. We induced SE in adult male mice by intrahippocampal kainic acid (KA) infusion. Acute administration of a cocktail of adrenergic receptor antagonists (propranolol, prazosin, and atipamezole: PPA), enhanced glymphatic flow and effectively reduced the severity of spontaneous seizures in the chronic phase. The PPA treatment also reduced reactive gliosis and inhibited the loss of polarized expression of AQP4 water channels in the vascular endfeet of astrocytes. Administration of PPA after cessation of SE (30 hours post KA) also effectively suppressed epileptogenesis and improved outcome. Conversely, mice with constitutively low glymphatic transport due to genetic deletion of the aquaporin 4 (AQP4) water channel showed exacerbation of KA-induced epileptogenesis. We conclude that the pharmacological modulation of glymphatic fluid transport may represent a potential strategy to dampen epileptogenesis and the occurrence of spontaneous seizures following KA-induced SE.
癫痫发生是指先前正常功能的大脑开始自发产生无诱因的癫痫发作的过程。癫痫持续状态（SE）是众所周知的癫痫发生的最佳触发因素之一，其涉及神经元谷氨酸和其他神经活性物质的大量释放。我们在这里询问在 SE 期间或之后通过药理学促进神经胶质淋巴清除是否有益，并且能够减轻随后的癫痫发生。我们通过海马内海人酸（KA）输注诱导成年雄性小鼠 SE。急性给予肾上腺素能受体拮抗剂混合物（普萘洛尔、哌唑嗪和阿替美唑：PPA）可增强神经胶质淋巴清除作用，并有效降低慢性期自发性癫痫发作的严重程度。PPA 治疗还减少了反应性神经胶质增生，并抑制了星形细胞血管足突中 AQP4 水通道极性表达的丧失。在 SE 停止后（KA 后 30 小时）给予 PPA 也能有效抑制癫痫发生并改善预后。相反，由于水通道蛋白 4（AQP4）水通道的基因缺失导致糖质淋巴转运固有降低的小鼠表现出 KA 诱导的癫痫发生加重。我们得出结论，神经胶质淋巴清除的药理学调节可能代表一种潜在的策略，可以抑制 SE 后 KA 诱导的癫痫发生和自发性癫痫发作的发生。
