美国罗切斯特大学Maiken Nedergaard等研究人员合作揭示去甲肾上腺素诱导的游离脂肪酸释放的抗癫痫效应。相关论文于2024年10月31日在线发表在《细胞—代谢》杂志上。

研究人员展示了去甲肾上腺素（NE）的暴露导致来自星形胶质细胞和神经元的游离脂肪酸（FFA）在质膜内的生成。反过来，FFA通过不同程度地调节星形胶质细胞和神经元的Na⁺、K⁺、ATP酶活性来抑制兴奋性。直接将FFA应用于清醒行为的小鼠的枕叶皮层，减弱了视觉诱发电位（VEP）。相反，通过局部施用脂肪酶抑制剂阻止FFA的产生则增强了VEP并引发癫痫样活动。这些结果表明，FFA的释放是NE信号传导中的一个关键步骤，可以保护大脑免受过度兴奋。靶向脂质信号通路可能为癫痫预防提供了一种新颖的治疗方法。

据了解，大脑在睡眠、安静清醒和高度警觉状态之间迅速过渡的能力非常显著。大脑NE在促进清醒方面起着关键作用，但大脑如何避免在觉醒时出现神经元过度兴奋仍不清楚。

附：英文原文

Title: Anti-seizure effects of norepinephrine-induced free fatty acid release

Author: Baoman Li, Qian Sun, Fengfei Ding, Qiwu Xu, Ning Kang, Yang Xue, Antonio Ladron-de-Guevara, Hajime Hirase, Pia Weikop, Sheng Gong, Smith Nathan, Maiken Nedergaard

Issue&Volume: 2024-10-31

Abstract: The brain’s ability to rapidly transition between sleep, quiet wakefulness, and states of high vigilance is remarkable. Cerebral norepinephrine (NE) plays a key role in promoting wakefulness, but how does the brain avoid neuronal hyperexcitability upon arousal Here, we show that NE exposure results in the generation of free fatty acids (FFAs) within the plasma membrane from both astrocytes and neurons. In turn, FFAs dampen excitability by differentially modulating the activity of astrocytic and neuronal Na+, K+, ATPase. Direct application of FFA to the occipital cortex in awake, behaving mice dampened visual-evoked potential (VEP). Conversely, blocking FFA production via local application of a lipase inhibitor heightened VEP and triggered seizure-like activity. These results suggest that FFA release is a crucial step in NE signaling that safeguards against hyperexcitability. Targeting lipid-signaling pathways may offer a novel therapeutic approach for seizure prevention.

DOI: 10.1016/j.cmet.2024.10.011

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00407-8