Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.
Department of Pharmacy, University of Washington, Seattle, WA 98195, USA.
Int J Mol Sci. 2022 Jan 27;23(3):1434. doi: 10.3390/ijms23031434.
Epilepsy is a heterogenous neurological disorder characterized by recurrent unprovoked seizures, mitochondrial stress, and neurodegeneration. Hydrogen sulfide (HS) is a gasotransmitter that promotes mitochondrial function and biogenesis, elicits neuromodulation and neuroprotection, and may acutely suppress seizures. A major gap in knowledge remains in understanding the role of mitochondrial dysfunction and progressive changes in HS levels following acute seizures or during epileptogenesis. We thus sought to quantify changes in HS and its methylated metabolite (MeSH) via LC-MS/MS following acute maximal electroshock and 6 Hz 44 mA seizures in mice, as well as in the early phases of the corneally kindled mouse model of chronic seizures. Plasma HS was acutely reduced after a maximal electroshock seizure. HS or MeSH levels and expressions of related genes in whole brain homogenates from corneally kindled mice were not altered. However, plasma HS levels were significantly lower during kindling, but not after established kindling. Moreover, we demonstrated a time-dependent increase in expression of mitochondrial membrane integrity-related proteins, OPA1, MFN2, Drp1, and Mff during kindling, which did not correlate with changes in gene expression. Taken together, short-term reductions in plasma HS could be a novel biomarker for seizures. Future studies should further define the role of HS and mitochondrial stress in epilepsy.
癫痫是一种异质性神经障碍，其特征是反复无诱因的发作、线粒体应激和神经退行性变。硫化氢（HS）是一种气体递质，可促进线粒体功能和生物发生，引起神经调节和神经保护，并且可能急性抑制癫痫发作。目前在理解急性癫痫发作或癫痫发生期间线粒体功能障碍和 HS 水平的进行性变化方面仍然存在很大的知识差距。因此，我们试图通过 LC-MS/MS 来定量检测急性最大电休克和 6 Hz 44 mA 癫痫发作后以及慢性癫痫角膜点燃模型的早期阶段 HS 及其甲基化代谢物（MeSH）的变化。最大电休克癫痫发作后，血浆 HS 急性减少。角膜点燃小鼠全脑匀浆中的 HS 或 MeSH 水平及其相关基因的表达没有改变。然而，在点燃过程中，血浆 HS 水平显著降低，但在建立点燃后没有改变。此外，我们证明了在点燃过程中与线粒体膜完整性相关的蛋白 OPA1、MFN2、Drp1 和 Mff 的表达呈时间依赖性增加，这与基因表达的变化无关。总之，血浆 HS 的短期减少可能是癫痫发作的一个新的生物标志物。未来的研究应进一步确定 HS 和线粒体应激在癫痫中的作用。
