Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China.
Psychology Laboratory, School of Management, Xuzhou Medical University, Xuzhou, China.
Animal Model Exp Med. 2023 Feb;6(1):41-50. doi: 10.1002/ame2.12310. Epub 2023 Feb 3.
Hippocampal damage caused by status epilepticus (SE) can bring about cognitive decline and emotional disorders, which are common clinical comorbidities in patients with epilepsy. It is therefore imperative to develop a novel therapeutic strategy for protecting hippocampal damage after SE. Mitochondrial dysfunction is one of contributing factors in epilepsy. Given the therapeutic benefits of mitochondrial replenishment by exogenous mitochondria, we hypothesized that transplantation of mitochondria would be capable of ameliorating hippocampal damage following SE.
Pilocarpine was used to induced SE in mice. SE-generated cognitive decline and emotional disorders were determined using novel object recognition, the tail suspension test, and the open field test. SE-induced hippocampal pathology was assessed by quantifying loss of neurons and activation of microglia and astrocytes. The metabolites underlying mitochondrial transplantation were determined using metabonomics.
The results showed that peripheral administration of isolated mitochondria could improve cognitive deficits and depressive and anxiety-like behaviors. Exogenous mitochondria blunted the production of reactive oxygen species, proliferation of microglia and astrocytes, and loss of neurons in the hippocampus. The metabonomic profiles showed that mitochondrial transplantation altered multiple metabolic pathways such as sphingolipid signaling pathway and carbon metabolism. Among potential affected metabolites, mitochondrial transplantation decreased levels of sphingolipid (d18:1/18:0) and methylmalonic acid, and elevated levels of D-fructose-1,6-bisphosphate.
To the best of our knowledge, these findings provide the first direct experimental evidence that artificial mitochondrial transplantation is capable of ameliorating hippocampal damage following SE. These new findings support mitochondrial transplantation as a promising therapeutic strategy for epilepsy-associated psychiatric and cognitive disorders.
癫痫持续状态（SE）引起的海马损伤可导致认知功能下降和情绪障碍，这是癫痫患者常见的临床合并症。因此，开发一种保护 SE 后海马损伤的新治疗策略迫在眉睫。线粒体功能障碍是癫痫的一个致病因素。鉴于外源性线粒体补充的治疗益处，我们假设移植线粒体能够改善 SE 后的海马损伤。
用匹罗卡品诱导小鼠 SE。使用新物体识别、悬尾试验和旷场试验来确定 SE 引起的认知下降和情绪障碍。通过定量神经元丢失和小胶质细胞和星形胶质细胞的激活来评估 SE 诱导的海马病理学。使用代谢组学来确定线粒体移植的代谢物。
结果表明，外周给予分离的线粒体可以改善认知缺陷和抑郁样和焦虑样行为。外源性线粒体减弱了活性氧的产生、小胶质细胞和星形胶质细胞的增殖以及海马神经元的丢失。代谢组学图谱显示，线粒体移植改变了鞘脂信号通路和碳代谢等多种代谢途径。在潜在受影响的代谢物中，线粒体移植降低了鞘脂（d18:1/18:0）和甲基丙二酸的水平，并升高了 D-果糖-1,6-二磷酸的水平。
据我们所知，这些发现提供了第一个直接的实验证据，证明人工线粒体移植能够改善 SE 后的海马损伤。这些新发现支持线粒体移植作为治疗癫痫相关精神和认知障碍的有前途的治疗策略。
