Mitochondrial transplantation ameliorates hippocampal damage following status epilepticus

Author:

Jia Xiaoxia1,Wang Qinghua1,Ji Jianlun1,Lu Wenchun2,Liu Zhidong3,Tian Hao4,Guo Lin13,Wang Yun1ORCID

Affiliation:

1. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy Xuzhou Medical University Xuzhou China

2. Psychology Laboratory, School of Management Xuzhou Medical University Xuzhou China

3. Department of Pharmacy The Affiliated Hospital of Xuzhou Medical University Xuzhou China

4. Agro‐Products Processing Research Institute Yunnan Academy of Agricultural Sciences Kunming China

Abstract

AbstractBackgroundHippocampal 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.MethodsPilocarpine 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.ResultsThe 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.ConclusionTo 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.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

Medical Laboratory Technology,Veterinary (miscellaneous),Molecular Biology,Biochemistry,Medicine (miscellaneous)

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