Mitochondrial transplantation ameliorates hippocampal damage following status epilepticus

Abstract

Background 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. Methods 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. Results 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. Conclusion 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.

Long-term environmental enrichment overcomes depression, learning, and memory impairment in elderly CD-1 mice with maternal sleep deprivation exposure

“…The hippocampus is an important region of the limbic system associated with depression and cognitive function ( Jia et al, 2023 ; Yoon et al, 2023 ). Under stimulation of various pathological factors, hippocampal immune cells release large amounts of proinflammatory cytokines that contribute to neuroinflammation, which could increase the risk of depression and cognitive decline ( Wu et al, 2021 ; Hao et al, 2022 ).…”

Benzyl isothiocyanate ameliorates cognitive function in mice of chronic temporal lobe epilepsy

“…Jia et al used male C57BL/6 J mice induced status epilepticus (SE) through pilocarpine hydrochloride injection (320 mg/kg) and conducted behavioral testing within 7–10 days post-surgery. SE reduced the recognition index of new and old objects in mice, leading to increased time spent in the central area during open field tests ( 32 ). Wu et al performed the Morris water maze test on a lithium-pilocarpine-induced epileptic rat model, revealing a significant impairment in spatial memory function ( 33 ).…”

Astrocyte mitochondria: Potential therapeutic targets for epilepsy

“…Ethologically, artificial mitochondrial transplantation can improve the cognitive dysfunction, anxiety and depression caused by SE. In terms of pathological changes, artificial mitochondrial transplantation can mitigate neuronal loss, inhibit the activation of microglia and astrocytes induced by SE [ 71 ]. However, whether the exogenous mitochondria incorporate into neurons, astrocytes or microglia, and through what mechanism affect neuronal survival and glial cell activation still need to be further explored.…”