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 d...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 strat-egy 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 de-cline 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 mitochon-dria could improve cognitive deficits and depressive and anxiety-like behaviors.Exogenous mitochondria blunted the production of reactive oxygen species,pro-liferation 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 ex-perimental evidence that artificial mitochondrial transplantation is capable of amelio-rating hippocampal damage following SE.These new findings support mitochondrial transplantation as a promising therapeutic strategy for epilepsy-associated psychiat-ric and cognitive disorders.展开更多
High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields,including neurology and neuroscience.High-mobility group box 1 in the ex...High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields,including neurology and neuroscience.High-mobility group box 1 in the extracellular space functions as a pro-inflammatory damage-associated molecular pattern,which has been proven to play an important role in a wide variety of central nervous system disorders such as ischemic stroke,Alzheimer’s disease,frontotemporal dementia,Parkinson’s disease,multiple sclerosis,epilepsy,and traumatic brain injury.Several drugs that inhibit high-mobility group box 1 as a damage-associated molecular pattern,such as glycyrrhizin,ethyl pyruvate,and neutralizing anti-high-mobility group box 1 antibodies,are commonly used to target high-mobility group box 1 activity in central nervous system disorders.Although it is commonly known for its detrimental inflammatory effect,high-mobility group box 1 has also been shown to have beneficial pro-regenerative roles in central nervous system disorders.In this narrative review,we provide a brief summary of the history of high-mobility group box 1 research and its characterization as a damage-associated molecular pattern,its downstream receptors,and intracellular signaling pathways,how high-mobility group box 1 exerts the repair-favoring roles in general and in the central nervous system,and clues on how to differentiate the pro-regenerative from the pro-inflammatory role.Research targeting high-mobility group box 1 in the central nervous system may benefit from differentiating between the two functions rather than overall suppression of high-mobility group box 1.展开更多
基金the National Natural Science Foundation of China(Grant No.82173803,81872847).
文摘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 strat-egy 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 de-cline 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 mitochon-dria could improve cognitive deficits and depressive and anxiety-like behaviors.Exogenous mitochondria blunted the production of reactive oxygen species,pro-liferation 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 ex-perimental evidence that artificial mitochondrial transplantation is capable of amelio-rating hippocampal damage following SE.These new findings support mitochondrial transplantation as a promising therapeutic strategy for epilepsy-associated psychiat-ric and cognitive disorders.
基金supported by a grant of the M.D.-Ph.D./Medical Scientist Training Program through the Korea Health Industry Development Institute(KHIDI)funded by the Ministry of Health&Welfare,Republic of Korea(to HK)+3 种基金supported by National Research Foundation of Korea(NRF)grants funded by the Korean government(MSITMinistry of Science and ICT)(NRF2019R1A5A2026045 and NRF-2021R1F1A1061819)a grant from the Korean Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI),funded by the Ministry of Health&Welfare,Republic of Korea(HR21C1003)New Faculty Research Fund of Ajou University School of Medicine(to JYC)。
文摘High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields,including neurology and neuroscience.High-mobility group box 1 in the extracellular space functions as a pro-inflammatory damage-associated molecular pattern,which has been proven to play an important role in a wide variety of central nervous system disorders such as ischemic stroke,Alzheimer’s disease,frontotemporal dementia,Parkinson’s disease,multiple sclerosis,epilepsy,and traumatic brain injury.Several drugs that inhibit high-mobility group box 1 as a damage-associated molecular pattern,such as glycyrrhizin,ethyl pyruvate,and neutralizing anti-high-mobility group box 1 antibodies,are commonly used to target high-mobility group box 1 activity in central nervous system disorders.Although it is commonly known for its detrimental inflammatory effect,high-mobility group box 1 has also been shown to have beneficial pro-regenerative roles in central nervous system disorders.In this narrative review,we provide a brief summary of the history of high-mobility group box 1 research and its characterization as a damage-associated molecular pattern,its downstream receptors,and intracellular signaling pathways,how high-mobility group box 1 exerts the repair-favoring roles in general and in the central nervous system,and clues on how to differentiate the pro-regenerative from the pro-inflammatory role.Research targeting high-mobility group box 1 in the central nervous system may benefit from differentiating between the two functions rather than overall suppression of high-mobility group box 1.
