The Protective Role of E-64d in Hippocampal Excitotoxic Neuronal Injury Induced by Glutamate in HT22 Hippocampal Neuronal Cells
Epilepsy is the most common childhood neurologic disorder. Status epilepticus (SE), which refers to continuous epileptic seizures, occurs more frequently in children than in adults, and approximately 40–50% of all cases occur in children under 2 years of age. Conventional antiepileptic drugs current...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Hindawi Limited
2021-01-01
|
| Series: | Neural Plasticity |
| Online Access: | http://dx.doi.org/10.1155/2021/7174287 |
| _version_ | 1798031659014029312 |
|---|---|
| author | RuiJin Xie TianXiao Li XinYu Qiao HuiYa Mei GuoQin Hu LongFei Li Chenyu Sun Ce Cheng Yin Cui Ni Hong Yueying Liu |
| author_facet | RuiJin Xie TianXiao Li XinYu Qiao HuiYa Mei GuoQin Hu LongFei Li Chenyu Sun Ce Cheng Yin Cui Ni Hong Yueying Liu |
| author_sort | RuiJin Xie |
| collection | DOAJ |
| description | Epilepsy is the most common childhood neurologic disorder. Status epilepticus (SE), which refers to continuous epileptic seizures, occurs more frequently in children than in adults, and approximately 40–50% of all cases occur in children under 2 years of age. Conventional antiepileptic drugs currently used in clinical practice have a number of adverse side effects. Drug-resistant epilepsy (DRE) can progressively develop in children with persistent SE, necessitating the development of novel therapeutic drugs. During SE, the persistent activation of neurons leads to decreased glutamate clearance with corresponding glutamate accumulation in the synaptic extracellular space, increasing the chance of neuronal excitotoxicity. Our previous study demonstrated that after developmental seizures in rats, E-64d exerts a neuroprotective effect on the seizure-induced brain damage by modulating lipid metabolism enzymes, especially ApoE and ApoJ/clusterin. In this study, we investigated the impact and mechanisms of E-64d administration on neuronal excitotoxicity. To test our hypothesis that E-64d confers neuroprotective effects by regulating autophagy and mitochondrial pathway activity, we simulated neuronal excitotoxicity in vitro using an immortalized hippocampal neuron cell line (HT22). We found that E-64d improved cell viability while reducing oxidative stress and neuronal apoptosis. In addition, E-64d treatment regulated mitochondrial pathway activity and inhibited chaperone-mediated autophagy in HT22 cells. Our findings indicate that E-64d may alleviate glutamate-induced damage via regulation of mitochondrial fission and apoptosis, as well as inhibition of chaperone-mediated autophagy. Thus, E-64d may be a promising therapeutic treatment for hippocampal injury associated with SE. |
| first_indexed | 2024-04-11T20:01:02Z |
| format | Article |
| id | doaj.art-26d984c5df0e4e3a938e0056b320e231 |
| institution | Directory Open Access Journal |
| issn | 2090-5904 1687-5443 |
| language | English |
| last_indexed | 2024-04-11T20:01:02Z |
| publishDate | 2021-01-01 |
| publisher | Hindawi Limited |
| record_format | Article |
| series | Neural Plasticity |
| spelling | doaj.art-26d984c5df0e4e3a938e0056b320e2312022-12-22T04:05:36ZengHindawi LimitedNeural Plasticity2090-59041687-54432021-01-01202110.1155/2021/71742877174287The Protective Role of E-64d in Hippocampal Excitotoxic Neuronal Injury Induced by Glutamate in HT22 Hippocampal Neuronal CellsRuiJin Xie0TianXiao Li1XinYu Qiao2HuiYa Mei3GuoQin Hu4LongFei Li5Chenyu Sun6Ce Cheng7Yin Cui8Ni Hong9Yueying Liu10Affiliated Hospital of Jiangnan University, No. 1000, Hefeng Avenue, Wuxi 214122, ChinaAffiliated Hospital of Jiangnan University, No. 1000, Hefeng Avenue, Wuxi 214122, ChinaWuxi School of Medicine, Jiangnan University, Wuxi, ChinaWuxi School of Medicine, Jiangnan University, Wuxi, ChinaWuxi School of Medicine, Jiangnan University, Wuxi, ChinaWuxi School of Medicine, Jiangnan University, Wuxi, ChinaAMITA Health Saint Joseph Hospital Chicago, 2900 N. Lake Shore Drive, Chicago, 60657 Illinois, USAThe University of Arizona College of Medicine at South Campus, 2800E. Ajo Way, Tucson, AZ, USAAffiliated Hospital of Jiangnan University, No. 1000, Hefeng Avenue, Wuxi 214122, ChinaChildren’s Hospital of Soochow University, Laboratory of Aging and Nervous Diseases, Soochow University, Suzhou 215003, ChinaAffiliated Hospital of Jiangnan University, No. 1000, Hefeng Avenue, Wuxi 214122, ChinaEpilepsy is the most common childhood neurologic disorder. Status epilepticus (SE), which refers to continuous epileptic seizures, occurs more frequently in children than in adults, and approximately 40–50% of all cases occur in children under 2 years of age. Conventional antiepileptic drugs currently used in clinical practice have a number of adverse side effects. Drug-resistant epilepsy (DRE) can progressively develop in children with persistent SE, necessitating the development of novel therapeutic drugs. During SE, the persistent activation of neurons leads to decreased glutamate clearance with corresponding glutamate accumulation in the synaptic extracellular space, increasing the chance of neuronal excitotoxicity. Our previous study demonstrated that after developmental seizures in rats, E-64d exerts a neuroprotective effect on the seizure-induced brain damage by modulating lipid metabolism enzymes, especially ApoE and ApoJ/clusterin. In this study, we investigated the impact and mechanisms of E-64d administration on neuronal excitotoxicity. To test our hypothesis that E-64d confers neuroprotective effects by regulating autophagy and mitochondrial pathway activity, we simulated neuronal excitotoxicity in vitro using an immortalized hippocampal neuron cell line (HT22). We found that E-64d improved cell viability while reducing oxidative stress and neuronal apoptosis. In addition, E-64d treatment regulated mitochondrial pathway activity and inhibited chaperone-mediated autophagy in HT22 cells. Our findings indicate that E-64d may alleviate glutamate-induced damage via regulation of mitochondrial fission and apoptosis, as well as inhibition of chaperone-mediated autophagy. Thus, E-64d may be a promising therapeutic treatment for hippocampal injury associated with SE.http://dx.doi.org/10.1155/2021/7174287 |
| spellingShingle | RuiJin Xie TianXiao Li XinYu Qiao HuiYa Mei GuoQin Hu LongFei Li Chenyu Sun Ce Cheng Yin Cui Ni Hong Yueying Liu The Protective Role of E-64d in Hippocampal Excitotoxic Neuronal Injury Induced by Glutamate in HT22 Hippocampal Neuronal Cells Neural Plasticity |
| title | The Protective Role of E-64d in Hippocampal Excitotoxic Neuronal Injury Induced by Glutamate in HT22 Hippocampal Neuronal Cells |
| title_full | The Protective Role of E-64d in Hippocampal Excitotoxic Neuronal Injury Induced by Glutamate in HT22 Hippocampal Neuronal Cells |
| title_fullStr | The Protective Role of E-64d in Hippocampal Excitotoxic Neuronal Injury Induced by Glutamate in HT22 Hippocampal Neuronal Cells |
| title_full_unstemmed | The Protective Role of E-64d in Hippocampal Excitotoxic Neuronal Injury Induced by Glutamate in HT22 Hippocampal Neuronal Cells |
| title_short | The Protective Role of E-64d in Hippocampal Excitotoxic Neuronal Injury Induced by Glutamate in HT22 Hippocampal Neuronal Cells |
| title_sort | protective role of e 64d in hippocampal excitotoxic neuronal injury induced by glutamate in ht22 hippocampal neuronal cells |
| url | http://dx.doi.org/10.1155/2021/7174287 |
| work_keys_str_mv | AT ruijinxie theprotectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT tianxiaoli theprotectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT xinyuqiao theprotectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT huiyamei theprotectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT guoqinhu theprotectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT longfeili theprotectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT chenyusun theprotectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT cecheng theprotectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT yincui theprotectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT nihong theprotectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT yueyingliu theprotectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT ruijinxie protectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT tianxiaoli protectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT xinyuqiao protectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT huiyamei protectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT guoqinhu protectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT longfeili protectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT chenyusun protectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT cecheng protectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT yincui protectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT nihong protectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells AT yueyingliu protectiveroleofe64dinhippocampalexcitotoxicneuronalinjuryinducedbyglutamateinht22hippocampalneuronalcells |