Pub Date : 2025-02-01DOI: 10.1016/j.neuint.2025.105928
Hyomin Ahn , Hyomin Lee , Wonseok Choi , Hyebin Lee , Kang-Gon Lee , Inchan Youn , Wooyoung Hur , Sungmin Han , Chiman Song
Glutamate-induced neuronal death is associated with neurodegeneration including cerebral ischemia. Several μ-opioid receptor antagonists exhibit a neuroprotective activity and have been considered as a potential therapeutic option for neurodegenerative disorders. For the first time, our current study unveiled the neuroprotective activity of selective δ-opioid receptor antagonists. A potent, selective δ-opioid receptor antagonist naltriben, also known as a potent TRPM7 agonist, displayed the prominent protective effect against glutamate-induced toxicity through opioid receptor-independent, TRPM7-independent mechanisms in HT22 cells. Naltriben activated Nrf2 pathway, and alleviated glutamate-induced Ca2+ influx, ROS production, and apoptosis. Moreover, intraperitoneal administration of naltriben at 20 mg/kg greatly reduced the infarct volume in the subcortical photothrombotic ischemia mouse model in vivo. The neuroprotective activity of naltriben was enhanced by a longer pretreatment, indicating that like Nrf2 activators, naltriben also requires the cellular priming for its full protective effects. Together, these results suggested naltriben as a potential therapeutic agent in conditions related with glutamate-induced neurotoxicity.
{"title":"Discovery of the therapeutic potential of naltriben against glutamate-induced neurotoxicity","authors":"Hyomin Ahn , Hyomin Lee , Wonseok Choi , Hyebin Lee , Kang-Gon Lee , Inchan Youn , Wooyoung Hur , Sungmin Han , Chiman Song","doi":"10.1016/j.neuint.2025.105928","DOIUrl":"10.1016/j.neuint.2025.105928","url":null,"abstract":"<div><div>Glutamate-induced neuronal death is associated with neurodegeneration including cerebral ischemia. Several μ-opioid receptor antagonists exhibit a neuroprotective activity and have been considered as a potential therapeutic option for neurodegenerative disorders. For the first time, our current study unveiled the neuroprotective activity of selective δ-opioid receptor antagonists. A potent, selective δ-opioid receptor antagonist naltriben, also known as a potent TRPM7 agonist, displayed the prominent protective effect against glutamate-induced toxicity through opioid receptor-independent, TRPM7-independent mechanisms in HT22 cells. Naltriben activated Nrf2 pathway, and alleviated glutamate-induced Ca<sup>2+</sup> influx, ROS production, and apoptosis. Moreover, intraperitoneal administration of naltriben at 20 mg/kg greatly reduced the infarct volume in the subcortical photothrombotic ischemia mouse model <em>in vivo</em>. The neuroprotective activity of naltriben was enhanced by a longer pretreatment, indicating that like Nrf2 activators, naltriben also requires the cellular priming for its full protective effects. Together, these results suggested naltriben as a potential therapeutic agent in conditions related with glutamate-induced neurotoxicity.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"183 ","pages":"Article 105928"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-28DOI: 10.1016/j.neuint.2025.105937
Peng Ren , Jing-Ya Wang , Meng-Jie Xu , Hong-Lei Chen , Jing-Yao Duan , Yun-Feng Li
The sigma-1 receptor (S1R) has garnered significant attention as a potential target for rapid-onset antidepressant-like effects, particularly owing to its ability to swiftly stimulate serotonergic neurons in the dorsal raphe nucleus (DRN). However, the precise mechanisms underlying its regulatory effects remain unclear. Therefore, this study aims to examine the interaction between SA-4503 (a selective S1R agonist) and 8-OH-DPAT (a serotonin1A (5-HT1A) receptor agonist) in mice with depressive-like behavior induced by chronic restraint stress (CRS). Preliminary studies were conducted to explore the potential mechanisms underlying the accelerated antidepressant-like effects resulting from the combined activation of S1R and 5-HT1A receptors. The results showed that the coadministration of SA4503 (1.0 mg/kg, orally) and 8-OH-DPAT (0.3 mg/kg, i. g.) produced antidepressant-like effects. However, the doses of 8-OH-DPAT used in this study did not exhibit intrinsic antidepressant-like activity in this model. Moreover, using an in-situ proximity ligation assay provided the first evidence of S1R-5-HT1A heteroreceptor complexes in the midbrain DRN and dentate gyrus (DG) of the forebrain in mice. The formation of these heterocomplexes was influenced by pharmacological agents and was closely associated with depressive-like behavior development in mice. Mechanistic analysis revealed that the combined activation of S1R and 5-HT1A receptors synergistically enhanced neurogenesis and plasticity in the dorsal DG region of the hippocampus in mice subjected to CRS. These findings significantly advance our understanding of S1R-mediated neuroplasticity, suggesting potential therapeutic strategies for developing rapid-acting antidepressants.
{"title":"Sigma-1 receptor activation produces faster antidepressant-like effect through enhancement of hippocampal neuroplasticity: Focus on sigma-1-5-HT1A heteroreceptor complex","authors":"Peng Ren , Jing-Ya Wang , Meng-Jie Xu , Hong-Lei Chen , Jing-Yao Duan , Yun-Feng Li","doi":"10.1016/j.neuint.2025.105937","DOIUrl":"10.1016/j.neuint.2025.105937","url":null,"abstract":"<div><div>The sigma-1 receptor (S1R) has garnered significant attention as a potential target for rapid-onset antidepressant-like effects, particularly owing to its ability to swiftly stimulate serotonergic neurons in the dorsal raphe nucleus (DRN). However, the precise mechanisms underlying its regulatory effects remain unclear. Therefore, this study aims to examine the interaction between SA-4503 (a selective S1R agonist) and 8-OH-DPAT (a serotonin1A (5-HT1A) receptor agonist) in mice with depressive-like behavior induced by chronic restraint stress (CRS). Preliminary studies were conducted to explore the potential mechanisms underlying the accelerated antidepressant-like effects resulting from the combined activation of S1R and 5-HT1A receptors. The results showed that the coadministration of SA4503 (1.0 mg/kg, orally) and 8-OH-DPAT (0.3 mg/kg, i. g.) produced antidepressant-like effects. However, the doses of 8-OH-DPAT used in this study did not exhibit intrinsic antidepressant-like activity in this model. Moreover, using an <em>in-situ</em> proximity ligation assay provided the first evidence of S1R-5-HT1A heteroreceptor complexes in the midbrain DRN and dentate gyrus (DG) of the forebrain in mice. The formation of these heterocomplexes was influenced by pharmacological agents and was closely associated with depressive-like behavior development in mice. Mechanistic analysis revealed that the combined activation of S1R and 5-HT1A receptors synergistically enhanced neurogenesis and plasticity in the dorsal DG region of the hippocampus in mice subjected to CRS. These findings significantly advance our understanding of S1R-mediated neuroplasticity, suggesting potential therapeutic strategies for developing rapid-acting antidepressants.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"184 ","pages":"Article 105937"},"PeriodicalIF":4.4,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amyotrophic lateral sclerosis (ALS) is characterized by the mislocalization and abnormal deposition of TAR DNA-binding protein 43 (TDP-43). This protein plays important roles in RNA metabolism and transport in motor neurons and glial cells. In addition, abnormal iron accumulation and oxidative stress are observed in the brain and spinal cord of patients with ALS exhibiting TDP-43 pathology and in animal models of ALS. We have previously demonstrated that TDP-43 downregulation significantly affects the expression of ferritin heavy chain (Fth1) mRNA in the axonal regions of neurons. Nevertheless, the mechanisms by which TDP-43 contributes to oxidative stress and iron accumulation in the central nervous system remain elusive. In this study, we aimed to investigate whether Fth1 mRNA is a target transported to the axon by TDP-43 using biophysical and biochemical analyses. Our results revealed Fth1 mRNA as a target mRNA transported to axons by TDP-43. Moreover, we demonstrated that TDP-43 regulates iron homeostasis and oxidative stress in neurons via Fth1 mRNA transport to the axons, possibly followed by a local translation of the ferritin heavy chain in the axons. This study suggests that TDP-43 plays an important role in preventing iron-mediated oxidative stress in neurons, with its loss contributing to ALS pathogenesis.
{"title":"TDP-43 transports ferritin heavy chain mRNA to regulate oxidative stress in neuronal axons","authors":"Jyunki Jinno , Rehab F. Abdelhamid , Junko Morita , Ryoko Saga , Yusuke Yamasaki , Atsushi Kadowaki , Kotaro Ogawa , Yasuyoshi Kimura , Kensuke Ikenaka , Goichi Beck , Kousuke Baba , Yoshitaka Nagai , Emiko Kasahara , Atsuo Sekiyama , Tasuku Hirayama , Isao Hozumi , Tatsuya Hasegawa , Toshiyuki Araki , Hideki Mochizuki , Seiichi Nagano","doi":"10.1016/j.neuint.2025.105934","DOIUrl":"10.1016/j.neuint.2025.105934","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is characterized by the mislocalization and abnormal deposition of TAR DNA-binding protein 43 (TDP-43). This protein plays important roles in RNA metabolism and transport in motor neurons and glial cells. In addition, abnormal iron accumulation and oxidative stress are observed in the brain and spinal cord of patients with ALS exhibiting TDP-43 pathology and in animal models of ALS. We have previously demonstrated that TDP-43 downregulation significantly affects the expression of ferritin heavy chain (<em>Fth1</em>) mRNA in the axonal regions of neurons. Nevertheless, the mechanisms by which TDP-43 contributes to oxidative stress and iron accumulation in the central nervous system remain elusive. In this study, we aimed to investigate whether <em>Fth1</em> mRNA is a target transported to the axon by TDP-43 using biophysical and biochemical analyses. Our results revealed <em>Fth1</em> mRNA as a target mRNA transported to axons by TDP-43. Moreover, we demonstrated that TDP-43 regulates iron homeostasis and oxidative stress in neurons via <em>Fth1</em> mRNA transport to the axons, possibly followed by a local translation of the ferritin heavy chain in the axons. This study suggests that TDP-43 plays an important role in preventing iron-mediated oxidative stress in neurons, with its loss contributing to ALS pathogenesis.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"184 ","pages":"Article 105934"},"PeriodicalIF":4.4,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.neuint.2024.105916
Elisa Angeloni, Lorenzo Germelli, Barbara Costa, Claudia Martini, Eleonora Da Pozzo
Neurosteroids have a crucial role in physiological intrinsic regulations of the Central Nervous System functions. They are derived from peripheral steroidogenic sources and from the de novo neurosteroidogenic capacity of brain cells. Significant alterations of neurosteroid levels have been frequently observed in neuroinflammation and neurodegenerative diseases. Such level fluctuations may be useful for both diagnosis and treatment of these pathological conditions. Beyond steroid administration, enhancing the endogenous production by Translocator Protein (TSPO) targeting has been proposed to restore these altered pathological levels. However, the neurosteroid quantification and the prediction of their final effects are often troublesome, sometimes controversial and context dependent, due to the complexity of neurosteroid biosynthetic pathway and to the low produced amounts. The aim of this review is to report recent advances, and technical limitations, in neurosteroid-related strategies against neuroinflammation.
{"title":"Neurosteroids and Translocator Protein (TSPO) in neuroinflammation","authors":"Elisa Angeloni, Lorenzo Germelli, Barbara Costa, Claudia Martini, Eleonora Da Pozzo","doi":"10.1016/j.neuint.2024.105916","DOIUrl":"10.1016/j.neuint.2024.105916","url":null,"abstract":"<div><div>Neurosteroids have a crucial role in physiological intrinsic regulations of the Central Nervous System functions. They are derived from peripheral steroidogenic sources and from the <em>d</em><em>e novo</em> neurosteroidogenic capacity of brain cells. Significant alterations of neurosteroid levels have been frequently observed in neuroinflammation and neurodegenerative diseases. Such level fluctuations may be useful for both diagnosis and treatment of these pathological conditions. Beyond steroid administration, enhancing the endogenous production by Translocator Protein (TSPO) targeting has been proposed to restore these altered pathological levels. However, the neurosteroid quantification and the prediction of their final effects are often troublesome, sometimes controversial and context dependent, due to the complexity of neurosteroid biosynthetic pathway and to the low produced amounts. The aim of this review is to report recent advances, and technical limitations, in neurosteroid-related strategies against neuroinflammation.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"182 ","pages":"Article 105916"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.neuint.2024.105903
Luyang Shi , Xue Wang , Hongzong Si , Wangdi Song
As the incidence of Alzheimer's disease (AD) continues to rise, the need for an effective PET radiotracer to facilitate early diagnosis has become more pressing than ever before in modern medicine. Phosphodiesterase (PDE) is closely related to cognitive impairment and neuroinflammatory processes in AD. Current research progress shows that specific PDE4D inhibitors radioligands can bind specifically to the PDE4D enzyme in the brain, thereby showing pathology-related signal enhancement in AD animal models, indicating the potential of these ligands as effective radiotracers. At the same time, we need to pay attention to the important role computer aided drug design (CADD) plays in advancing AD drug design and PET imaging. Future research will verify the potential of these ligands in clinical applications through computer simulation techniques, providing patients with timely intervention and treatment, which is of great significance.
{"title":"PDE4D inhibitors: Opening a new era of PET diagnostics for Alzheimer's disease","authors":"Luyang Shi , Xue Wang , Hongzong Si , Wangdi Song","doi":"10.1016/j.neuint.2024.105903","DOIUrl":"10.1016/j.neuint.2024.105903","url":null,"abstract":"<div><div>As the incidence of Alzheimer's disease (AD) continues to rise, the need for an effective PET radiotracer to facilitate early diagnosis has become more pressing than ever before in modern medicine. Phosphodiesterase (PDE) is closely related to cognitive impairment and neuroinflammatory processes in AD. Current research progress shows that specific PDE4D inhibitors radioligands can bind specifically to the PDE4D enzyme in the brain, thereby showing pathology-related signal enhancement in AD animal models, indicating the potential of these ligands as effective radiotracers. At the same time, we need to pay attention to the important role computer aided drug design (CADD) plays in advancing AD drug design and PET imaging. Future research will verify the potential of these ligands in clinical applications through computer simulation techniques, providing patients with timely intervention and treatment, which is of great significance.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"182 ","pages":"Article 105903"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The disturbances in thyroid hormones lead to altered brain metabolism, function, and cognition. Neuroimaging studies have shown structural and functional changes in hypothyroidism. Present study investigates the neuro-metabolite changes in dorsolateral prefrontal cortex (DLPFC) and posterior parietal cortex (PPC) and associated decline cognitive function in hypothyroid patients before and after thyroxine treatment. We performed neuropsychological test and 1H MRS in hypothyroid patients (n = 25) and controls (n = 30). In addition, follow-up data was also collected from 19 patients treated with levo-thyroxine for 32 weeks. The concentration of the neurometabolites were calculated using LCModel. MRS data were analyzed using analysis of covariance (ANCOVA), with age and gender as covariates. A paired t-test was conducted to compare the baseline hypothyroid with the follow-up. Partial correlations were utilised to assess possible associations between neuropsychological scores and neurometabolites with age and gender as covariates. Spearman correlation was performed between thyroid hormone levels and neurometabolites. Hypothyroid patients showed an impairment in delayed recall, immediate recall of semantic, visual retention, recognition of objects memory, attention, and motor function at baseline, which improved significantly after thyroxine therapy. At baseline, patients with hypothyroidism exhibited significantly higher levels of choline compounds (GPC + PCh) [Cho]. No significant normalization of Cho levels was observed, despite achieving euthyroidism with thyroxine treatment. Cho levels showed a positive correlation with TSH in PPC and a negative correlation with T4 in DLPFC and PCC. Cho levels also showed negative correlations with delayed recall, immediate recall of semantic, visual retention memory and MMSE scores. The MRS findings show increased levels of Cho in hypothyroid patients compared to healthy controls. These Cho levels are not reversible within 32 weeks of treatment, suggesting that a longer follow-up may be needed to see if levels can be normalized.
{"title":"Neurometabolite and cognitive changes in hypothyroid patients in response to treatment: In-vivo 1H MRS study","authors":"Mukesh Kumar , Sadhana Singh , Poonam Rana , Maria D'souza , S Senthil Kumaran , Tarun Sekhri , Subash Khushu","doi":"10.1016/j.neuint.2024.105915","DOIUrl":"10.1016/j.neuint.2024.105915","url":null,"abstract":"<div><div>The disturbances in thyroid hormones lead to altered brain metabolism, function, and cognition. Neuroimaging studies have shown structural and functional changes in hypothyroidism. Present study investigates the neuro-metabolite changes in dorsolateral prefrontal cortex (DLPFC) and posterior parietal cortex (PPC) and associated decline cognitive function in hypothyroid patients before and after thyroxine treatment. We performed neuropsychological test and <sup>1</sup>H MRS in hypothyroid patients (n = 25) and controls (n = 30). In addition, follow-up data was also collected from 19 patients treated with levo-thyroxine for 32 weeks. The concentration of the neurometabolites were calculated using LCModel. MRS data were analyzed using analysis of covariance (ANCOVA), with age and gender as covariates. A paired <em>t</em>-test was conducted to compare the baseline hypothyroid with the follow-up. Partial correlations were utilised to assess possible associations between neuropsychological scores and neurometabolites with age and gender as covariates. Spearman correlation was performed between thyroid hormone levels and neurometabolites. Hypothyroid patients showed an impairment in delayed recall, immediate recall of semantic, visual retention, recognition of objects memory, attention, and motor function at baseline, which improved significantly after thyroxine therapy. At baseline, patients with hypothyroidism exhibited significantly higher levels of choline compounds (GPC + PCh) [Cho]. No significant normalization of Cho levels was observed, despite achieving euthyroidism with thyroxine treatment. Cho levels showed a positive correlation with TSH in PPC and a negative correlation with T4 in DLPFC and PCC. Cho levels also showed negative correlations with delayed recall, immediate recall of semantic, visual retention memory and MMSE scores. The MRS findings show increased levels of Cho in hypothyroid patients compared to healthy controls. These Cho levels are not reversible within 32 weeks of treatment, suggesting that a longer follow-up may be needed to see if levels can be normalized.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"182 ","pages":"Article 105915"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.neuint.2024.105917
Xinghua Liang , Yuan Hu , Xinyue Li , Xi Xu , Zhonglan Chen , Yalin Han , Yingying Han , Guangping Lang
Phosphoinositide 3-kinase γ (PI3Kγ) is a signaling protein that is constitutively expressed in immune competent cells and plays a crucial role in cell proliferation, apoptosis, migration, deformation, and immunology. Several studies have shown that high expression of PI3Kγ can inhibit the occurrence of inflammation in microglia while also regulating the polarization of microglia to inhibit inflammation and enhance microglial migration and phagocytosis. It is well known that the regulation of microglial polarization, migration, and phagocytosis is key to the treatment of most neurodegenerative diseases. Therefore, in this article, we review the important regulatory role of PI3Kγ in microglia to provide a basis for the treatment of neurodegenerative diseases.
{"title":"Role of PI3Kγ in the polarization, migration, and phagocytosis of microglia","authors":"Xinghua Liang , Yuan Hu , Xinyue Li , Xi Xu , Zhonglan Chen , Yalin Han , Yingying Han , Guangping Lang","doi":"10.1016/j.neuint.2024.105917","DOIUrl":"10.1016/j.neuint.2024.105917","url":null,"abstract":"<div><div>Phosphoinositide 3-kinase γ (PI3Kγ) is a signaling protein that is constitutively expressed in immune competent cells and plays a crucial role in cell proliferation, apoptosis, migration, deformation, and immunology. Several studies have shown that high expression of PI3Kγ can inhibit the occurrence of inflammation in microglia while also regulating the polarization of microglia to inhibit inflammation and enhance microglial migration and phagocytosis. It is well known that the regulation of microglial polarization, migration, and phagocytosis is key to the treatment of most neurodegenerative diseases. Therefore, in this article, we review the important regulatory role of PI3Kγ in microglia to provide a basis for the treatment of neurodegenerative diseases.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"182 ","pages":"Article 105917"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.neuint.2024.105914
Jiaxin Li , Gaimei Hao , Yupeng Yan , Ming Li , Gaifen Li , Zhengmin Lu , Zhibo Sun , Yanjing Chen , Haixia Liu , Yukun Zhao , Meng Wu , Xiangxin Bao , Yong Wang , Yubo Li
Background and purpose
The field of hydrogen medicine has garnered extensive attention since Professor Ohsawa established that low concentrations of hydrogen (2%–4%) exert antioxidant effects. The present study aimed to evaluate the therapeutic effect of molecular hydrogen in a CUMS rat model.
Methods
A total of 40 SD rats were randomly divided into a control group, a model group, a hydrogen group, and a positive drug group. Four weeks post-modeling, hydrogen inhalation and other treatments were administered. Behavioral, biochemical, and immunohistochemical evaluations were performed after treatment.
Results
Hydrogen inhalation alleviated depressive behavior and hippocampal neuronal damage in CUMS rats, as well as restored the levels of neurotransmitters, inflammatory factors, and oxidative stress. Moreover, it maintained mitochondrial homeostasis and up-regulated the expression of PGC-1α, PINK1, and Parkin.
Conclusions
The results collectively indicated that hydrogen significantly attenuated CUMS-induced depressive-like behavior and monoamine neurotransmitter deficiency, as well as protected the brain from oxidative stress and inflammatory damage and effectively preserved mitochondrial homeostasis.
{"title":"Hydrogen restores central tryptophan and metabolite levels and maintains mitochondrial homeostasis to protect rats from chronic mild unpredictable stress damage","authors":"Jiaxin Li , Gaimei Hao , Yupeng Yan , Ming Li , Gaifen Li , Zhengmin Lu , Zhibo Sun , Yanjing Chen , Haixia Liu , Yukun Zhao , Meng Wu , Xiangxin Bao , Yong Wang , Yubo Li","doi":"10.1016/j.neuint.2024.105914","DOIUrl":"10.1016/j.neuint.2024.105914","url":null,"abstract":"<div><h3>Background and purpose</h3><div>The field of hydrogen medicine has garnered extensive attention since Professor Ohsawa established that low concentrations of hydrogen (2%–4%) exert antioxidant effects. The present study aimed to evaluate the therapeutic effect of molecular hydrogen in a CUMS rat model.</div></div><div><h3>Methods</h3><div>A total of 40 SD rats were randomly divided into a control group, a model group, a hydrogen group, and a positive drug group. Four weeks post-modeling, hydrogen inhalation and other treatments were administered. Behavioral, biochemical, and immunohistochemical evaluations were performed after treatment.</div></div><div><h3>Results</h3><div>Hydrogen inhalation alleviated depressive behavior and hippocampal neuronal damage in CUMS rats, as well as restored the levels of neurotransmitters, inflammatory factors, and oxidative stress. Moreover, it maintained mitochondrial homeostasis and up-regulated the expression of PGC-1α, PINK1, and Parkin.</div></div><div><h3>Conclusions</h3><div>The results collectively indicated that hydrogen significantly attenuated CUMS-induced depressive-like behavior and monoamine neurotransmitter deficiency, as well as protected the brain from oxidative stress and inflammatory damage and effectively preserved mitochondrial homeostasis.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"182 ","pages":"Article 105914"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Diabetic peripheral neuropathy, characterized by symptoms such as paresthesia, neuropathic pain, and potential lower limb amputation, poses significant clinical management challenges. Recent studies suggest that chronic hyperglycemia-induced Schwann cells (SCs) apoptosis contributes to neurodegeneration and impaired nerve regeneration, but the detailed mechanisms are still unknown. Our study investigated a mixed-sex type 2 diabetes mellitus (T2DM) rat model using leptin knockout (KO) to simulate obesity and diabetes-related conditions. Through extensive assessments, including mechanical allodynia, electrophysiology, and microcirculation analyses, along with myelin degradation studies in KO versus wild-type rats, we focused on apoptosis, autophagy, and SCs dedifferentiation in the sciatic nerve and examined nerve regeneration in KO rats. KO rats exhibited notable reductions in mechanical withdrawal force, prolonged latency, decreased compound muscle action potential (CMAP) amplitude, reduced microcirculation, myelin sheath damage, and increases in apoptosis, autophagy, and SCs dedifferentiation. Moreover, leptin KO was found to impair peripheral nerve regeneration postinjury, as indicated by reduced muscle weight, lower CMAP amplitude, extended latency, and decreased remyelination and SCs density. These findings underscore the effectiveness of the T2DM rat model in clarifying the impact of leptin KO on SCs apoptosis, dedifferentiation, and demyelination, providing valuable insights into new therapeutic avenues for treating T2DM-induced peripheral neuropathy.
{"title":"Leptin deficiency leads to nerve degeneration and impairs axon remyelination by inducing Schwann cell apoptosis and demyelination in type 2 diabetic peripheral neuropathy in rats","authors":"Yuan-Shuo Hsueh , Szu-Han Chen , Wan-Ling Tseng , Sheng-Che Lin , De-Quan Chen , Chih-Chung Huang , Yuan-Yu Hsueh","doi":"10.1016/j.neuint.2024.105908","DOIUrl":"10.1016/j.neuint.2024.105908","url":null,"abstract":"<div><div>Diabetic peripheral neuropathy, characterized by symptoms such as paresthesia, neuropathic pain, and potential lower limb amputation, poses significant clinical management challenges. Recent studies suggest that chronic hyperglycemia-induced Schwann cells (SCs) apoptosis contributes to neurodegeneration and impaired nerve regeneration, but the detailed mechanisms are still unknown. Our study investigated a mixed-sex type 2 diabetes mellitus (T2DM) rat model using leptin knockout (KO) to simulate obesity and diabetes-related conditions. Through extensive assessments, including mechanical allodynia, electrophysiology, and microcirculation analyses, along with myelin degradation studies in KO versus wild-type rats, we focused on apoptosis, autophagy, and SCs dedifferentiation in the sciatic nerve and examined nerve regeneration in KO rats. KO rats exhibited notable reductions in mechanical withdrawal force, prolonged latency, decreased compound muscle action potential (CMAP) amplitude, reduced microcirculation, myelin sheath damage, and increases in apoptosis, autophagy, and SCs dedifferentiation. Moreover, leptin KO was found to impair peripheral nerve regeneration postinjury, as indicated by reduced muscle weight, lower CMAP amplitude, extended latency, and decreased remyelination and SCs density. These findings underscore the effectiveness of the T2DM rat model in clarifying the impact of leptin KO on SCs apoptosis, dedifferentiation, and demyelination, providing valuable insights into new therapeutic avenues for treating T2DM-induced peripheral neuropathy.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"182 ","pages":"Article 105908"},"PeriodicalIF":4.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142745657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-23DOI: 10.1016/j.neuint.2024.105907
Martyna Nalepa , Beata Toczyłowska , Aleksandra Owczarek , Aleksandra Skweres , Elżbieta Ziemińska , Michał Węgrzynowicz
Arginase 2 (Arg2) is the predominant arginase isoenzyme in the brain, however its distribution appears to be limited to selected, region-specific subpopulations of cells. Although striatum is highly enriched with Arg2, precise localization and function of striatal Arg2 have never been studied. Here, we confirm that Arg2 is the only arginase isoenzyme in the striatum, and, using genetic model of total Arg2 loss, we show that Arg2 in this region is fully responsible for arginase catalytic activity, and its loss doesn't induce compensatory activation of Arg1. We exhibit that Arg2 is present in medium spiny neurons (MSNs), striatum-specific projecting neurons, where it localizes in soma and neuronal processes, and is absent in astrocytes or microglia. Finally, analysis of NMR spectroscopy-measured metabolic profiles of striata of Arg2-null mice enabled to recognize two metabolites (NADH and malonic acid) to be significantly altered compared to control animals. Multivariate comparison of the data using orthogonal projections to latent structures discriminant analysis, allowed for discrimination between control and Arg2-null mice and identified metabolites that contributed the most to this between-group dissimilarity. Our study reveals for the first time the localization of Arg2 in MSNs and demonstrates significant role of this enzyme in regulating striatal metabolism. These findings may be especially interesting in the context of Huntington's disease (HD), a disorder that specifically affects MSNs and in which, with the use of mouse models, the onset of pathological phenotypes was recently shown to be preceded by progressive impairment of striatal Arg2, a phenomenon of an unknown significance for disease pathogenesis.
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