Pub Date : 2025-02-19DOI: 10.1016/j.neuint.2025.105951
Cheng-Wei Lu , Tzu-Yu Lin , Kun-Chieh Yeh , Pei‐Wen Hsieh , Kuan-Ming Chiu , Ming-Yi Lee , Su-Jane Wang
This study aimed to investigate whether lupeol, a pentacyclic triterpenoid, affects glutamate release in isolated nerve terminals (synaptosomes) from the rat cerebral cortex and whether lupeol affects the excitotoxicity induced by kainic acid (KA) in rats. In rat cerebrocortical synaptosomes, lupeol reduced glutamate release in a manner that could be blocked by extracellular Ca2+-free medium or P/Q-type Ca2+ channel antagonism. The synaptosomal membrane potential was not affected by lupeol treatment. Docking data also revealed that lupeol formed a hydrogen bond with amino acid residues of the P/Q-type Ca2+ channel. In the KA-induced acute excitotoxicity model, lupeol pretreatment ameliorated cortical neurodegeneration and downregulated the expression of glutamate release-related proteins vesicular glutamate transporter 1 (VGLUT1) and phospho-synapsin I, thereby reducing the glutamate levels in the cortices of rats. Our findings suggest that lupeol may exert a neuroprotective effect by reducing glutamate excitotoxicity through the inhibition of presynaptic glutamate release. These results indicate that lupeol could be a promising candidate for the treatment of glutamatergic excitotoxicity and related neurological diseases.
{"title":"Reduction in presynaptic glutamate release and the prevention of glutamate excitotoxicity by lupeol in rats","authors":"Cheng-Wei Lu , Tzu-Yu Lin , Kun-Chieh Yeh , Pei‐Wen Hsieh , Kuan-Ming Chiu , Ming-Yi Lee , Su-Jane Wang","doi":"10.1016/j.neuint.2025.105951","DOIUrl":"10.1016/j.neuint.2025.105951","url":null,"abstract":"<div><div>This study aimed to investigate whether lupeol, a pentacyclic triterpenoid, affects glutamate release in isolated nerve terminals (synaptosomes) from the rat cerebral cortex and whether lupeol affects the excitotoxicity induced by kainic acid (KA) in rats. In rat cerebrocortical synaptosomes, lupeol reduced glutamate release in a manner that could be blocked by extracellular Ca<sup>2+</sup>-free medium or P/Q-type Ca<sup>2+</sup> channel antagonism. The synaptosomal membrane potential was not affected by lupeol treatment. Docking data also revealed that lupeol formed a hydrogen bond with amino acid residues of the P/Q-type Ca<sup>2+</sup> channel. In the KA-induced acute excitotoxicity model, lupeol pretreatment ameliorated cortical neurodegeneration and downregulated the expression of glutamate release-related proteins vesicular glutamate transporter 1 (VGLUT1) and phospho-synapsin I, thereby reducing the glutamate levels in the cortices of rats. Our findings suggest that lupeol may exert a neuroprotective effect by reducing glutamate excitotoxicity through the inhibition of presynaptic glutamate release. These results indicate that lupeol could be a promising candidate for the treatment of glutamatergic excitotoxicity and related neurological diseases.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"185 ","pages":"Article 105951"},"PeriodicalIF":4.4,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472084","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 : 2025-02-18DOI: 10.1016/j.neuint.2025.105946
Ye-ji Yu , Mujeeb Ur Rahman , Rengasamy Balakrishnan , Jong-Min Kim , Jae Ho Kim , Dong-Kug Choi
Microglial-mediated neuroinflammation significantly impacts cognitive impairment, and modulating neuroinflammatory responses has emerged as a promising target for treatment. However, the specific role of microglial-mediated neuroinflammation in cognitive impairment associated with Alzheimer's disease (AD) remains unclear. In our continuous endeavors to seek potent anti-Alzheimer's agents, we recently synthesized and developed a series of peptidomimetic compounds, including dipeptide-68 bis-cyclohexylpropyl histidinamide (DBCH), derived from a caryopsis-1 peptide that has demonstrated anti-inflammatory and anti-microbial properties in various infectious diseases. Among the bioactive peptides synthesized, DBCH exhibited good neuroprotective and anti-inflammatory activity and high potency. Therefore, in this study, the neuroprotective and anti-inflammatory effects of DBCH were assessed in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and a scopolamine-induced C57BL/6 N amnesic mouse model. In the in vitro study, DBCH effectively suppressed the production and expression of nitric oxide (NO) and proinflammatory cytokines in BV-2 microglial cells stimulated with LPS. Furthermore, it effectively inhibited the LPS-triggered phosphorylation and activation of NF-κB/MAPK signaling and modulated inflammatory mediators, including iNOS and COX-2, in BV-2 microglial cells. In vivo results showed that DBCH administration of 5 or 10 mg/kg improved spatial memory learning and cognitive function in scopolamine-induced amnesic mice. Furthermore, DBCH treatment upregulated phosphorylated cAMP-response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) levels and downregulated the inflammatory response. Overall, DBCH effectively prevented both scopolamine-induced cognitive impairment and neuroinflammation. Our research findings suggest that DBCH may serve as a medication for cognitive decline associated with AD.
{"title":"The novel peptide DBCH reduces LPS-stimulated NF-κB/MAPK signaling in BV-2 microglia and ameliorates cognitive impairment in scopolamine-treated mice by modulating BDNF/CREB","authors":"Ye-ji Yu , Mujeeb Ur Rahman , Rengasamy Balakrishnan , Jong-Min Kim , Jae Ho Kim , Dong-Kug Choi","doi":"10.1016/j.neuint.2025.105946","DOIUrl":"10.1016/j.neuint.2025.105946","url":null,"abstract":"<div><div>Microglial-mediated neuroinflammation significantly impacts cognitive impairment, and modulating neuroinflammatory responses has emerged as a promising target for treatment. However, the specific role of microglial-mediated neuroinflammation in cognitive impairment associated with Alzheimer's disease (AD) remains unclear. In our continuous endeavors to seek potent anti-Alzheimer's agents, we recently synthesized and developed a series of peptidomimetic compounds, including dipeptide-68 bis-cyclohexylpropyl histidinamide (DBCH), derived from a caryopsis-1 peptide that has demonstrated anti-inflammatory and anti-microbial properties in various infectious diseases. Among the bioactive peptides synthesized, DBCH exhibited good neuroprotective and anti-inflammatory activity and high potency. Therefore, in this study, the neuroprotective and anti-inflammatory effects of DBCH were assessed in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and a scopolamine-induced C57BL/6 N amnesic mouse model. In the <em>in vitro</em> study, DBCH effectively suppressed the production and expression of nitric oxide (NO) and proinflammatory cytokines in BV-2 microglial cells stimulated with LPS. Furthermore, it effectively inhibited the LPS-triggered phosphorylation and activation of NF-κB/MAPK signaling and modulated inflammatory mediators, including iNOS and COX-2, in BV-2 microglial cells. <em>In vivo</em> results showed that DBCH administration of 5 or 10 mg/kg improved spatial memory learning and cognitive function in scopolamine-induced amnesic mice. Furthermore, DBCH treatment upregulated phosphorylated cAMP-response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) levels and downregulated the inflammatory response. Overall, DBCH effectively prevented both scopolamine-induced cognitive impairment and neuroinflammation. Our research findings suggest that DBCH may serve as a medication for cognitive decline associated with AD.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"185 ","pages":"Article 105946"},"PeriodicalIF":4.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456385","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 : 2025-02-17DOI: 10.1016/j.neuint.2025.105950
Hao Tang , Jun Wen , Ling Wang , Qinghuan Yang , Ting Qin , Yu Ren , Yong Zhao , Changqing Li , Jiani Li , Hui Cao , Jianfeng Xu , Qin Yang
Vagus nerve stimulation (VNS) can promote neurofunctional recovery following cerebral ischemic stroke (CIS), but the underlying mechanism remains unclear. PANoptosis, a novel form of inflammatory programmed cell death, may play a role in the progression of CIS. Our previous studies have indicated that Sirt1 exerts neuroprotection against CIS by modulating various programmed cell death pathways. It needs to be clarified whether and how VNS regulates PANoptosis through Sirt1, thereby affecting the recovery of CIS. This study aims to clarify the role of VNS in modulating neuronal PANoptosis following CIS, and elucidate its underlying mechanisms. Models of middle cerebral artery occlusion/reperfusion (MCAO/R) in rats and oxygen-glucose deprivation/reoxygenation (OGD/R) in primary neurons were established to assess the occurrence of neuronal PANoptosis following CIS. Circulating Sirt1 levels were measured in two independent cohorts of acute ischemic stroke (AIS) patients. VNS was administered to activate Sirt1, and its effects on PANoptosis and neurological recovery were evaluated. We found that neuronal PANoptosis was induced following CIS, which was reversed via VNS intervention. Sirt1 levels in serum of AIS patients were significantly increased, and positively correlated with infarct volume and National Institutes of Health Stroke Scale scores. In contrast, Sirt1 was downregulated in brain tissue from rodent models and AIS patients. This discrepancy in expression levels can be attributed to the increased generation of Sirt1 by peripheral macrophages. VNS upregulated Sirt1 expression, while the Sirt1 inhibitor EX527 negated the effects of VNS on PANoptosis, infarct volume, and neurofunctional recovery. These findings indicate that VNS may inhibit PANoptosis and promote neurofunctional recovery following CIS in a Sirt1-dependent manner, which may be a new potential target for stroke therapy. Sirt1 may also serve as a blood biomarker for patient stratification with independent prognostic value in AIS patients.
{"title":"Vagus nerve stimulation inhibits PANoptosis and promotes neurofunctional recovery of cerebral ischemic stroke in a Sirt1-dependent manner","authors":"Hao Tang , Jun Wen , Ling Wang , Qinghuan Yang , Ting Qin , Yu Ren , Yong Zhao , Changqing Li , Jiani Li , Hui Cao , Jianfeng Xu , Qin Yang","doi":"10.1016/j.neuint.2025.105950","DOIUrl":"10.1016/j.neuint.2025.105950","url":null,"abstract":"<div><div>Vagus nerve stimulation (VNS) can promote neurofunctional recovery following cerebral ischemic stroke (CIS), but the underlying mechanism remains unclear. PANoptosis, a novel form of inflammatory programmed cell death, may play a role in the progression of CIS. Our previous studies have indicated that Sirt1 exerts neuroprotection against CIS by modulating various programmed cell death pathways. It needs to be clarified whether and how VNS regulates PANoptosis through Sirt1, thereby affecting the recovery of CIS. This study aims to clarify the role of VNS in modulating neuronal PANoptosis following CIS, and elucidate its underlying mechanisms. Models of middle cerebral artery occlusion/reperfusion (MCAO/R) in rats and oxygen-glucose deprivation/reoxygenation (OGD/R) in primary neurons were established to assess the occurrence of neuronal PANoptosis following CIS. Circulating Sirt1 levels were measured in two independent cohorts of acute ischemic stroke (AIS) patients. VNS was administered to activate Sirt1, and its effects on PANoptosis and neurological recovery were evaluated. We found that neuronal PANoptosis was induced following CIS, which was reversed via VNS intervention. Sirt1 levels in serum of AIS patients were significantly increased, and positively correlated with infarct volume and National Institutes of Health Stroke Scale scores. In contrast, Sirt1 was downregulated in brain tissue from rodent models and AIS patients. This discrepancy in expression levels can be attributed to the increased generation of Sirt1 by peripheral macrophages. VNS upregulated Sirt1 expression, while the Sirt1 inhibitor EX527 negated the effects of VNS on PANoptosis, infarct volume, and neurofunctional recovery. These findings indicate that VNS may inhibit PANoptosis and promote neurofunctional recovery following CIS in a Sirt1-dependent manner, which may be a new potential target for stroke therapy. Sirt1 may also serve as a blood biomarker for patient stratification with independent prognostic value in AIS patients.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"184 ","pages":"Article 105950"},"PeriodicalIF":4.4,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436682","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 : 2025-02-14DOI: 10.1016/j.neuint.2025.105947
Nasif Hussain , Mohd Moin Khan , Ayushi Sharma , Rakesh K. Singh , Rizwan Hasan Khan
The interplay between immune cell dysfunction and associated neuroinflammation plays a critical role in the pathogenesis of Alzheimer's disease. Neuroinflammation, orchestrated by microglia and peripheral immune cells, exacerbates synaptic dysfunction and neurodegeneration in AD. Emerging evidence suggests a systemic immune response in AD, challenging traditional views of neurocentric pathology. Therapeutic strategies targeting neuroinflammation hold promise, yet translating preclinical findings into clinical success remains elusive. This article presents recent advances in AD scientific studies, highlighting the pivotal role of immune cell dysfunction and signaling pathways in disease progression. We also discussed therapeutic studies targeting immune cell dysregulation, as treatment methods. This advocates for a paradigm shift towards holistic approaches that integrate peripheral and central immune responses, fostering a comprehensive understanding of AD pathophysiology and paving the way for transformative interventions.
{"title":"Beyond plaques and tangles: The role of immune cell dysfunction in Alzheimer's disease","authors":"Nasif Hussain , Mohd Moin Khan , Ayushi Sharma , Rakesh K. Singh , Rizwan Hasan Khan","doi":"10.1016/j.neuint.2025.105947","DOIUrl":"10.1016/j.neuint.2025.105947","url":null,"abstract":"<div><div>The interplay between immune cell dysfunction and associated neuroinflammation plays a critical role in the pathogenesis of Alzheimer's disease. Neuroinflammation, orchestrated by microglia and peripheral immune cells, exacerbates synaptic dysfunction and neurodegeneration in AD. Emerging evidence suggests a systemic immune response in AD, challenging traditional views of neurocentric pathology. Therapeutic strategies targeting neuroinflammation hold promise, yet translating preclinical findings into clinical success remains elusive. This article presents recent advances in AD scientific studies, highlighting the pivotal role of immune cell dysfunction and signaling pathways in disease progression. We also discussed therapeutic studies targeting immune cell dysregulation, as treatment methods. This advocates for a paradigm shift towards holistic approaches that integrate peripheral and central immune responses, fostering a comprehensive understanding of AD pathophysiology and paving the way for transformative interventions.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"184 ","pages":"Article 105947"},"PeriodicalIF":4.4,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143430226","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 : 2025-02-13DOI: 10.1016/j.neuint.2025.105948
K P Mohanakumar, Catarina Rendeiro, Philip M Beart
The editors in assembling this Special Issue, "Neuro-nutraceuticals: Emerging Molecular and Functional Insights into how Natural Products Improve Brain Health", sought to advance our understanding of how such chemical entities alone or in group maintain brain metabolism and homeostasis so that neurons, glia and endothelial cells are healthy during development, ageing and in neuropathologies. The growth of interest in neuro-nutraceuticals and all aspects of their actions relevant to the health of the nervous system continues to amaze all. This Special Issue # 4 contains 39 articles, and we sought to highlight in this Special Issue important new advances and key issues pertinent to future clinical application of neuro-nutraceuticals. The diversity of topics covered is quite broad and includes significant articles on enteric microbiome and brain health. The Editors have tried to provide an up-to-date account of how nutraceuticals work at the molecular and cellular level, and what are the known molecular targets that ultimately can be leveraged clinically to enable the brain to function better. With respect to brain ailments and treatments, single molecule effects, and a therapeutic group of molecules from dietary herbals are discussed in this Special Issue.
{"title":"Neuro-nutraceuticals: Emerging molecular and functional insights into how natural products improve brain health.","authors":"K P Mohanakumar, Catarina Rendeiro, Philip M Beart","doi":"10.1016/j.neuint.2025.105948","DOIUrl":"10.1016/j.neuint.2025.105948","url":null,"abstract":"<p><p>The editors in assembling this Special Issue, \"Neuro-nutraceuticals: Emerging Molecular and Functional Insights into how Natural Products Improve Brain Health\", sought to advance our understanding of how such chemical entities alone or in group maintain brain metabolism and homeostasis so that neurons, glia and endothelial cells are healthy during development, ageing and in neuropathologies. The growth of interest in neuro-nutraceuticals and all aspects of their actions relevant to the health of the nervous system continues to amaze all. This Special Issue # 4 contains 39 articles, and we sought to highlight in this Special Issue important new advances and key issues pertinent to future clinical application of neuro-nutraceuticals. The diversity of topics covered is quite broad and includes significant articles on enteric microbiome and brain health. The Editors have tried to provide an up-to-date account of how nutraceuticals work at the molecular and cellular level, and what are the known molecular targets that ultimately can be leveraged clinically to enable the brain to function better. With respect to brain ailments and treatments, single molecule effects, and a therapeutic group of molecules from dietary herbals are discussed in this Special Issue.</p>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":" ","pages":"105948"},"PeriodicalIF":4.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424638","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 : 2025-02-04DOI: 10.1016/j.neuint.2025.105940
Yufei Wang , Youfei Zhou , Jinhao Liu , Chen Liu , Zirui Li , Xuehua Sun
Background
Macrophage phenotype transformation is vital in sciatic nerve injury. The study of biomolecule expression and its impact on macrophage phenotype transformation is a current research focus.
Material and methods
We created a rat model of sciatic nerve compression injury to examine the expression of PDE4B and the distribution of M1 and M2 macrophages over time and their relationship. We confirmed the effect of inhibiting PDE4B expression on macrophage phenotype changes and its role in sciatic nerve injury repair. The experiments consisted of immunofluorescence, western blotting, HE staining, TEM, and behavioral evaluation. Investigate in vivo experiment results with RAW264.7 cells in vitro. PDE4B knockdown lentivirus was transfected into RAW264.7 cells and stimulated with LPS and IFN-γ. We assessed CD86 and CD206 expression using flow cytometry and western blot. The relationship between PDE4B and the TLR4/NF-κB pathway was studied.
Results
PDE4B peaked on day 7 after surgery, alongside the highest M1 macrophages count. PDE4B and M1 macrophages decreased, and M2 macrophages increased. PDE4B inhibition reduced M1 macrophages, increased M2 macrophages, suppressed inflammation, and promoted sciatic nerve repair while alleviating pain. In vitro experiments confirmed that PDE4B regulated macrophage phenotype via the TLR4/NF-κB pathway. Inhibiting PDE4B disrupted this pathway and promoted M2 macrophage transformation.
Conclusions
In the sciatic nerve injury, PDE4B expression is linked to the M1 macrophage phenotype. Low PDE4B expression facilitates the M1 to M2 macrophage transformation and supports sciatic nerve repair. The TLR4/NF-κB pathway is involved in this process.
{"title":"Temporal and spatial expression of Phosphodiesterase-4B after sciatic nerve compression in rats and its mechanism of action on sciatic nerve repair","authors":"Yufei Wang , Youfei Zhou , Jinhao Liu , Chen Liu , Zirui Li , Xuehua Sun","doi":"10.1016/j.neuint.2025.105940","DOIUrl":"10.1016/j.neuint.2025.105940","url":null,"abstract":"<div><h3>Background</h3><div>Macrophage phenotype transformation is vital in sciatic nerve injury. The study of biomolecule expression and its impact on macrophage phenotype transformation is a current research focus.</div></div><div><h3>Material and methods</h3><div>We created a rat model of sciatic nerve compression injury to examine the expression of PDE4B and the distribution of M1 and M2 macrophages over time and their relationship. We confirmed the effect of inhibiting PDE4B expression on macrophage phenotype changes and its role in sciatic nerve injury repair. The experiments consisted of immunofluorescence, western blotting, HE staining, TEM, and behavioral evaluation. Investigate in vivo experiment results with RAW264.7 cells in vitro. PDE4B knockdown lentivirus was transfected into RAW264.7 cells and stimulated with LPS and IFN-γ. We assessed CD86 and CD206 expression using flow cytometry and western blot. The relationship between PDE4B and the TLR4/NF-κB pathway was studied.</div></div><div><h3>Results</h3><div>PDE4B peaked on day 7 after surgery, alongside the highest M1 macrophages count. PDE4B and M1 macrophages decreased, and M2 macrophages increased. PDE4B inhibition reduced M1 macrophages, increased M2 macrophages, suppressed inflammation, and promoted sciatic nerve repair while alleviating pain. In vitro experiments confirmed that PDE4B regulated macrophage phenotype via the TLR4/NF-κB pathway. Inhibiting PDE4B disrupted this pathway and promoted M2 macrophage transformation.</div></div><div><h3>Conclusions</h3><div>In the sciatic nerve injury, PDE4B expression is linked to the M1 macrophage phenotype. Low PDE4B expression facilitates the M1 to M2 macrophage transformation and supports sciatic nerve repair. The TLR4/NF-κB pathway is involved in this process.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"185 ","pages":"Article 105940"},"PeriodicalIF":4.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363500","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 : 2025-02-03DOI: 10.1016/j.neuint.2025.105939
Shamseldin Metwally , Okan Capuk , Jun Wang , Mohammad Iqbal H. Bhuiyan , Qiang Li , Kathiravan Kaliyappan , Bo Chen , Daryl Fields , Dandan Sun
Background
Recent evidence suggests extra-cortical adaptations within the cerebellum may contribute to motor recovery in patients with cortical ischemic strokes. The molecular/cellular adaptations enabling this effect to have not been identified. Chloride transport proteins (NKCC1 and KCC2) are important regulators of neuronal transmission and may underlie adaptive changes following ischemic stroke.
Objective
Examine changes in cerebellar NKCC1 and KCC2 protein expression following cortical ischemic stroke.
Methods
Adult C57BL/6J male mice underwent sham or the left middle cerebral artery occlusion (tMCAo)-induced ischemic stroke. Changes of NKCC1 and KCC2 proteins within the deep cerebellar nuclei (DCN) were assessed by immunofluorescence staining.
Results
tMCAo induced selective infarct lesion in the left striatum and cortex of the stroke mice but not in other brain regions including cerebellum. The inwardly directed chloride transporter NKCC1 was equivocally expressed within bi-hemispheric DCN of both sham control and stroke mice. In contrast, the outwardly directed chloride transporter KCC2 protein expression was significantly higher in the bi-hemispheric DCN of stroke brains, compared to sham controls. Double immunostaining analysis revealed a statistically significant increase in KCC2 intensity within VGLUT-1+ neurons of the ipsilateral DCN of the stroke mice, but not in the VGAT+ neurons.
Conclusions
Ischemic cortical stroke stimulates KCC2 protein expression in the DCN VGLUT-1+ neurons, without a change in NKCC1 protein expression.
{"title":"Cerebellum KCC2 protein expression plasticity in response to cerebral cortical stroke","authors":"Shamseldin Metwally , Okan Capuk , Jun Wang , Mohammad Iqbal H. Bhuiyan , Qiang Li , Kathiravan Kaliyappan , Bo Chen , Daryl Fields , Dandan Sun","doi":"10.1016/j.neuint.2025.105939","DOIUrl":"10.1016/j.neuint.2025.105939","url":null,"abstract":"<div><h3>Background</h3><div>Recent evidence suggests extra-cortical adaptations within the cerebellum may contribute to motor recovery in patients with cortical ischemic strokes. The molecular/cellular adaptations enabling this effect to have not been identified. Chloride transport proteins (NKCC1 and KCC2) are important regulators of neuronal transmission and may underlie adaptive changes following ischemic stroke.</div></div><div><h3>Objective</h3><div>Examine changes in cerebellar NKCC1 and KCC2 protein expression following cortical ischemic stroke.</div></div><div><h3>Methods</h3><div>Adult C57BL/6J male mice underwent sham or the left middle cerebral artery occlusion (tMCAo)-induced ischemic stroke. Changes of NKCC1 and KCC2 proteins within the deep cerebellar nuclei (DCN) were assessed by immunofluorescence staining.</div></div><div><h3>Results</h3><div>tMCAo induced selective infarct lesion in the left striatum and cortex of the stroke mice but not in other brain regions including cerebellum. The inwardly directed chloride transporter NKCC1 was equivocally expressed within bi-hemispheric DCN of both sham control and stroke mice. In contrast, the outwardly directed chloride transporter KCC2 protein expression was significantly higher in the bi-hemispheric DCN of stroke brains, compared to sham controls. Double immunostaining analysis revealed a statistically significant increase in KCC2 intensity within VGLUT-1<sup>+</sup> neurons of the ipsilateral DCN of the stroke mice, but not in the VGAT<sup>+</sup> neurons.</div></div><div><h3>Conclusions</h3><div>Ischemic cortical stroke stimulates KCC2 protein expression in the DCN VGLUT-1<sup>+</sup> neurons, without a change in NKCC1 protein expression.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"184 ","pages":"Article 105939"},"PeriodicalIF":4.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254027","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 : 2025-02-02DOI: 10.1016/j.neuint.2025.105938
Qianqian Gao , Muhammad Asim
The endocannabinoid system (ECS) is crucial in the pathophysiology of mental disorders. Historically, cannabis has been utilized for centuries to mitigate symptoms of anxiety and depression; however, the precise role of cannabinoids in these conditions has only recently garnered extensive research attention. Despite the growing body of literature on the ECS and its association with mental health, several critical questions remain unresolved. This review primarily focuses on cannabinoid CB1 receptors (CB1R), providing an examination of their regulatory roles in states related to mental disorders. Evidence suggests that CB1R distribution occurs among various neuronal types, astrocytes, and subcellular membranes across multiple brain regions, potentially exhibiting both analogous and antagonistic effects. Additionally, various forms of stress have been shown to produce divergent impacts on CB1R signaling pathways. Furthermore, numerous CB1R agonists demonstrate biphasic, dose-dependent effects on anxiety and depression; specifically, low doses may exert anxiolytic effects, while higher doses can induce anxiogenic responses, a phenomenon observed in both rodent models and human studies. We also discuss the diverse underlying mechanisms that mediate these effects. We anticipate that this review will yield valuable insights into the role of CB1R in mental disorders and provide a framework for future research endeavors on CB1R and the ECS. This knowledge may ultimately inform therapeutic strategies aimed at alleviating symptoms associated with mental health conditions.
{"title":"CB1 receptor signaling: Linking neuroplasticity, neuronal types, and mental health outcomes","authors":"Qianqian Gao , Muhammad Asim","doi":"10.1016/j.neuint.2025.105938","DOIUrl":"10.1016/j.neuint.2025.105938","url":null,"abstract":"<div><div>The endocannabinoid system (ECS) is crucial in the pathophysiology of mental disorders. Historically, cannabis has been utilized for centuries to mitigate symptoms of anxiety and depression; however, the precise role of cannabinoids in these conditions has only recently garnered extensive research attention. Despite the growing body of literature on the ECS and its association with mental health, several critical questions remain unresolved. This review primarily focuses on cannabinoid CB<sub>1</sub> receptors (CB<sub>1</sub>R), providing an examination of their regulatory roles in states related to mental disorders. Evidence suggests that CB<sub>1</sub>R distribution occurs among various neuronal types, astrocytes, and subcellular membranes across multiple brain regions, potentially exhibiting both analogous and antagonistic effects. Additionally, various forms of stress have been shown to produce divergent impacts on CB<sub>1</sub>R signaling pathways. Furthermore, numerous CB<sub>1</sub>R agonists demonstrate biphasic, dose-dependent effects on anxiety and depression; specifically, low doses may exert anxiolytic effects, while higher doses can induce anxiogenic responses, a phenomenon observed in both rodent models and human studies. We also discuss the diverse underlying mechanisms that mediate these effects. We anticipate that this review will yield valuable insights into the role of CB<sub>1</sub>R in mental disorders and provide a framework for future research endeavors on CB<sub>1</sub>R and the ECS. This knowledge may ultimately inform therapeutic strategies aimed at alleviating symptoms associated with mental health conditions.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"184 ","pages":"Article 105938"},"PeriodicalIF":4.4,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187730","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 : 2025-02-01DOI: 10.1016/j.neuint.2025.105929
Yufen Tang , Lu Zhang , Peng Huang , Zhou She , Senlin Luo , Hong Peng , Yuqiong Chen , Jinwen Luo , Wangxin Duan , Yangyang Xiao , Lingjuan Liu , Liqun Liu
The term “circadian rhythm” refers to the 24-h oscillations found in various physiological processes in organisms, responsible for maintaining bodily homeostasis. Many neurological diseases mainly involve the process of demyelination, and remyelination is crucial for the treatment of neurological diseases. Current research mainly focuses on the key role of circadian clocks in the pathophysiological mechanisms of multiple sclerosis. Various studies have shown that the circadian rhythm regulates various cellular molecular mechanisms and signaling pathways involved in remyelination. The process of remyelination is primarily mediated by oligodendrocyte precursor cells (OPCs), oligodendrocytes, microglia, and astrocytes. OPCs are activated, proliferate, migrate, and ultimately differentiate into oligodendrocytes after demyelination, involving many key signaling pathway and regulatory factors. Activated microglia secretes important cytokines and chemokines, promoting OPC proliferation and differentiation, and phagocytoses myelin debris that inhibits remyelination. Astrocytes play a crucial role in supporting remyelination by secreting signals that promote remyelination or facilitate the phagocytosis of myelin debris by microglia. Additionally, cell-to-cell communication via gap junctions allows for intimate contact between astrocytes and oligodendrocytes, providing metabolic support for oligodendrocytes. Therefore, gaining a deeper understanding of the mechanisms and molecular pathways of the circadian rhythm at various stages of remyelination can help elucidate the fundamental characteristics of remyelination and provide insights into treating demyelinating disorders.
{"title":"Understanding the intricacies of cellular mechanisms in remyelination: The role of circadian rhythm","authors":"Yufen Tang , Lu Zhang , Peng Huang , Zhou She , Senlin Luo , Hong Peng , Yuqiong Chen , Jinwen Luo , Wangxin Duan , Yangyang Xiao , Lingjuan Liu , Liqun Liu","doi":"10.1016/j.neuint.2025.105929","DOIUrl":"10.1016/j.neuint.2025.105929","url":null,"abstract":"<div><div>The term “circadian rhythm” refers to the 24-h oscillations found in various physiological processes in organisms, responsible for maintaining bodily homeostasis. Many neurological diseases mainly involve the process of demyelination, and remyelination is crucial for the treatment of neurological diseases. Current research mainly focuses on the key role of circadian clocks in the pathophysiological mechanisms of multiple sclerosis. Various studies have shown that the circadian rhythm regulates various cellular molecular mechanisms and signaling pathways involved in remyelination. The process of remyelination is primarily mediated by oligodendrocyte precursor cells (OPCs), oligodendrocytes, microglia, and astrocytes. OPCs are activated, proliferate, migrate, and ultimately differentiate into oligodendrocytes after demyelination, involving many key signaling pathway and regulatory factors. Activated microglia secretes important cytokines and chemokines, promoting OPC proliferation and differentiation, and phagocytoses myelin debris that inhibits remyelination. Astrocytes play a crucial role in supporting remyelination by secreting signals that promote remyelination or facilitate the phagocytosis of myelin debris by microglia. Additionally, cell-to-cell communication via gap junctions allows for intimate contact between astrocytes and oligodendrocytes, providing metabolic support for oligodendrocytes. Therefore, gaining a deeper understanding of the mechanisms and molecular pathways of the circadian rhythm at various stages of remyelination can help elucidate the fundamental characteristics of remyelination and provide insights into treating demyelinating disorders.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"183 ","pages":"Article 105929"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930426","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 : 2025-02-01DOI: 10.1016/j.neuint.2024.105922
Lucia Lisi , Alessandro Olivi , Gabriella Maria Pia Ciotti , Salvatore Marino , Chiara Ferraro , Grazia Menna , Maria Martire , Giovanni Pennisi , Pierluigi Navarra , Giuseppe Maria della Pepa
In glioblastoma, glioma-associated microglia/macrophages (GAMs) represent the major population of tumor infiltrating cells, with up to one half of the cells of the tumor mass. Recent studies have shown that microglia are involved in the maintenance of immunological homeostasis and protection against autoimmunity. However, despite the growing body of evidence on the topic, many aspects are yet to be clarified. In our study, 3 different situations emerged concerning the markers of microglial/macrophage-related and other cell types in GBM patients: i) most of the markers (IBA1, TMEM119, CD206 and CD86) show an ascending gradient from the tumor center to the non-tumor/healthy area of the brain; ii) one marker (CD204) shows a descending gradient, going from the center of the tumor to the non-tumor/healthy brain area; iii) two markers (CD163 and P2RY12) show no gradient. These observations support the idea that the magnitude of the diverted inflammation is a ‘extensive’ rather than a ‘local’ phenomenon and that could possibly play a role in disease resistance and relapse.
{"title":"A topographic approach to the markers of macrophage/microglia and other cell types in high grade glioma","authors":"Lucia Lisi , Alessandro Olivi , Gabriella Maria Pia Ciotti , Salvatore Marino , Chiara Ferraro , Grazia Menna , Maria Martire , Giovanni Pennisi , Pierluigi Navarra , Giuseppe Maria della Pepa","doi":"10.1016/j.neuint.2024.105922","DOIUrl":"10.1016/j.neuint.2024.105922","url":null,"abstract":"<div><div>In glioblastoma, glioma-associated microglia/macrophages (GAMs) represent the major population of tumor infiltrating cells, with up to one half of the cells of the tumor mass. Recent studies have shown that microglia are involved in the maintenance of immunological homeostasis and protection against autoimmunity. However, despite the growing body of evidence on the topic, many aspects are yet to be clarified. In our study, 3 different situations emerged concerning the markers of microglial/macrophage-related and other cell types in GBM patients: i) most of the markers (IBA1, TMEM119, CD206 and CD86) show an ascending gradient from the tumor center to the non-tumor/healthy area of the brain; ii) one marker (CD204) shows a descending gradient, going from the center of the tumor to the non-tumor/healthy brain area; iii) two markers (CD163 and P2RY12) show no gradient. These observations support the idea that the magnitude of the diverted inflammation is a ‘extensive’ rather than a ‘local’ phenomenon and that could possibly play a role in disease resistance and relapse.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"183 ","pages":"Article 105922"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902487","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号