Neurochemistry international最新文献

{"title":"The potential of mulberry (Morus alba L.) leaf extract against pro-aggregant tau-mediated inflammation and mitochondrial dysfunction","authors":"Te-Hsien Lin ,&nbsp;Pei-Hsuan Tseng ,&nbsp;I-Cheng Chen ,&nbsp;Chung-Yin Lin ,&nbsp;Ming-Chung Lee ,&nbsp;Kuo-Hsuan Chang ,&nbsp;Guey-Jen Lee-Chen ,&nbsp;Chiung-Mei Chen","doi":"10.1016/j.neuint.2025.106042","DOIUrl":"10.1016/j.neuint.2025.106042","url":null,"abstract":"<div><div>In Alzheimer's disease (AD), Tau aggregates trigger microglial activation to release inflammatory factors and cause mitochondrial dysfunction, oxidative stress, and neuronal damage. With abundant potent antioxidants, mulberry (<em>Morus alba</em> L.) leaf extract has the potential to treat diseases associated with neuroinflammation, mitochondrial dysfunction, and oxidative stress. This study examined the neuroprotective effects of a mulberry leaf extract against pro-aggregant Tau-mediated inflammation and mitochondrial dysfunction in SH-SY5Y cells expressing the ΔK280 Tau repeat domain (Tau_RD). His-tagged ΔK280 Tau_RD fibrils prepared from <em>E. coli</em> activated BV-2 microglia, as revealed by their altered morphology, increased nitric oxide production, and elevated ionized calcium binding adaptor molecule 1 (IBA1) and major histocompatibility complex 2 (MHCII) expression. The mulberry leaf extract suppressed the production of pro-inflammatory mediators, including NO, IL-1β, IL-6, and TNF-α, and the expression of NLR family pyrin domain-containing 3 (NLRP3) and caspase-1 (CASP1) in ΔK280 Tau_RD fibril-stimulated BV-2 cells. Application of conditioned media collected from ΔK280 Tau_RD fibril-activated BV-2 cells induced cellular inflammation in ΔK280 Tau_RD-DsRed-expressing SH-SY5Y cells. The mulberry leaf extract protected these cells by suppressing lactate dehydrogenase (LDH) release, caspase-3 activity, NLR family pyrin domain-containing 1 (NLRP1), CASP1, IL-1β, IL-6, TNF-α, and reactive oxygen species as well as by enhancing neurite outgrowth. In addition, mulberry leaf extract increased mitochondrial membrane potential, lowered mitochondrial superoxide levels, and increased superoxide dismutase 2 (SOD2), NAD(P)H quinone dehydrogenase 1 (NQO1), glutamate-cysteine ligase catalytic subunit (GCLC), and nuclear factor erythroid 2-related factor 2 (NRF2) levels in SH-SY5Y cells. In conclusion, mulberry leaf extract displayed neuroprotective effects by exerting anti-inflammatory and antioxidative activities to ameliorate pathological Tau-mediated mitochondrial dysfunction in a human Tau cell model. The results of this study support the notion that the mulberry leaf extract is a potential disease-modifying therapeutic agent for <span>AD</span>.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106042"},"PeriodicalIF":4.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144907678","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}

{"title":"Activation of the β2-adrenoceptor by formoterol induces calcium-dependent exocytosis of synaptic vesicles at the neuromuscular junction in a sex-specific manner","authors":"Kivia B.S. Santos ,&nbsp;Matheus de Castro Fonseca ,&nbsp;Gabriel H.M. Teixeira ,&nbsp;Bruno Sanches ,&nbsp;Silvia Guatimosim ,&nbsp;Leonardo Rossi ,&nbsp;Pablo W. Verly ,&nbsp;Elisa Santiago Pereira ,&nbsp;Walter Cavalcante ,&nbsp;Alexander Birbrair ,&nbsp;Enrrico Bloise ,&nbsp;Juan C. Tapia ,&nbsp;Cristina Guatimosim","doi":"10.1016/j.neuint.2025.106040","DOIUrl":"10.1016/j.neuint.2025.106040","url":null,"abstract":"<div><div>Increasing evidence suggests that the sympathetic nervous system profoundly interacts with skeletal muscle, influencing both muscle fiber function and composition. β₂-ARs, the predominant adrenergic receptor subtype in muscle fibers, have been shown to enhance protein synthesis, reduce protein degradation, facilitate muscle contraction and relaxation, and improve neuromuscular junction (NMJ) transmission upon activation. In this study, we investigated the effects of Formoterol, a highly selective β₂-adrenoceptors (β₂-AR) agonist, on the presynaptic terminal of motor neurons. We used myography, FM1-43 fluorescent dye assays, and transmission electron microscopy (TEM) to evaluate the NMJ following β₂-AR activation. We demonstrated that β₂-AR activation by Formoterol enhances muscle contractility and both spontaneous and evoked exocytosis of acetylcholine (ACh)-containing synaptic vesicles at the mouse diaphragm NMJ. Formoterol-induced morphological changes in diaphragmatic NMJs were consistent with increased exo-endocytic activity. Notably, Formoterol-evoked exocytosis displayed sexual dimorphism, with females showing a significantly milder response compared to males. In females, Formoterol-induced synaptic vesicles exocytosis was mediated solely by P/Q-type voltage-activated Ca²⁺ channels, whereas in males, it involved both P/Q-type channels, transient receptor potential channel of the vanilloid subtype (TRPV) 1 calcium channels, and an additional, yet unidentified, component. Orchiectomized males exhibited responses to Formoterol similar to the females, whereas ovariectomy did not modify female drug responses, indicating that male hormonal environment orchestrates the sex-differences herein described. These findings not only highlight the importance of sex-specific mechanisms but also reveal a novel effect of β₂-AR activation directly on presynaptic terminals by Formoterol, enhancing exocytosis at the NMJ and thereby increasing neuromuscular transmission.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106040"},"PeriodicalIF":4.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144919857","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}

{"title":"Targeting ferroptosis by electroacupuncture offers a therapeutic regimen for brain injury after ischemic stroke","authors":"Wenjing Li,&nbsp;Qiang Li","doi":"10.1016/j.neuint.2025.106038","DOIUrl":"10.1016/j.neuint.2025.106038","url":null,"abstract":"<div><div>Ischemic stroke (IS), the most prevalent form of stroke, remains a significant healthcare challenge and imposes a considerable burden on affected individuals. Ferroptosis, a form of regulated cell death (RCD) characterized by iron overload -induced lipid peroxidation, was identified as a contributor to induce cell death following brain injury after ischemic stroke. Targeting ferroptosis is a novel therapy regimen for IS. And seeking novel therapy is unmet need for IS. Electroacupuncture (EA) has been revealed to have neuroprotective effect against IS and recommended to treat IS by World Health Organization (WHO) for years, but the specific mechanism underlying EA-mediated neuroprotection is still elusive. Emerging evidences have shown that EA alleviates brain injury after ischemic stroke by inhibiting ferroptosis; however, the mechanism by which EA suppresses ferroptosis against IS has not been sufficiently clarified. In this review, we first summarizes the core molecular mechanism of ferroptosis, with an focus on interpret how ferroptosis leads to the genesis of brain injury after ischemic stroke and the novel regulation of ferroptosis during the brain injury after ischemic stroke. We then highlights our emphasize on the emerging evidences that have revealed EA inhibit ferroptosis and review their pharmacological mechanisms against brain injury after ischemic stroke. This review highlights EA as a novel therapeutic regimen for ischemic stroke by suppressing ferroptosis, synthesizing mechanistic insights into iron-dependent lipid peroxidation pathways, evaluating emerging experimental evidence of EA's neuroprotection, and proposing targeted clinical strategies to mitigate post-stroke brain injury.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106038"},"PeriodicalIF":4.0,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896185","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}

{"title":"Epitranscriptomic dysregulation in neurodegenerative diseases and its implications for disease pathology and mechanisms","authors":"Andrew M. Shafik,&nbsp;Peng Jin","doi":"10.1016/j.neuint.2025.106037","DOIUrl":"10.1016/j.neuint.2025.106037","url":null,"abstract":"<div><div>RNA modifications, collectively referred to as the epitranscriptome, play a crucial role in regulating RNA metabolism, influencing key processes such as splicing, stability, localization, and translation. Increasing evidence now links dysregulation of the epitranscriptome to neurodegenerative diseases. In this review, we focus on four RNA modifications and their influence on neurodegenerative pathways, including synaptic function, neuroinflammatory signaling, and stress granule formation. These findings highlight the complex and multifaceted roles that RNA modifications play in neurodegeneration, emphasizing their emerging potential as biomarkers and therapeutic targets.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106037"},"PeriodicalIF":4.0,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896186","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}

{"title":"Opioids induce constipation by prompting alpha-Synuclein hyperphosphorylation in the colonic myenteric plexus","authors":"Binghan Jia ,&nbsp;Yuqiong Zhao ,&nbsp;Xiaojie Ren ,&nbsp;Dandan Zhang ,&nbsp;Hua Jia ,&nbsp;Dengke Wang ,&nbsp;Lixin Wang ,&nbsp;Junping Li","doi":"10.1016/j.neuint.2025.106036","DOIUrl":"10.1016/j.neuint.2025.106036","url":null,"abstract":"<div><div>Opioid-induced constipation (OIC) is the most common gastrointestinal disorder associated with opioid use. It is linked to impaired neurotransmitter release. Alpha-Synuclein (α-Syn) plays a crucial role in maintaining neurotransmitter homeostasis and regulating synaptic plasticity in the nervous system. However, its role in the disease progression remains unclear. In the present study, we investigated the impact of α-Syn hyperphosphorylation on colonic dysmotility and constipation symptoms using a Sprague-Dawley rat model of OIC. Our results suggest that α-Syn expression at the Ser129 phosphorylation site (pS129-α-Syn) is significantly increased in the colonic myenteric layer of OIC rats. Conversely, inhibiting pS129-α-Syn reversed the colonic dysmotility and increased the expression of synaptic functional proteins, such as Synapsin-1, Synaptotagmin-1, vesicle-associated membrane protein 2 (VAMP-2), and Syntaxin-1, as well as enteric neurotransmitter synthases, including neuronal nitric oxide synthase (nNOS) and adenosine triphosphate synthase (ATPB). Additionally, we found that opioids downregulate GSK3β protein expression at the Ser9 site by activating the μ-opioid receptors (MOR). This increases GSK3β kinase activity, ultimately inducing pS129-α-Syn overexpression. In summary, the development of OIC correlates with α-Syn hyperphosphorylation in myenteric plexus neurons in the colon. Opioids can inhibit synaptic vesicle trafficking and enteric neurotransmitter release via the GSK3β/α-Syn hyperphosphorylation signaling axis, ultimately leading to colonic dysmotility and constipation.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106036"},"PeriodicalIF":4.0,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889131","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}

{"title":"Circulating metabolomic changes in Lennox-Gastaut syndrome: correlation with clinico-radiological severity","authors":"Jayantee Kalita ,&nbsp;Aditi Pandey ,&nbsp;Firoz M. Nizami ,&nbsp;Ashish K. Dubey ,&nbsp;Bikash Baishya","doi":"10.1016/j.neuint.2025.106032","DOIUrl":"10.1016/j.neuint.2025.106032","url":null,"abstract":"<div><div>Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy characterized by multiple types of seizures typically occurring between 1 and 7 years of age, cognitive impairment and characteristic electroencephalographic abnormalities. Circulating metabolomic profile may give insight into the ongoing metabolic pathway abnormalities in these patients, but there is no such study. We report NMR based metabolomic profile in LGS and its association with clinical severity, MRI changes and EEG findings. LGS children between 2 and 18 years were included based on clinical and EEG diagnostic criteria. Detailed neurological examinations, frequency and type of seizures, EEG changes, cranial MRI and NMR based serum metabolomic profile were measured. The Clinical Global Impairment Severity Scale (CGI-S) was used to rate severity of LGS. Twenty-six LGS patients and 11 healthy matched controls were included. The median age of the patients was 6 (range 2–17) years, and 19 were males. Their median CGI-S score was 6, and all had more than one type of seizures. Seven metabolites namely lactate, glucose, glutamate, pyruvate, glutamine, glycine, citrate and creatinine were crucial for discrimination of LGS from the controls, among which glutamate was upregulated and citrate, pyruvate, and glutamine were down regulated in LGS. Glutamate associated with developmental quotient (r = −0.48) and pyruvate with focal seizures (r = 0.47) and cystic encephalomalacia on cranial MRI (p = 0.02). NMR metabolomic profile including glutamate, glutamine, glycine, glucose, pyruvate, lactate, citrate and creatinine can discriminate LGS from the controls. Role of antiglutamatergic drugs may be beneficial in controlling seizures, and needs future study.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"189 ","pages":"Article 106032"},"PeriodicalIF":4.0,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854188","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}

{"title":"Combined supplementation of short-chain fatty acids reduces hyperphosphorylation of Tau at T181,T231 and S396 sites and improves cognitive impairment in a chemically induced AD mouse model via regulation of HDAC and Keap1","authors":"Dan Pu ,&nbsp;Ye Jin ,&nbsp;Longxing Wang ,&nbsp;Renjun Wang ,&nbsp;Lingyu Li ,&nbsp;Yang Song ,&nbsp;Xiaofei Han","doi":"10.1016/j.neuint.2025.106034","DOIUrl":"10.1016/j.neuint.2025.106034","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is characterized by the pathological hallmarks of β-amyloid deposition and Tau protein hyperphosphorylation, with memory loss and cognitive dysfunction as its primary clinical manifestations. The incidence of AD has been progressively increasing in recent years. Short-chain fatty acids (SCFAs), key effector molecules in host-gut microbial interactions, play a crucial role in maintaining central nervous system homeostasis. In this study, AD mouse model was established via AlCl₃/D-gal induction. The effects of mixed SCFA intervention on spatial learning and memory in AD model mice were assessed using behavioral tests, including the Morris Water Maze. Levels of pro-inflammatory cytokines and activities of oxidative stress-related enzymes in brain and colon tissues were quantified using ELISA and commercial kits. Key protein expression levels were analyzed by Western blot, immunohistochemistry, and immunofluorescence. Results demonstrated that SCFAs significantly alleviated cognitive dysfunction in AD model, reduced Tau hyperphosphorylation at T181, T231 and S396 sites, suppressed pro-inflammatory cytokine release, and enhanced antioxidant capacity, but with no reversal in elevated Aβ levels in AD model. Mechanistically, SCFAs inhibited glial cell activation, upregulated MCT-1 and tight junction proteins in the blood-brain barrier and strengthened gut-brain barrier integrity, potentially regulating small molecule <em>trans</em>-barrier transport. Furthermore, examination of relevant protein expressions revealed that SCFAs activated HDAC1 and inhibited overexpressed HDAC3 and Keap-1 in AD mice model. These findings suggest that SCFAs may regulate epigenetic modifications in the brain of AD to exert neuroprotective effects. This study provides novel evidence supporting the potential of symbiotic microbe-derived SCFAs in alleviating AD.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"189 ","pages":"Article 106034"},"PeriodicalIF":4.0,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144852112","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}

{"title":"Epigenetic dysregulation and the etiology of spina bifida","authors":"Tabitha Lumour-Mensah ,&nbsp;Susan Korrick ,&nbsp;Bernardo Lemos ,&nbsp;Maitreyi Mazumdar","doi":"10.1016/j.neuint.2025.106033","DOIUrl":"10.1016/j.neuint.2025.106033","url":null,"abstract":"<div><div>Spina bifida is a complex and multifactorial congenital defect driven by both genetic and environmental factors. As such, epigenetic studies of spina bifida present an opportunity to study the joint contribution of both genes and the environment in the development of this disorder. This review focuses specifically on epigenetic research that may help us to understand the ways in which dysregulation of the epigenome and downstream cellular processes can confer increased risk of spina bifida. To do so, we discuss the epigenetic regulation of genes linked to spina bifida risk among children born with the disorder and their parents as well as evidence from experimental studies. We also discuss pathways necessary for normal neural tube development and specific documented dysregulation of these pathways in individuals with spina bifida. We conclude that the epigenome plays an important role in spina bifida etiology and should be further studied in additional populations, and tissue types, as well as cellular and animal models.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"189 ","pages":"Article 106033"},"PeriodicalIF":4.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144843983","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}

{"title":"TRPM8 modulation alters uptake of Transferrin-mediated Fe3+, mitochondrial Fe2+ and intracellular Ca2+-levels in microglia","authors":"Raima Sing ,&nbsp;Deep Shikha ,&nbsp;Chandan Goswami","doi":"10.1016/j.neuint.2025.106031","DOIUrl":"10.1016/j.neuint.2025.106031","url":null,"abstract":"<div><div>Microglia play an important role in the immunity of the central nervous system, crucial in maintaining homeostasis. However, under diseased conditions, this cell accumulates Fe^2+/3+, triggering inflammatory and neurotoxic effects that contribute to neurodegenerative disorders such as Alzheimer's and Parkinson's. Hence, the study of dysregulated microglial activation and overload of Fe^2+/3+ is crucial in the context of neurodegenerative conditions. Emerging research has identified cold-sensitive ion channels, i.e., TRPM8 in microglia, which can regulate key subcellular functions. This study explores the regulatory function of the TRPM8 in Fe^2+/3+ metabolism and its implications for potential ferroptosis in BV2 microglial cells. We used highly specific fluorescence probes, pharmacological modulators of TRPM8 and performed life cell imaging to understand the uptake of Transferrin-488, mitochondrial Fe²⁺-level, cellular Ca²⁺-levels in live BV2 cells under different experimental conditions. Our findings reveal that TRPM8 activation leads to enhanced Transferrin-488-mediated cytosolic Fe³⁺-uptake, disrupts mitochondrial superoxide levels, and promotes cell death. Interestingly, under inflammatory conditions induced by LPS treatment, TRPM8 exhibits a distinct functional role. These results position TRPM8 as an important regulator of microglial Fe^2+/3+ metabolism. This study indicates the involvement of TRPM8 in overload of Fe^2+/3+ leading to ferroptosis and potential for M1-M2 polarization in microglia. These findings impose TRPM8 as a potential therapeutic target for neurodegenerative diseases, and aging.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"189 ","pages":"Article 106031"},"PeriodicalIF":4.0,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144815473","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}

{"title":"Increased spinal adenosine after subacute cervical injury correlates with sustained upregulation of CD39 and CD73 in microglia","authors":"Mackenzie R. Berschel ,&nbsp;Maria Nikodemova ,&nbsp;Jose R. Oberto,&nbsp;Alexandria B. Marciante,&nbsp;Alysha Michaelson,&nbsp;Gordon S. Mitchell","doi":"10.1016/j.neuint.2025.106030","DOIUrl":"10.1016/j.neuint.2025.106030","url":null,"abstract":"<div><div>Cervical spinal cord injuries (cSCI) are associated with decreased breathing ability. Although no treatment options are currently available, moderate acute intermittent hypoxia (mAIH) is a promising therapeutic modality to improve breathing function after cSCI. Moderate AIH elicits phrenic motor plasticity <em>via</em> distinct, competing serotonin- or adenosine-driven mechanisms that interact <em>via</em> powerful crosstalk inhibition that constrains or even abolishes plasticity. The dominant mechanism driving plasticity depends on the spinal serotonin/adenosine balance. Shortly after cSCI, repeated AIH exposure elicits plasticity <em>via</em> an adenosine-dependent mechanism but reverts to serotonin-dominance with chronic cSCI. In healthy CNS, microglia regulate AIH-induced phrenic motor plasticity <em>via</em> enzymatic activities of ectonucleotidases (CD39, CD73) by converting extracellular ATP to adenosine. We hypothesized that cSCI increases microglial ectonucleotidase expression, elevating adenosine levels that may alter therapeutic responses to mAIH post-cSCI. We assessed microglial CD39 and CD73 expression at the subacute (1 &amp; 2 weeks) and chronic (8 weeks) stages post C2-hemisection, both at the injury site (C1–C3) and in spinal segments containing phrenic motor neurons below the injury (C3–C6). Both enzymes were upregulated (mRNA &amp; protein) 1- and 2-weeks post injury but returned to baseline by 8 weeks. In association, spinal adenosine increased significantly at 2, but not 8 weeks post-injury. Further, microglial CD39 and CD73 expression strongly correlate with P2Y12 receptor expression. Thus, shifting adenosine levels between subacute and early chronic cSCI may impact mechanism regulating mAIH-induced respiratory motor plasticity and breathing recovery at different times post-cSCI.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"189 ","pages":"Article 106030"},"PeriodicalIF":4.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144779560","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}