Neuropharmacology最新文献

{"title":"The novel PSD-95 inhibitor BXOS110 provides neuroprotection in acute ischemic stroke","authors":"Huan-Yu Zheng ,&nbsp;Ya-Rong Ding ,&nbsp;Fei-Yang Guo ,&nbsp;Tian-Jie Lyu ,&nbsp;Bao-Yu Feng ,&nbsp;He Li ,&nbsp;Shu-Ya Li ,&nbsp;Ge-Hong Dong ,&nbsp;Yong-Jun Wang ,&nbsp;Zi-Xiao Li ,&nbsp;Hua-Min Han","doi":"10.1016/j.neuropharm.2026.110845","DOIUrl":"10.1016/j.neuropharm.2026.110845","url":null,"abstract":"<div><div>Acute ischemic stroke remains a major public health challenge due to its high incidence and limited effective treatment options. Reperfusion therapies, including thrombolysis and endovascular intervention, help restore blood flow in some patients but often fall short due to ineffective recanalization or reperfusion injury, emphasizing the urgent need for adjunctive neuroprotective strategies. BXOS110, a novel neuroprotective agent, targets PSD-95, a postsynaptic density protein that mediates excitotoxic damage by interacting with <em>N</em>-methyl-D-aspartate (NMDA) receptors and neuronal nitric oxide synthase. In this study, BXOS110 demonstrated a higher binding affinity for PSD-95 than its predecessor, nerinetide (NA-1). Our data further confirmed that BXOS110 directly binds to PSD-95 and mitigates NMDA-induced neurotoxicity in vitro. In vivo, BXOS110 exhibited robust brain penetration and sustained localization in ischemic brain regions of rats, as well as significant neuroprotective effects in both rat and primate models of ischemic stroke when administered within 1 h of ischemia onset. Additionally, we determined that BXOS110 administration must be carefully timed with thrombolytic agents to prevent its degradation, identifying optimal dosing intervals to maximize therapeutic efficacy. These findings highlight the potential of BXOS110 as an integrated stroke therapeutic agent, which combines vascular recanalization with targeted neuroprotection to enhance patient outcomes.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"288 ","pages":"Article 110845"},"PeriodicalIF":4.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Psilocin mediates long-term synaptic depression in the prelimbic cortex through 5-HT2A receptor-independent mechanisms","authors":"Ana Domi ,&nbsp;Erika Lucente ,&nbsp;Davide Cadeddu ,&nbsp;Niklas Bengtsson ,&nbsp;Erik Smedler ,&nbsp;Louise Adermark","doi":"10.1016/j.neuropharm.2026.110854","DOIUrl":"10.1016/j.neuropharm.2026.110854","url":null,"abstract":"<div><div>Psilocybin is a naturally occurring psychedelic compound with potential antidepressant effects. Although it has long been used by humans, primarily for recreational purposes, the molecular mechanisms underlying its actions remain incompletely understood. Here, we examined the acute effects of psilocin, the active metabolite of psilocybin, on excitatory neurotransmission in the prefrontal cortex (PFC). Slice electrophysiological whole-cell and field potential recordings were conducted in the rat prelimbic cortex during bath application of psilocin. We observed a sex-independent long-term synaptic depression (LTD) of presynaptic origin. This effect was independent of 5-HT_2A and metabotropic glutamatergic receptor group 2 and mediated through enhanced GABAergic tone. The effect was partially inhibited by 5-HT_1A receptor antagonist and completely blocked in slices pre-treated with the neuronal receptor tyrosine kinase 2 (TrkB) receptor antagonist ANA-12. These findings suggest that psilocin exerts a complex modulatory influence on excitatory neurotransmission in the prelimbic PFC, involving GABAergic and serotonergic interactions, and producing sustained alterations in synaptic activity that persist beyond drug exposure. Psilocin-induced LTD, independent of 5-HT_2A receptor activation, may be associated with the reduced prefrontal connectivity reported in humans after psilocin administration and could have implications for cognitive function.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"288 ","pages":"Article 110854"},"PeriodicalIF":4.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adolescent cannabinoid vapour exposure sex-dependently alters the relationship between vulnerability traits and ethanol self-administration and modifies naltrexone actions on ethanol intake in rats","authors":"Jairo S. Acosta-Vargas ,&nbsp;Natalia de las Heras-Martínez ,&nbsp;Alberto Marcos ,&nbsp;Leonor Nozal ,&nbsp;Antonio L. Crego ,&nbsp;Marcos Ucha ,&nbsp;Alejandro Higuera-Matas","doi":"10.1016/j.neuropharm.2026.110843","DOIUrl":"10.1016/j.neuropharm.2026.110843","url":null,"abstract":"<div><div>Cannabis use during adolescence is common and may predispose individuals to substance use disorders. Animal studies have explored the gateway hypothesis, but data on ethanol consumption are limited. This study aimed to investigate the potential link between adolescent cannabis exposure and ethanol self-administration, as well as the relationship between predisposing behavioural traits and ethanol consumption. Adolescent rats were exposed to vaporized Δ⁹-tetrahydrocannabinol (THC) alone or with cannabidiol (CBD) at different ratios, or to a vehicle, from postnatal day (PND) 28–44, every other day. Behavioural assessments, including novelty and saccharin preference, goal-tracking, elevated plus maze, and ethanol self-administration (fixed and progressive ratio, punished seeking), were conducted from PND 70. Naltrexone was administered to assess its effects on ethanol intake. Cannabinoid exposure did not significantly affect behavioural traits or ethanol self-administration. However, sex differences emerged, with females showing a more vulnerable pattern of ethanol consumption and seeking. In THC-exposed males, a negative correlation was observed between sucrose preference and compulsive ethanol seeking. In females, THC exposure disrupted the correlation between novelty preference and ethanol intake and was associated with a negative correlation between goal-tracking and compulsive seeking. Naltrexone was most effective in reducing ethanol intake in THC-exposed rats as compared to rats exposed to a high CBD/low THC cannabinoid mixture. Adolescent cannabinoid exposure has limited effects on overall alcohol risk but may alter the psychological framework of alcohol-related behaviours and increase naltrexone potency. The observed sex differences highlight the need for personalized interventions.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"288 ","pages":"Article 110843"},"PeriodicalIF":4.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The interaction between FLOT1 and FOSL2 promotes EphA2 transcription, regulating microglial polarization and affecting neuroinflammation in Alzheimer's disease","authors":"Biyan Li,&nbsp;Jiangxi Xu,&nbsp;Hong Zhu,&nbsp;Dan Ren,&nbsp;Lan Xiao,&nbsp;Ting Zhang,&nbsp;Ruomeng Li","doi":"10.1016/j.neuropharm.2026.110844","DOIUrl":"10.1016/j.neuropharm.2026.110844","url":null,"abstract":"<div><h3>Background</h3><div>Microglial activation plays a crucial role in Alzheimer's disease (AD), responding to amyloid-beta (Aβ) plaques and tau tangles. Initially protective, microglia clear Aβ deposits and support neuronal health, but later adopt a pro-inflammatory, neurotoxic state, releasing cytokines that exacerbate neuroinflammation and neuronal damage. Understanding the mechanisms driving this shift is essential for developing therapies to modulate microglial activation and slow AD progression.</div></div><div><h3>Methods</h3><div>Quantitative PCR (qPCR), Western blotting, immunohistochemistry (IHC), and immunofluorescence (IF) assays were performed to confirm gene and protein expression levels. Chromatin immunoprecipitation (ChIP), co-immunoprecipitation (CoIP), and dual-luciferase assays were conducted to assess the interactions among FLOT1, FOSL2, and EphA2. The Morris water maze test was used to evaluate spatial learning and memory, with experiments conducted using the APP/PS1 mouse model.</div></div><div><h3>Results</h3><div>In this study, we found that silencing of FLOT1 in APP/PS1 mice significantly reduced neuroinflammatory markers, prevented pro-inflammatory polarization, and improved spatial memory. Mechanistically, we observed that FLOT1 interacted with the transcription factor FOSL2, which upregulated EphA2 expression, leading to activation of the p38/MAPK signaling pathway. Disrupting EphA2 expression deactivated this pathway, reducing pro-inflammatory polarization in microglia. Our findings further confirmed that the FLOT1-FOSL2 axis regulated microglial polarization <em>in vivo</em> and that targeting this pathway improved cognitive outcomes in AD models.</div></div><div><h3>Conclusion</h3><div>Overall, these results highlight the FLOT1-FOSL2-EphA2 pathway as a potential therapeutic target for AD, as modulating this axis may reduce neurotoxic inflammation and help preserve cognitive function.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"288 ","pages":"Article 110844"},"PeriodicalIF":4.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ivabradine reduces seizure susceptibility in a genetic model of mixed epilepsies","authors":"Gleice Kelli Silva-Cardoso,&nbsp;Prosper N'Gouemo","doi":"10.1016/j.neuropharm.2026.110853","DOIUrl":"10.1016/j.neuropharm.2026.110853","url":null,"abstract":"<div><div>Ivabradine is an approved medication that lowers heart rate by inhibiting hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which are critical regulators of neuronal excitability. This study investigated the effects of ivabradine on seizure susceptibility in genetically epilepsy-prone rats (GEPR-3s), known for their seizure phenotypes driven by the brainstem and limbic system. In the initial experiments, male and female GEPR-3s were administered ivabradine at acute doses (0, 5, 10, or 20 mg/kg, p. o.) or at repeated doses (5 mg/kg, p. o.). Following treatment, GEPR-3s were evaluated for acoustically evoked generalized tonic-clonic seizures (GTCS). Seizure severity, latency, and duration were recorded at various time intervals (0.5, 1, 2, 4, and 24 h). In subsequent experiments, GEPR-3s underwent repeated episodes of acoustically evoked seizure or audiogenic kindling, leading to generalized clonic seizures (GCSs) seen in fully kindled GEPR-3s. The results revealed that acute administration of ivabradine significantly decreased the incidence and severity of GTCSs, while increasing seizure latencies and reducing seizure durations in both male and female GEPR-3s. Furthermore, repeated administration of ivabradine over five days resulted in notable suppression of GTCSs in both sexes. Additionally, acute ivabradine treatment effectively decreased the severity of GCSs in kindled GEPR-3s. In conclusion, Ivabradine exhibits notable anticonvulsant effects by modulating seizure activity within both the brainstem and limbic networks of the GEPR-3, an inherited model of epilepsy characterized by mixed seizure phenotypes.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"288 ","pages":"Article 110853"},"PeriodicalIF":4.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the utility of the neurosteroid zuranolone to modify alcohol-related behaviours","authors":"Lauren T. Ursich ,&nbsp;Amy J. Pearl ,&nbsp;Xavier J. Maddern ,&nbsp;Andrew J. Lawrence ,&nbsp;Leigh C. Walker","doi":"10.1016/j.neuropharm.2026.110833","DOIUrl":"10.1016/j.neuropharm.2026.110833","url":null,"abstract":"<div><div>Alcohol use is a leading risk factor for premature mortality, yet effective pharmacotherapies remain limited. Neurosteroids, such as allopregnanolone, modulate γ-aminobutyric acid type A (GABA_A) receptors and influence alcohol-related behaviours. Zuranolone, an orally bioavailable synthetic analogue of allopregnanolone recently approved for postpartum depression, represents a potential candidate for therapeutic repurposing in alcohol use disorder (AUD). Here, we assessed the effects of acute and daily zuranolone on alcohol-related behaviours in a preclinical binge drinking model, comparing outcomes across sexes and contrasted to the effects of allopregnanolone. Allopregnanolone produced dose-related locomotor responses, characterised by mid dose transient hyperlocomotion and high dose sedation; the mid dose also reduced alcohol intake in both sexes. In contrast, zuranolone produced sex- and dosing schedule-related effects on alcohol consumption: acute high dose administration transiently reduced intake in males in the Latin square design, whereas mid dose administration increased intake under dose escalation in both sexes, particularly in males; however, total intake was unchanged across dosing schedules. Daily zuranolone transiently reduced alcohol intake in males during the first week only. In locomotor assays, acute high dose zuranolone induced sustained hyperactivity in males that was attenuated in females, supporting sex-related differences in sensitivity. Despite its structural similarity to allopregnanolone, zuranolone produced unique behavioural responses, suggesting their pharmacological profiles may differ. Overall, our data do not show robust reductions in alcohol intake following zuranolone administration across dosing schedules in either sex in preclinical models of binge drinking. Future studies are required to explore its potential relevance in comorbid AUD and affective disorders.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"288 ","pages":"Article 110833"},"PeriodicalIF":4.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The potent and selective adenosine A2AR antagonists P400 and P625 protect against symptoms in autoimmune experimental encephalomyelitis by attenuating neuroinflammation and demyelination","authors":"M. Morozzi ,&nbsp;V. Borgonetti ,&nbsp;C. Sasia ,&nbsp;G. Videtta ,&nbsp;S. Calenda ,&nbsp;D. Catarzi ,&nbsp;F. Varano ,&nbsp;V. Colotta ,&nbsp;N. Galeotti","doi":"10.1016/j.neuropharm.2026.110857","DOIUrl":"10.1016/j.neuropharm.2026.110857","url":null,"abstract":"<div><div>Multiple sclerosis (MS) is an autoimmune chronic inflammatory disease of the central nervous system characterized by oxidative stress, demyelination, and neuronal damage. Current MS therapies are unsatisfactory and new therapies are encouraged. Adenosine is highly implicated in MS as it regulates, via activation of its A_2A receptor (A_2AR), the inflammatory and immune response. The aim of this study is to investigate the therapeutic potential of new selective A_2AR antagonists, P400 and P625, in the experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS. P400 and P625 administration (10 μg/mouse intranasal) for 14 days reduced motor disability (clinical score, rotarod) and thermal (hot plate) and mechanical (von Frey) hypernociceptive symptoms associated with a chronic MS model. Quantitative analysis of lymphocytes infiltration in the spinal cord sections stained with hematoxylin and eosin (H&amp;E) showed a larger number of inflammatory cells in EAE sections that were markedly reduced by P400 and P625. P400 also reduced the immunostaining of Iba1, marker of microglia. Luxol Fast Blue (LFB) staining and myelin basic protein (MBP) immunostaining of spinal cord sections showed a robust loss of myelin that was partially restored by P400 and P625. Both treatments increased spinal neurofilament H (NfH) and GAP43 protein expression compared to untreated immunize mice. These data illustrate the efficacy of the new selective A_2AR antagonists in ameliorating EAE symptoms by attenuating neuroinflammation and demyelination. These findings further highlight A_2AR blocking as a promising perspective to control neurological disturbances in MS patients.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"288 ","pages":"Article 110857"},"PeriodicalIF":4.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146079669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short RFamide, CFamide and FCamide peptides as novel positive modulators of ASIC3 with similar potentiating effects but different reversibility","authors":"Maurizio Toft ,&nbsp;Maëva Meynier ,&nbsp;Hélène Lubrano Di Scampamorte ,&nbsp;Cédric Vallée ,&nbsp;Miguel Salinas ,&nbsp;Peijun Zhang ,&nbsp;Jessica Tacco ,&nbsp;Anne-Sophie Gay ,&nbsp;Emmanuel Bourinet ,&nbsp;Eric Lingueglia ,&nbsp;Emmanuel Deval","doi":"10.1016/j.neuropharm.2025.110813","DOIUrl":"10.1016/j.neuropharm.2025.110813","url":null,"abstract":"<div><div>Acid-sensing ion channels (ASICs) are members of the DEG/ENaC family that includes the only known peptide-gated ion channels. While ASICs are gated by protons, they are also sensitive to peptides and are modulated by the molluscan FMRFamide and other mammalian neuropeptides ending by the RFamide motif. We identified a set of synthetic short amidated hexapeptides, which not only end by the RFamide motif but also by CFamide and FCamide, as potent positive modulators of ASIC3 acid-induced activity. We focused on two of them, a RFamide peptide (FR<span><math><mrow><mover><mtext>CC</mtext><mo>‾</mo></mover></mrow></math></span>RFamide) and a CFamide peptide (FR<span><math><mrow><mover><mtext>CRC</mtext><mo>‾</mo></mover></mrow></math></span>Famide), demonstrating that they have similar specificity for and effects on ASIC3. The potentiating effects of the two peptides are due to a strong slow-down of desensitization, leading to an increase in the amount of current induced by acid pH (≤pH6.6), with apparent affinities ranging from 1 to 5 μM. Surprisingly, the washout kinetic of FR<span><math><mrow><mover><mtext>CC</mtext><mo>‾</mo></mover></mrow></math></span>RFamide peptide was much slower than those of FR<span><math><mrow><mover><mtext>CRC</mtext><mo>‾</mo></mover></mrow></math></span>Famide and other known RFamide peptides, suggesting potential differences in their mechanisms of action. Computational modeling and structure-function analysis reveal interactions of both peptides with the non-proton binding site of ASIC3 as already reported before for other RFamide peptides, but our data also suggest possible additional effects of FR<span><math><mrow><mover><mtext>CC</mtext><mo>‾</mo></mover></mrow></math></span>RFamide involving directly or indirectly the proton binding domain. These findings expand our understanding of ASICs’ modulation by peptides, identifying novel short modulators of ASIC3, including peptides with new CFamide and FCamide ending motifs, and showing differences between these peptides using their washout kinetic as a new parameter.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110813"},"PeriodicalIF":4.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NLRP10 ablation alleviates neuropathic pain by inhibiting excessive NIX/LC3-dependent mitophagy in the spinal cord","authors":"Xiaoyu Zhang,&nbsp;Jiale Sun,&nbsp;Fengtian Zhao,&nbsp;Ting Liu,&nbsp;Shangchen Yu,&nbsp;Wen Zhang,&nbsp;Xuebi Tian","doi":"10.1016/j.neuropharm.2026.110831","DOIUrl":"10.1016/j.neuropharm.2026.110831","url":null,"abstract":"<div><h3>Objective</h3><div>Neuropathic pain (NP) presents a significant clinical challenge due to its physical and psychological impact and the lack of effective treatments. While the pathogenesis of NP remains incompletely understood, emerging evidence suggests that Nod-like receptor pyrin domain-containing protein 10 (NLRP10) participates in neurological disorders via neuroinflammation and mitochondrial autophagy. This study investigates roles of NLRP10 in NP pathogenesis and elucidates its mechanism in triggering neuroinflammation-mediated NIX/LC3-dependent mitochondrial dysfunction.</div></div><div><h3>Methods</h3><div>A spared nerve injury (SNI) mouse model was established to investigate neuropathic pain (NP) mechanisms. Pain behaviors were assessed using the mechanical pain withdrawal threshold (MPWT). Adeno-associated virus (AAV) was administered to the spinal dorsal horn (SDH) to downregulate NLRP10 or overexpress NIX. Neuroinflammatory responses and alterations in mitophagy were subsequently evaluated using Western blotting, ELISA, immunofluorescence, and transmission electron microscopy.</div></div><div><h3>Results</h3><div>SNI mice exhibited upregulated NLRP10 inflammasome expression and enhanced activation of the downstream NLRP12/ASC/Caspase1 pathway in the SDH. This was accompanied by significant increases in NIX/LC3 protein concentrations and decreased mitochondrial-related protein levels after surgery. NLRP10 predominantly colocalized with neuronal marker NeuN in SDH. Transmission electron microscopy revealed characteristic mitochondrial damage. Knockdown of NLRP10 with mNLRP10 effectively suppressed inflammatory activation, attenuated excessive mitochondrial autophagy, and alleviated NP manifestations. Notably, NIX overexpression abolished the protective effects of NLRP10 reduction in SNI mice.</div></div><div><h3>Conclusion</h3><div>In summary, our findings demonstrate that NLRP10 downregulation inhibit NLRP12/ASC/Caspase1 pathway activation and prevents pathological mitochondrial autophagy, ultimately alleviating NP. These results identify NLRP10 as a promising therapeutic target for NP management.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110831"},"PeriodicalIF":4.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRPC6 mediates neuronal hyperexcitability in the lateral habenula to drive trigeminal neuralgia-associated anxiety","authors":"Fengxian Hu ,&nbsp;Zhenling Liu ,&nbsp;Xiaoman Min ,&nbsp;Kaixin Zhang ,&nbsp;Hengye Zhao ,&nbsp;Wei Liu ,&nbsp;Yi Tao ,&nbsp;Qingyue Jia ,&nbsp;Yaqing Gao ,&nbsp;Xianrui Meng ,&nbsp;Yu Wang ,&nbsp;Hongyun Wu ,&nbsp;Wenqiang Cui","doi":"10.1016/j.neuropharm.2025.110818","DOIUrl":"10.1016/j.neuropharm.2025.110818","url":null,"abstract":"<div><div>Persistent facial and oral discomfort, particularly trigeminal neuralgia (TN), is frequently accompanied by anxiety, which has been closely linked to increased excitability of neurons in the lateral habenula (LHb). However, the mechanisms underlying this hyperexcitability remain unclear. Here, we show that partial transection of the infraorbital nerve (pT-ION) significantly upregulated the expression of transient receptor potential canonical 6 (TRPC6), β isoform of calcium/calmodulin-dependent protein kinase II (βCaMKII), phosphorylated extracellular regulated kinase (p-ERK), and phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB) in the LHb. Pharmacological blockade of either TRPC6 or βCaMKII effectively reversed pT-ION-induced mechanical hypersensitivity and anxiety-like behaviors. TRPC6 overexpression in the LHb reproduced the behavioral and electrophysiological phenotypes observed in pT-ION mice, including increased LHb neuronal excitability. In contrast, bilateral knockdown of TRPC6 attenuated both pain- and anxiety-like behaviors and normalized neuronal activity in the LHb. Our study identified TRPC6 as a key mediator of LHb neuronal hyperexcitability, contributing to trigeminal neuralgia-associated pain and anxiety via the βCaMKII/ERK/CREB pathway, and suggests its potential as a target for treatment.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110818"},"PeriodicalIF":4.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}