Neuropharmacology最新文献

{"title":"GLP-1 receptor agonist semaglutide ameliorates motor deficits and tau pathology in the rTg4510s mouse model","authors":"Meng-Wei Zhang ,&nbsp;Wan-Yi Zhou ,&nbsp;Xin-Yi Li ,&nbsp;Zhi-Heng Xu ,&nbsp;Hua-Mei Lin ,&nbsp;Yi-Lin Tang ,&nbsp;Jue Zhao ,&nbsp;Chen Chen ,&nbsp;Feng-Tao Liu ,&nbsp;Yi-Min Sun ,&nbsp;Chuan-Tao Zuo ,&nbsp;Jian-Jun Wu ,&nbsp;Jian Wang ,&nbsp;Wen-Bo Yu","doi":"10.1016/j.neuropharm.2025.110659","DOIUrl":"10.1016/j.neuropharm.2025.110659","url":null,"abstract":"<div><h3>Background</h3><div>Tauopathies, including Alzheimer's disease, are characterized by progressive neurodegeneration manifesting as motor and cognitive impairments. This study evaluated the therapeutic potential of semaglutide, a clinically approved glucagon-like peptide-1 receptor agonist, in the rTg4510 mouse model of tauopathy.</div></div><div><h3>Methods</h3><div>Starting at three months of age, rTg4510 mice and wild-type littermates received semaglutide (0.10 mg kg⁻¹, intraperitoneal) or vehicle (PBS) every other day for 16 weeks. Motor coordination, anxiety-like behavior, spatial working memory, and associative fear memory were assessed using behavioral paradigms. Tau accumulation was monitored via 18F-PM-PBB3 micro-PET/CT imaging. Immunohistochemistry and immunoblot analyses quantified tau pathology, neuronal integrity, and glial activation.</div></div><div><h3>Results</h3><div>Semaglutide significantly improved motor coordination in rTg4510 mice on the pole test, though not rotarod endurance. While spontaneous locomotion, anxiety-like behaviors, and Y-maze spatial working memory remained unchanged, semaglutide significantly enhanced cue-dependent freezing in fear conditioning, indicating improved associative memory. ¹⁸F-PM-PBB3 PET imaging revealed a pronounced reduction in cortical and hippocampal tracer uptake, indicative of reduced tau burden. Immunohistochemistry and Western blotting confirmed significantly decreased cortical phosphorylated tau (AT8) levels. Semaglutide preserved cortical neuronal integrity; however, no hippocampal changes were detected, likely due to minimal baseline neuron loss at this age. Astrocytic (GFAP) and microglial (Iba1) activation remained unaffected.</div></div><div><h3>Conclusion</h3><div>Semaglutide ameliorated domain-specific motor impairments, enhanced associative fear memory, and attenuated cortical tau pathology in rTg4510 mice. These findings highlight therapeutic promise of semaglutide as a disease-modifying agent for tauopathies, justifying further dose-response, mechanistic, and translational studies.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"280 ","pages":"Article 110659"},"PeriodicalIF":4.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144916940","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":"IDOR-1104-0086, a novel Kv7 channel activator with antiseizure effects in rodents","authors":"Melanie Kessler,&nbsp;Andreas Mühlemann ,&nbsp;Malgorzata Anna Mis ,&nbsp;Romain Siegrist,&nbsp;Swen Seeland ,&nbsp;Caroline Deymier,&nbsp;Cary-Ann Mathieu ,&nbsp;Hélène Roellinger ,&nbsp;Tsvetomira Atanasova ,&nbsp;Catherine Roch ,&nbsp;Michel Alexander Steiner","doi":"10.1016/j.neuropharm.2025.110658","DOIUrl":"10.1016/j.neuropharm.2025.110658","url":null,"abstract":"<div><div>A neuronal, phenotypic <em>in vitro</em> screen at Idorsia identified IDOR-1104-0086 as a small molecule with antiseizure effects and drug-like properties. Target deconvolution revealed its mechanism as activating voltage-gated potassium (Kv7) channels, which stabilize the resting membrane potential and modulate cellular excitability.</div><div>In the current study, we further investigated IDOR-1104-0086's potency and selectivity profile on Kv7.1–7.5 isoforms and compared it to the known Kv7 channel opener and antiseizure medication retigabine. We studied its effects in the amygdala-kindling and 6 Hz rodent models of focal-onset seizures, the maximal electroshock threshold test of generalized convulsive seizures in mice, and a model of absence-like epilepsy in rats featuring non-convulsive generalized seizures.</div><div>IDOR-1104-0086 demonstrated greater potency than retigabine on various Kv7 isoforms, including the brain-specific Kv7.2/3 and Kv7.3/5 heterotetramers, and was inactive on the peripheral Kv7.1 isoform expressed on cardiac myocytes. It reduced focal-onset and generalized convulsive seizures in a dose-dependent manner in the employed models. However, it aggravated non-convulsive seizures similarly to retigabine. Unbound IDOR-1104-0086 plasma concentrations that were well tolerated and efficacious <em>in vivo</em> caused a therapeutically relevant shift of the Kv7.2/3 current activation in whole-cell patch-clamp electrophysiology recordings, consistent with retigabine's effects.</div><div>IDOR-1104-0086 is a potent activator of Kv7.2/3 channels that reduces focal-onset and generalized convulsive seizures in rodent models while being well tolerated. Its efficacious Kv7 channel activation properties make it a promising drug candidate for the treatment of drug-resistant epilepsy with focal-onset or generalized convulsive seizures.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"280 ","pages":"Article 110658"},"PeriodicalIF":4.6,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144920315","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":"Metoprolol exacerbates dementia in scopolamine-induced cognitive impairment in rats: A potential role of NADPH oxidase","authors":"Amal M. Sharaf ,&nbsp;Radwa N. Muhammad ,&nbsp;Hazim O. Khalifa ,&nbsp;Esraa A. Kandil ,&nbsp;Lamiaa A. Ahmed","doi":"10.1016/j.neuropharm.2025.110657","DOIUrl":"10.1016/j.neuropharm.2025.110657","url":null,"abstract":"<div><div>β-blockers have been implicated in cognitive impairment, with some studies suggesting their role in increasing the risk of vascular dementia (VD). While previous clinical and preclinical research has linked β-blockers, including metoprolol, to cognitive decline, the molecular mechanisms remain unclear. This study aims to elucidate the impact of metoprolol on scopolamine-induced cognitive impairment in rats, focusing on the role of NADPH oxidase-mediated oxidative stress. Adult male Wistar rats were administered metoprolol (30 mg/kg/day; p.o) alone or in combination with scopolamine (1 mg/kg/day; i.p). To assess the involvement of NADPH oxidase, a subset of rats also received apocynin (10 mg/kg/day; i.p), a specific NADPH oxidase inhibitor. Behavioral tests were performed to evaluate cognitive function, while biochemical analyses were conducted to measure oxidative stress markers, neuroinflammatory mediators, and mitochondrial biogenesis-related proteins. Metoprolol exacerbated scopolamine-induced cognitive decline, which was unvieled through the impaired learning and memory performance. This effect was accompanied by increased hippocampal NADPH oxidase activity, oxidative stress biomarkers, and p38 MAPK/NF-κB-mediated neuroinflammation. Subsequently, metoprolol disrupted mitochondrial biogenesis machinery through the negative regulation of the SIRT1/PGC-1α/NRF1/TFAM signaling axis, which was followed by apoptotic cell death. Co-administration of apocynin reversed most of these alterations, where attenuation of oxidative stress, neuroinflammation, and mitochondrial dysfunction were identified. In conclusion, metoprolol significantly worsens cognitive impairment, likely through oxidative stress amplification, neuroinflammation, and mitochondrial biogenesis impairment. These findings suggest that caution is needed when prescribing metoprolol to elderly patients, especially those at risk of cognitive decline. Targeting NADPH oxidase may offer a potential therapeutic approach to counteract metoprolol's adverse effects on cognitive function.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"280 ","pages":"Article 110657"},"PeriodicalIF":4.6,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144920314","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":"Early treatment with vildagliptin and linagliptin reduces social fear and prevents the onset of comorbid depression in a mouse model of social anxiety disorder","authors":"Iulia Zoicas,&nbsp;Johannes Kornhuber","doi":"10.1016/j.neuropharm.2025.110656","DOIUrl":"10.1016/j.neuropharm.2025.110656","url":null,"abstract":"<div><div>We have previously shown that sitagliptin, a widely used dipeptidyl peptidase-4 (DPP4) inhibitor for the treatment of type 2 diabetes mellitus, effectively reduces social fear in an animal model that closely mimics the main behavioral symptoms of social anxiety disorder (SAD). This social fear conditioning (SFC) model induces social fear without comorbidities in the short term, but over time, a depressive-like phenotype emerges, mimicking the comorbidity often observed in SAD patients. In this study, we investigated the effects of two DPP4 inhibitors, vildagliptin and linagliptin, both of which have distinct pharmacokinetic profiles compared to sitagliptin, on social fear and the prevention of comorbid depressive-like behavior. We show that administration of vildagliptin (50 mg/kg/day and 100 mg/kg/day) and linagliptin (5 mg/kg/day and 10 mg/kg/day) via the drinking water significantly reduced social fear in male CD1 mice subjected to SFC. Importantly, both gliptins also prevented the onset of comorbid depressive-like behavior in these mice. These results have important clinical connotations, as they suggest that early treatment with DPP4 inhibitors such as sitagliptin, vildagliptin and linagliptin could serve as promising therapeutic strategy for SAD, not only reducing the main symptoms of social anxiety but also the risk of developing comorbid mood disorders that often exacerbate the severity of symptoms and complicate treatment outcomes.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110656"},"PeriodicalIF":4.6,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144902152","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":"Hypocretin signaling in the central amygdala drives methamphetamine self-administration in male rats","authors":"Tyler A. Zarin ,&nbsp;Adam J. Brandner ,&nbsp;Yanan Zhang ,&nbsp;George F. Koob ,&nbsp;Brooke E. Schmeichel","doi":"10.1016/j.neuropharm.2025.110653","DOIUrl":"10.1016/j.neuropharm.2025.110653","url":null,"abstract":"<div><div>Methamphetamine use is growing in the United States and around the world. Hypocretin/orexin (HCRT) is a neuropeptide closely associated with drug-taking behaviors and stress response systems in humans and rodents. HCRT signaling occurs at HCRT-receptor 1 (HCRT-R1) and -receptor 2 (HCRT-R2); the contribution of signaling at each of these receptors to methamphetamine self-administration in rodents is largely unknown. These studies investigate the extent to which pharmacological HCRT-R1 and -R2 antagonists (RTIOX-276 [RTI] and JNJ-10397049 [JNJ], respectively) attenuate methamphetamine intake in adult male Wistar rats allowed either short or long access to intravenous methamphetamine self-administration under fixed and progressive ratio schedules of reinforcement. RTI and JNJ each elicited a dose-dependent attenuation of methamphetamine intake in rats allowed long, but not short, access to methamphetamine. Each antagonist also produced mild sedative-like effects on locomotor activity in drug naïve and short, but not long, access self-administration in rats. To further examine the role of HCRT in methamphetamine long access conditions, we measured HCRT-1 and HCRT-receptor densities in the amygdala, finding increased HCRT-1 and HCRT-R1 in the central amygdala (CeA), suggesting CeA as a target for HCRT activity in methamphetamine addiction-like behavior. Subsequent chemogenetic silencing of HCRT-neuronal projections from the dorsal hypothalamus to the CeA, a stress sensitive brain region implicated in addiction-like behaviors, significantly attenuated methamphetamine self-administration in rats allowed long access. Combined, these results suggest that HCRT signaling in the CeA is necessary for escalated methamphetamine-taking behavior characteristic of methamphetamine addiction.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110653"},"PeriodicalIF":4.6,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144903760","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":"Role of the dopamine D3 receptor in the core and shell of the nucleus accumbens in conditioned modulation of memory consolidation","authors":"Thomas Lapointe ,&nbsp;Nana Baidoo ,&nbsp;Briana Renda ,&nbsp;Francesco Leri","doi":"10.1016/j.neuropharm.2025.110651","DOIUrl":"10.1016/j.neuropharm.2025.110651","url":null,"abstract":"<div><div>There is evidence suggesting that the effect of conditioned stimuli (CS) on memory consolidation is mediated by the dopamine D3 receptor (D3R). The current study explored the hypothesis that D3Rs located in the nucleus accumbens core (NAcC) and shell (NAcS) are involved in this effect. Therefore, using male Sprague-Dawley rats and the object recognition memory task, it was tested whether: 1) intra-NAcC or intra-NAcS infusions of the selective D3R antagonist SB-277011A (0, 1 and 4 μg/side) could block facilitation of memory consolidation by a CS stablished through optimal conditioning on a signaled active avoidance task; and 2) intra-NAcC or intra-NAcS infusions of the D3R agonist 7-OH-DPAT (0 and 10 μg/side) could enhance conditioned memory facilitation by a CS which was ineffective on its own due to suboptimal conditioning. It was found that both 1 and 4 μg/side SB-277011A blocked CS-induced modulation of object memory when infused in NAcC, but not in the NAcS. In contrast, 10 μg/side 7-OH-DPAT infused in the NAcS, but not in the NAcC, enhanced modulation of object memory by a CS that was ineffective by itself. Taken together, these results suggest complementary roles of NAcS and NAcC D3Rs under varying CS predictability conditions in modulation of memory consolidation.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"280 ","pages":"Article 110651"},"PeriodicalIF":4.6,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144912683","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":"Positive allosteric modulation of M1 mAChRs with VU0486846 reverses cognitive deficits in male APPswe/PSEN1ΔE9 alzheimer's mice","authors":"Karim S. Ibrahim ,&nbsp;Tash-Lynn L. Colson ,&nbsp;Stephen S.G. Ferguson ,&nbsp;Khaled S. Abd-Elrahman","doi":"10.1016/j.neuropharm.2025.110654","DOIUrl":"10.1016/j.neuropharm.2025.110654","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is an age-associated neurodegenerative disease marked by progressive cognitive deterioration and beta-amyloid (Aβ) protein buildup, which currently lacks therapeutic interventions to decelerate its pathogenesis. The M1 muscarinic acetylcholine receptor (mAChR) is integral to synaptic plasticity and memory processes and has emerged as a critical target for ameliorating AD-associated cognitive deficits. Although M1 mAChR agonists have pro-cognitive potential, their clinical application is limited by significant cholinergic side effects. Our recent findings demonstrate that VU0486846, an M1 mAChR positive allosteric modulator (PAM) devoid of cholinergic toxicity, exhibits therapeutic benefits in a female APPswe/PSEN1ΔE9 (APP/PS1) Alzheimer's disease mouse model. This compound reversed memory deficits, alleviated anxiety-like behaviours, reduced Aβ pathology, and attenuated neuroinflammation in female mice. However, its therapeutic potential in male AD models remains to be fully characterized. In this study, we find that VU0486846 treatment restored cognitive function in male APP/PS1 mice, as evidenced by improved performance in the novel object recognition and Morris water maze tasks, and reduced anxiety-like behaviours in the open field test. VU0486846 ameliorates impaired autophagy signaling in the hippocampus, however, it does not alter hippocampal Aβ oligomer or plaque burden, despite decreasing BACE1 expression. These findings suggest that VU0486846 exerts behavioural and cognitive benefits via Aβ-independent mechanism(s). Collectively, this study highlights the therapeutic potential of VU0486846 in modulating AD pathophysiology, albeit via sex-specific signaling pathways.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"280 ","pages":"Article 110654"},"PeriodicalIF":4.6,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962574","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":"Anterior cingulate cortex dysfunction underlies anxiety-like behaviors in MT2-deficient mice","authors":"Xiaodan Wang ,&nbsp;Lixia Zhuo ,&nbsp;Wei Wu ,&nbsp;Dongqi Cui ,&nbsp;Huan Sun ,&nbsp;Feidi Wang ,&nbsp;Peiyu Luo ,&nbsp;Yixuan Lyu ,&nbsp;Yifang Zhai ,&nbsp;Jiao Han ,&nbsp;Yan Li ,&nbsp;Xin Shen ,&nbsp;Ying Xiao ,&nbsp;Ruosong Ai","doi":"10.1016/j.neuropharm.2025.110652","DOIUrl":"10.1016/j.neuropharm.2025.110652","url":null,"abstract":"<div><div>Anxiety disorders are prevalent mental health conditions with significant impacts on quality of life. While the melatonin type 2 receptor (MT2) has been implicated in anxiety, its specific role and neural mechanisms remain unclear. This study investigates the deficiency of MT2 induces robust anxiety-like phenotypes in mice, mediated through anterior cingulate cortex (ACC) dysfunction. Global knockout (MT2-KO) and conditional ACC-targeted deletion (MT2-cKO) models consistently demonstrated increased anxiety responses in standardized behavioral batteries, establishing ACC MT2 as a key neuromodulator in emotional regulation. Electrophysiological recordings revealed that MT2 deficiency disrupted excitatory-inhibitory (E/I) balance of ACC pyramidal neurons. Chemogenetic activation of MT2-positive neurons in the ACC restored E/I balance and ameliorated anxiety-like behaviors in chronic immobility stress (CIS) model mice. These findings establish MT2 as a pivotal regulator of ACC neurocircuitry and implicate targeted modulation of ACC MT2 signaling as a potential therapeutic strategy for anxiety disorders.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110652"},"PeriodicalIF":4.6,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144902718","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":"Reduced activation of pain-related brain regions with lysophosphatidic acid receptor subtype-1 antagonist PIPE-791 in a nonhuman primate model of chronic peripheral neuropathy","authors":"Aldric Hama ,&nbsp;Christopher Baccei ,&nbsp;Austin Chen ,&nbsp;Michael Poon ,&nbsp;Karin Stebbins ,&nbsp;Ken Okamoto ,&nbsp;Yoshitaka Itani ,&nbsp;Tae Kosugi ,&nbsp;Mayumi Matsushita ,&nbsp;Kenya Nozawa ,&nbsp;Takahiro Natsume ,&nbsp;Hiroryuki Takamatsu ,&nbsp;Daniel S. Lorrain","doi":"10.1016/j.neuropharm.2025.110647","DOIUrl":"10.1016/j.neuropharm.2025.110647","url":null,"abstract":"<div><div>Lysophosphatidic acid (LPA) has been suggested to be a key mediator of painful peripheral neuropathy and blocking its action on LPA receptors could reduce symptoms by decreasing the neuroinflammatory cascade underlying neuropathic pain. The current study examined the effect of PIPE-791, a novel and potent LPA subtype-1 receptor (LPA1R) antagonist which has previously been shown to block demyelination in rodent preclinical models, on regional brain activation in response to non-noxious mechanical stimulation of the foot in male macaques with a unilateral right sciatic nerve injury. Thirteen days after nerve injury, stimuli that did not previously lead to activation in naïve macaques activated the anterior cingulate cortex (ACC) and contralateral insular/secondary somatosensory cortex (Ins/SII). Beginning two weeks after nerve injury, macaques were treated for 28 days with daily oral administration of PIPE-791 by gavage. Six weeks after nerve injury (one day after the last dose of PIPE-791) activation of the contralateral Ins/SII was reduced. Eight weeks after nerve injury (15 days after the last dose), activation of the ipsilateral thalamus, as well as activation of the ACC and contralateral thalamus and Ins/SII was observed. An overall pattern of elevated LPA species following nerve injury and decline with treatment was observed. Evoked brain activation could be related to painful peripheral neuropathy and reduced brain activation could be a direct indicator of reduced pain perception following treatment. The current findings suggest decreasing neuroinflammation by blocking LPA1Rs could be a novel approach to the management chronic painful peripheral neuropathy.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"280 ","pages":"Article 110647"},"PeriodicalIF":4.6,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144920313","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":"Lithium restores inhibitory function and neuronal excitability through GSK-3β inhibition in a bipolar disorder-associated Ank3 variant mouse model","authors":"René N. Caballero-Florán ,&nbsp;Kendall P. Dean ,&nbsp;Andrew D. Nelson ,&nbsp;Lia Min ,&nbsp;Paul M. Jenkins","doi":"10.1016/j.neuropharm.2025.110649","DOIUrl":"10.1016/j.neuropharm.2025.110649","url":null,"abstract":"<div><div>Bipolar disorder (BD) is a prevalent psychiatric condition characterized by mood dysregulation, psychosocial impairment, and an increased risk of suicide. The gene <em>ANK3</em> has been identified as a risk locus for BD through multiple genome-wide association studies (GWAS). However, the mechanisms by which <em>ANK3</em> variants influence BD pathophysiology and treatment response remain unclear. <em>ANK3</em> encodes ankyrin-G, a protein that organizes the axon initial segment (AIS) and nodes of Ranvier by scaffolding ion channels and cell adhesion molecules to the cytoskeleton. Recent studies show that ankyrin-G interacts with the GABA_A receptor-associated protein (GABARAP) to stabilize inhibitory synapses, potentially linking <em>ANK3</em> variants to inhibitory (GABAergic) signaling deficits associated with BD. We previously demonstrated that the BD-associated variant, <em>ANK3</em> p.W1989R, disrupts the ankyrin-G/GABARAP interaction, resulting in inhibitory deficits and cortical pyramidal neuron hyperexcitability in mice. In this study, we investigate how lithium, a common BD therapeutic, modulates neuronal excitability in this model. Our findings show that chronic lithium treatment selectively enhances presynaptic GABAergic neurotransmission, reduces neuronal hyperexcitability, and partially rescues AIS length, without altering the density of GABAergic synapses. We also show that the selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor Tideglusib recapitulates the enhancement of presynaptic GABAergic signaling. These findings shed new light on how <em>ANK3</em> variants may contribute to inhibitory deficits in BD and demonstrate that lithium treatment is able to restore these deficits, likely through GSK-3β inhibition. Furthermore, these findings highlight GSK-3β inhibition as a promising therapeutic strategy for treating BD and other neurological disorders affected by GABAergic dysfunction.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110649"},"PeriodicalIF":4.6,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144902772","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}