Neuropharmacology最新文献

{"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}

{"title":"Acetazolamide alleviates motion sickness by inhibiting inner ear carbonic anhydrase 2 and reducing endolymph volume","authors":"Miao-Miao Chen ,&nbsp;Chao-Yue Tian ,&nbsp;Jian-Gang Ge ,&nbsp;Xia Li ,&nbsp;Bin Peng ,&nbsp;Wei Ji ,&nbsp;Lei Cui ,&nbsp;Li-Hua Xu ,&nbsp;Zheng-Lin Jiang","doi":"10.1016/j.neuropharm.2026.110829","DOIUrl":"10.1016/j.neuropharm.2026.110829","url":null,"abstract":"<div><div>Motion sickness is common in aerospace, aviation and maritime operations, and travel by vehicles or ships. Existing preventive and therapeutic drugs for motion sickness induce central nervous system (CNS)-related side effects; therefore, there is an urgent need to find new anti-motion sickness targets and to develop novel drugs with reduced adverse effects. In this study, we found that rotational stimulation significantly upregulated carbonic anhydrase 2 (CA2) expression in the inner ears of guinea pigs and mice. Pretreatment with acetazolamide (AZ), an inhibitor of carbonic anhydrase, effectively mitigated motion sickness-related behavioral symptoms in both species and inhibited increase in the inner ear endolymph volume induced by rotational stimulation. Further investigations revealed that AZ mediated its anti-motion sickness effects primarily through mechanisms involving the reduction of intracellular H⁺ concentrations in vestibular epithelial cells, inhibition of Na⁺-K⁺-ATPase activity, and modulation of intracellular Na⁺ and K⁺ homeostasis, thereby attenuating endolymph accumulation in the inner ear. This study demonstrated for the first time an involvement of the inner ear CA2 in the induction of motion sickness and an anti-motion sickness effect of its inhibitor AZ, providing a new strategy for developing anti-motion sickness drugs acting on the inner ear.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110829"},"PeriodicalIF":4.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145940484","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":"Spinal Shati/nat8l regulates mechanical hyperalgesia through NAAG-mGluR3 signaling in neuropathic pain","authors":"Keisuke Miyamoto ,&nbsp;Kousuke Tatsuta ,&nbsp;Kazuyuki Sumi ,&nbsp;Kyosuke Uno ,&nbsp;Kazuki Tokoro ,&nbsp;Shin-ichi Muramatsu ,&nbsp;Naotaka Izuo ,&nbsp;Kazuhiko Kume ,&nbsp;Atsumi Nitta ,&nbsp;Masahiro Ohsawa","doi":"10.1016/j.neuropharm.2025.110819","DOIUrl":"10.1016/j.neuropharm.2025.110819","url":null,"abstract":"<div><div><em>Shati/nat8l</em> catalyzes the synthesis of N-acetylaspartate (NAA), a precursor for N-acetylaspartylglutamate (NAAG), an endogenous agonist of group II metabotropic glutamate receptor 3 (mGluR3). Although spinal mGluR3 is known to modulate nociceptive signaling, the functional role of <em>Shati/nat8l</em> in pain transmission has remained unclear. In this study, we investigated the involvement of spinal <em>Shati/nat8l</em> in mechanical nociceptive processing and neuropathic pain.</div><div>We found that <em>Shati/nat8l</em> knockout (Shati−/−) mice exhibited a significantly decreased mechanical pain threshold compared to wild-type controls. This hypersensitivity was reversed by adeno-associated virus (AAV)-mediated expression of <em>Shati/nat8l</em> in the spinal dorsal horn. Intrathecal administration of NAAG—but not NAA—restored mechanical thresholds in Shati−/− mice, and this effect was blocked by the group II mGluR antagonist LY341495. In addition, treatment with LY341495 showed antinociceptive effect in normal mice at higher doses. In a peripheral nerve injury model, expression of <em>Shati/nat8l</em> mRNA in the ipsilateral dorsal horn was significantly decreased. Importantly, AAV-mediated restoration of <em>Shati/nat8l</em> expression in the dorsal horn alleviated neuropathic mechanical hyperalgesia and normalized <em>Shati/nat8l</em> mRNA levels.</div><div>These findings suggest that downregulation of spinal <em>Shati/nat8l</em> contributes to mechanical hypersensitivity by impairing the NAAG-mGluR3 signaling pathway. Targeting the <em>Shati/nat8l</em>–NAAG–mGluR3 axis may offer a novel therapeutic strategy for the treatment of neuropathic pain.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110819"},"PeriodicalIF":4.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892969","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 frequency of binge-like ethanol exposure bidirectionally regulates hippocampal mGlu-LTD via synaptic mechanisms and this effect is reversed by minocycline","authors":"M. Debris ,&nbsp;C. Deschamps ,&nbsp;M. Martin ,&nbsp;L. Zabijak ,&nbsp;M. Ouriemi ,&nbsp;M. Ropiquet ,&nbsp;C. Vilpoux ,&nbsp;M. Naassila ,&nbsp;O. Pierrefiche","doi":"10.1016/j.neuropharm.2026.110836","DOIUrl":"10.1016/j.neuropharm.2026.110836","url":null,"abstract":"<div><div>Alcohol addiction may begin in young adults through binge drinking (BD) with its frequency as key criterion. In rodents, BD impairs memory and hippocampal synaptic plasticity on the short term and induced neuroinflammation. Memory impairments may persist into adulthood, whereas long-lasting disturbances in hippocampus synaptic plasticity have not been documented. Moreover, the impact of BD frequency on such disturbances and the potential of anti-inflammatory agents to reverse BD-induced alterations remain unclear. Using hippocampal slices from male rats subjected to eight binge-like episodes delivered at high (HF) or low (LF) frequency during adolescence, we found that alterations in group I metabotropic long-term depression (mGlu_1/5-LTD) were related to binge-like exposure frequency, with HF reducing mGlu_1/5-LTD and intriguingly, LF increasing it. Inhibiting mTORC1 with rapamycin partially corrected LF and HF effects, without alteration of ribosomal protein S6 phosphorylation, a protein downstream of mTORC1, after LF and, a decrease of rp-S6^235/236 after HF. Moreover, LF decreased presynaptic GABA vesicular transporter and bicuculline replicated the increased mGlu_1/5-LTD after LF. Additionally, <em>N</em>-methyl-D-aspartate receptor-dependent LTD was transiently reduced after HF or LF and rescued with a GluN2B antagonist. Finally, the anti-inflammatory agent, minocycline, administered after the ethanol exposure, reversed all synaptic plasticity alterations. We concluded that bidirectional alteration in mGlu_1/5-LTD is a hallmark of ethanol binge exposure frequency, involving pre- and postsynaptic mechanisms. Targeting GluN2B and using anti-inflammatory agents offers promising therapeutic strategies to mitigate the synaptic effects of BD. Our findings highlight the frequency of ethanol exposure as a key determinant of neuronal impact.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110836"},"PeriodicalIF":4.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145979710","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":"Incubation of oxycodone craving is associated with CP-AMPAR upregulation in D1 and A2a receptor-expressing medium spiny neurons in nucleus accumbens core and shell","authors":"Kimberley A. Mount ,&nbsp;Hayley M. Kuhn,&nbsp;Eun-Kyung Hwang,&nbsp;Madelyn M. Beutler,&nbsp;Marina E. Wolf","doi":"10.1016/j.neuropharm.2025.110816","DOIUrl":"10.1016/j.neuropharm.2025.110816","url":null,"abstract":"<div><div>A major problem in treating opioid use disorder is persistence of craving after protracted abstinence. This has been modeled in rodents using the incubation of craving model, in which cue-induced drug seeking increases over the first weeks of abstinence from drug self-administration and then remains high for an extended period. Incubation has been reported for several opioids, including oxycodone, but little is known about underlying synaptic plasticity. In contrast, it is well established that incubation of cocaine and methamphetamine craving depends on strengthening of glutamate synapses in the nucleus accumbens (NAc) through incorporation of calcium-permeable AMPARs (CP-AMPARs). CP-AMPARs have higher conductance than the calcium-impermeable AMPARs that mediate NAc excitatory transmission in drug-naïve animals, as well as other distinct properties. Here we examined AMPAR transmission in medium spiny neurons (MSN) of NAc core and shell subregions after forced abstinence from extended-access oxycodone or saline self-administration, using male and female wild-type and transgenic rats. Before incubation (abstinence days 1–2), CP-AMPAR upregulation was not detected in either D1 or A2a (D2) receptor-expressing MSN. After incubation had stably plateaued (abstinence days 17–33), CP-AMPARs were elevated in both MSN subtypes in both subregions. These results explain the prior demonstration that infusion of a selective CP-AMPAR antagonist into NAc core or shell prevents expression of oxycodone incubation. However, CP-AMPAR upregulation on both MSN subtypes contrasts with selective upregulation on D1 MSN after cocaine and methamphetamine incubation. Our results demonstrate a common role for CP-AMPAR upregulation in psychostimulant and oxycodone incubation, albeit with differences in MSN subtype-specificity.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110816"},"PeriodicalIF":4.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850515","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":"Peripheral alpha-2 antagonist vatinoxan improves dexmedetomidine-induced perivascular cerebrospinal fluid flow without affecting electroencephalogram activity in female rats","authors":"Hanna Antila ,&nbsp;Sonja C. Jalonen ,&nbsp;Niklas Daniel Åke Persson ,&nbsp;Martta Peltoniemi ,&nbsp;Terhi J. Lohela ,&nbsp;Tuomas O. Lilius","doi":"10.1016/j.neuropharm.2026.110828","DOIUrl":"10.1016/j.neuropharm.2026.110828","url":null,"abstract":"<div><h3>Background</h3><div>The glymphatic concept represents a brain-wide perivascular fluid network contributing to brain metabolite clearance. Dexmedetomidine, a sedative α₂-adrenergic receptor agonist, enhances perivascular cerebrospinal fluid (CSF) flow by reducing central noradrenergic tone and inducing sleep-like electroencephalogram (EEG) slow-wave activity. Concurrently, α₂-adrenergic agonists modulate peripheral physiological functions, possibly influencing the central glymphatic dynamics. Utilizing peripherally restricted α₂-adrenergic antagonist vatinoxan, we evaluated the role of physiological parameters on the glymphatic-enhancing properties of dexmedetomidine.</div></div><div><h3>Methods</h3><div>The effects of vatinoxan on the EEG spectral signature of dexmedetomidine and physiological parameters were investigated in female Sprague-Dawley rats. The whole-body distribution of intracisternally infused radiolabeled CSF tracer technetium-99m-labeled diethylenetriaminepentaacetic acid ([⁹⁹ᵐTc]Tc-DTPA) was quantified utilizing single-photon emission computed tomography (SPECT).</div></div><div><h3>Results</h3><div>While vatinoxan had no influence on the EEG spectral signature of dexmedetomidine sedation, it alleviated the peripheral effects, such as peripheral vasoconstriction, hyperglycemia, diuresis, and hyperosmolality. Vatinoxan created a unique CSF tracer distribution pattern by elevating the cortical tracer availability, quantified as area under the time–activity curve (AUC_0-91), by 36 % (AUC_0–91 ratio, 1.36; 95 % CI, 1.0–1.8), increasing the maximum tracer concentration (C_max) in the intracranial space by 39 % (C_max ratio, 1.39; 95 % CI, 1.06–1.81), and decreasing the tracer availability in the spinal canal by 25 % (AUC_0–91 ratio, 0.75; 95 % CI, 0.66–0.85). Simultaneously, vatinoxan promoted the tracer egress from the CNS by 360 % (AUC_0–91 ratio, 4.6; 95 % CI, 2.7–7.8).</div></div><div><h3>Conclusions</h3><div>Antagonism of peripheral α₂-adrenergic receptors with vatinoxan during dexmedetomidine sedation enhances perivascular CSF influx, irrespective of slow-wave activity.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110828"},"PeriodicalIF":4.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900861","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":"Brain-penetrant microtubule-stabilizer epothilone B delays isoflurane-induced unconsciousness in mice","authors":"Yixiang Huang ,&nbsp;Zitong Qiu ,&nbsp;Xinyue Yu,&nbsp;Sophia Lee,&nbsp;Xiran Zeng,&nbsp;Abbie Chang,&nbsp;Michael C. Wiest","doi":"10.1016/j.neuropharm.2026.110834","DOIUrl":"10.1016/j.neuropharm.2026.110834","url":null,"abstract":"<div><div>Inhalational anesthetics are currently believed to cause unconsciousness by acting on multiple molecular targets including neural ion channels, receptors, mitochondria, synaptic proteins, and cytoskeletal proteins. Inhalational anesthetics including isoflurane bind to cytoskeletal microtubules (MTs), potentially contributing to causing unconsciousness. This possibility is supported by our demonstration of isoflurane resistance in rats treated once with the brain-penetrant MT-stabilizing drug epothilone B (epoB), and by a recent study in mice using a similar drug given daily over two weeks, which found <em>increased</em> sensitivity to isoflurane. To further characterize the contribution of MTs as functionally relevant targets of volatile anesthetics in mice, we measured latencies to loss of righting reflex (LORR) under isoflurane in mice injected once subcutaneously with vehicle or epoB.</div><div>We found significantly increased LORR latencies (i.e., anesthetic resistance) in 8 mg/kg epoB-treated mice on the day following injection, with reduced effects on subsequent days. The 29-s within-subject increase in LORR latencies is not large compared to the variability among different animals, but it represents a statistically large within-subject effect as represented by a Cohen's d of 0.8. The effect could not be accounted for by tolerance from repeated exposure to isoflurane. Our results support that binding of the inhalational anesthetic isoflurane to MTs contributes to LORR in mice, as it does in rats. Our findings support the Orchestrated Objective Reduction (Orch OR) model that posits consciousness as a property of a quantum physical state of neural MTs. We also discuss possible sex differences in anesthetic mechanisms suggested by our data.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110834"},"PeriodicalIF":4.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948989","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":"Lactate-driven H3K27 lactylation promotes Olig2-dependent remyelination and motor recovery after spinal cord injury","authors":"Zongxin Zhu ,&nbsp;Ximiao Chen ,&nbsp;Hanwen Zhang ,&nbsp;Ronghui Miao ,&nbsp;Huiling Yu ,&nbsp;Shiying Zhao ,&nbsp;Youli Zhang ,&nbsp;Tanxin Yu ,&nbsp;Di Zhang ,&nbsp;Yifei Zhou ,&nbsp;Xiaolei Zhang ,&nbsp;Wei Zhang","doi":"10.1016/j.neuropharm.2026.110832","DOIUrl":"10.1016/j.neuropharm.2026.110832","url":null,"abstract":"<div><div>Demyelination caused by oligodendrocyte death is a key contributor to neurological deficits after spinal cord injury (SCI), highlighting the critical need to promote oligodendrocyte precursor cell (OPC) differentiation and remyelination. The transcription factor Olig2 is a master regulator of this process; however, its activation mechanism remains unclear. Given the marked lactate accumulation in post-SCI ischemic microenvironments, we investigated the role of lactate in SCI as well as its regulation on OPC differentiation. In a rat SCI model, it is found that exogenous lactate administration significantly improves motor recovery, preserves neurons and axons, modulates the glial response. Mechanistically, lactate induces histone H3K27 lactylation (H3K27la), which specifically upregulates Olig2 expression, thereby activating OPC differentiation and remyelination. This study uncovers the lactate-H3K27la-Olig2 metabolic-epigenetic axis as a novel endogenous repair mechanism for SCI, providing a foundation for metabolism-targeted therapeutic strategies.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110832"},"PeriodicalIF":4.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145960024","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}