Neuropharmacology[JOURNAL]
Sun
200 papers
NADPH exerts neuroprotection in ischemic stroke by reinforcing blood-brain barrier integrity and stimulating angiogenesis.
Xu H, Zhang H, Shi RR … +4 more , Ge JB, Wu F, Qin ZH, Gu JH
Neuropharmacology · 2026 May · PMID 41638470 · Publisher ↗
Ischemic stroke (IS) represents a significant global health burden with increasing incidence, creating an urgent need for novel therapeutic approaches. This study explored the neuroprotective effects of nicotinamide aden...
Ischemic stroke (IS) represents a significant global health burden with increasing incidence, creating an urgent need for novel therapeutic approaches. This study explored the neuroprotective effects of nicotinamide adenine dinucleotide phosphate (NADPH) in preserving blood-brain barrier (BBB) integrity and promoting angiogenesis after IS. Through network pharmacology analysis and molecular docking, five key molecular targets of NADPH in IS were identified: HIF-1α, SRC, NLRP3, CASP3, and AKT1. In vivo, NADPH treatment conferred significant protection against cerebral ischemia in the transient middle cerebral artery occlusion (tMCAO) model. At the optimal dose of 7.5 mg/kg, it substantially reduced infarct volume (∼50%), attenuated cerebral edema (from 81% to 76%), improved neurological function (∼58%), and preserved BBB integrity. Mechanistically, NADPH protected the BBB by upregulating key tight junction (TJ) proteins, including a ∼29% increase in ZO-1 expression, with electron microscopy confirming strengthened TJ structure. NADPH also reduced the protein levels of matrix metalloproteinase-9 (MMP9) and caveolin-1 by ∼23% and 50%, respectively. Furthermore, it suppressed NLRP3 inflammasome activation, decreased the expression of NLRP3 (∼14%), ASC (∼24%), Caspase-1 (∼30%), and interleukin-1β (IL-1β; ∼16%), thereby attenuating inflammation. In vitro, NADPH enhanced endothelial cell proliferation, migration, and tube formation under oxygen-glucose deprivation (OGD) conditions. Additionally, NADPH further elevated the expression of key pro-angiogenic markers, increasing HIF-1α protein by ∼77.1% and vascular endothelial growth factor (VEGF) by ∼44.8% at day 7 post-tMCAO. These findings suggest that NADPH confers neuroprotection in IS by preserving BBB integrity, inhibiting NLRP3 inflammasome-mediated damage, and stimulating angiogenesis through HIF-1α/VEGF signaling. Our results highlight NADPH's dual therapeutic mechanisms and its potential as a promising neuroprotective agent for IS.
Sex-dependent disruption of affective behaviors by GBR 12909: relevance to bipolar disorders.
Certon M, Brizard B, Belzung C … +3 more , Surget A, Tanti A, Bloch S
Neuropharmacology · 2026 May · PMID 41638469 · Publisher ↗
Bipolar disorders (BD) are defined by a chronic recurrence of manic and depressive phases. Along with mood, acute phases are associated with altered emotions. The biological underpinnings of these changes are unresolved,...
Bipolar disorders (BD) are defined by a chronic recurrence of manic and depressive phases. Along with mood, acute phases are associated with altered emotions. The biological underpinnings of these changes are unresolved, mostly because modeling the cycling nature of BD is still a major challenge in preclinical studies. One pharmacological model is based on GBR 12909 administration, a dopamine transporter inhibitor aiming at mimicking some dimensions of mania. Recent findings indicate that this model generates a mixed phenotype, combining hyperlocomotion with negative hedonic biases and anxiety. These studies have only been performed in male animals, and other behavioral dimensions relevant for BD remain to be explored, in particular recognition of conspecific emotional states and reactivity to danger. The objective of this study is to further characterize the GBR model in mice of both sexes by introducing two novel behavioral assays, the sweeping/looming disk and the negative emotion recognition tasks to evaluate response to threat and emotion discrimination. First, we replicated the previous results in the GBR model: higher anxiety, hyperlocomotion, anhedonia in males. These phenotypes were less pronounced and did not reach significance in females. GBR also induced a hypersensitivity to threat in both sexes in the sweeping/looming disk. GBR abolished preference for the emotional target only in males, suggesting altered emotion recognition. This work introduces new phenotypic dimensions relevant to study BD and highlights the necessity to study both sexes which are not strictly equivalent in their behavioral responses.
Discovery of a novel IMS48 as a dual inhibitor of acetylcholinesterase and butyrylcholinesterase: In vitro and in vivo study for Alzheimer therapy.
Munir S, Chauhdary Z, Khan IA … +3 more , Ahmad M, Khurshid M, Ashfaq UA
Neuropharmacology · 2026 May · PMID 41628818 · Publisher ↗
Current medications for Alzheimer's disease (AD) provide symptomatic relief only and fail to prevent neurodegeneration, necessitating the development of new therapeutic agents. This study aimed to evaluate benzimidazole...
Current medications for Alzheimer's disease (AD) provide symptomatic relief only and fail to prevent neurodegeneration, necessitating the development of new therapeutic agents. This study aimed to evaluate benzimidazole (BIM) analogs as potential inhibitors for AD. In vitro screening identified 1-benzyl-3-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1H-benzo[d]imidazole-3-ium chloride (IMS48) as a potent inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with IC values of 0.31 ± 0.04 μM and 1.85 ± 0.05 μM, respectively, outperforming the standard drug donepezil. In the in vivo study, rats were administered D-gal (300 mg/kg) and AlCl (150 mg/kg) orally for three weeks to induce AD-like symptoms. Concurrently, IMS48 was administered at doses of 0.75 mg/kg and 1.5 mg/kg for 21 days. Donepezil (DON) was used as a positive control to evaluate the therapeutic efficacy of the IMS8 compound. IMS48 treatment significantly reversed behavioral alterations and improved learning ability. Histopathological analysis demonstrated that IMS48 effectively inhibited neuronal death and neurofibrillary tangles in the brain tissue. Furthermore, IMS48 restored the altered antioxidant enzyme levels (p < 0.001), reducing malondialdehyde (MDA) concentration and enhancing superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT) concentrations. IMS48 also downregulated the gene expression of AChE (1.56 ± 0.10-fold and 1.71 ± 1.76-fold), APP (1.96 ± 0.17-fold and 3.39 ± 0.139-fold), BACE1 (1.92 ± 0.10-fold and 2.59 ± 0.04-fold), TNFα (2.16 ± 0.21-fold and 3.35 ± 0.17-fold), IL-1α (1.86 ± 0.236-fold and 2.56 ± 0.15-fold), and IL-1β (1.58 ± 1.82-fold and 2.32 ± 0.13-fold), associated with AD pathology and neuroinflammation. Overall, these findings highlight the neuroprotective potential of IMS48 in enhancing cognitive function and mitigating neurodegeneration in AD.
Sevoflurane, but not alphaxalone, causes lasting autism spectrum disorder-like pathology in male mice after exposure occurs during synaptogenesis.
Volvovitz B, Newson A, Milosevic A … +5 more , Timic Stamenic T, Useinovic N, Milosavljevic N, Todorovic SM, Jevtovic-Todorovic V
Neuropharmacology · 2026 May · PMID 41621700 · Full text
BACKGROUND AND PURPOSE: Early-life general anesthesia (GA) may cause changes in socio-emotional behaviors in animals and autism spectrum disorder (ASD) in humans. The mechanisms behind GA-induced ASD symptoms are unknown...
BACKGROUND AND PURPOSE: Early-life general anesthesia (GA) may cause changes in socio-emotional behaviors in animals and autism spectrum disorder (ASD) in humans. The mechanisms behind GA-induced ASD symptoms are unknown. We investigate the mTOR activation as a potential cause of ASD. We assess ASD-like pathology after neonatal GA exposure to a volatile agent, sevoflurane, or an injectable GA, alphaxalone. EXPERIMENTAL APPROACH: We exposed male mouse pups on postnatal day 7 (PND7) to sevoflurane or alphaxalone (and their respective vehicles) for 6 h. We performed histomorphological analysis of caspase-3 activity in subiculum 2 h post-GA exposure and Western blot analysis of mTOR activation in hippocampus 24 h post-GA exposure. Spike firing in thalamic neurons was assessed at 4-6 weeks post-GA exposure. Behavioral tests for ASD-like features, including ultrasonic vocalization (USV) at PND8, nestlet shredding, marble burying, and 3-chamber social tests were conducted in adulthood. KEY RESULTS: Sevoflurane, unlike alphaxalone, induced more nestlet shredding/marble burying compared to controls, and caused a shift away from the social preference and towards inanimate object. USV suggested a reduction in ultrasonic calls after sevoflurane, but not alphaxalone. The behavioral changes with sevoflurane were accompanied by an increase in caspase-3 activation, hyperactivation of mTOR, and an increase in neuronal firing compared to controls. The sevoflurane effects were largely reversed with rapamycin (a negative modulator of mTOR). CONCLUSION AND IMPLICATIONS: Unlike sevoflurane, alphaxalone does not cause long-lasting ASD-type behaviors and does not affect the mTOR activation and histomorphology, suggesting that alphaxalone could be a safer alternative to sevoflurane.
Pharmacological modulation of wakefulness and extracellular hypothalamic histamine release in adult male mice using TAK-925, modafinil, pitolisant, MK-8133 and Lu AF11167.
Hviid CG, Sørensen G, Kornum BR … +1 more , Herrik KF
Neuropharmacology · 2026 May · PMID 41621699 · Publisher ↗
Histamine is a key regulator of wake and arousal, however its role in pharmacological modulation of wake is largely unknown. Specifically, whether histamine is always activated during pharmacologically induced wake promo...
Histamine is a key regulator of wake and arousal, however its role in pharmacological modulation of wake is largely unknown. Specifically, whether histamine is always activated during pharmacologically induced wake promotion or even necessary for wake remains unclear. This study therefore measured EEG/EMG and accelerometer activity to determine sleep/wake states and locomotor activity and determined extracellular hypothalamic histamine levels using microdialysis following treatment with five wake- and sleep-modulatory compounds. We investigated the effects of three presumed wake-promoting compounds TAK-925 (danavorexton), modafinil and pitolisant as well as two presumed sleep-inducing compounds MK-8133 and Lu AF11167 in adult male mice. TAK-925 and modafinil dose-dependently prolonged wakefulness, whereas pitolisant had no effect. In contrast, TAK-925 and pitolisant increased extracellular histamine levels in hypothalamus, whereas modafinil had no effect. MK-8133 and Lu AF11167 both reduced wakefulness and decreased extracellular hypothalamic histamine levels. In vehicle-treated male mice, histamine levels were correlated with wakefulness but in pharmacologically treated male mice, this correlation was decoupled. These data demonstrate that wake can be modulated without modulating histamine signaling and vice versa.
Fentanyl reinforcement history has sex-specific effects on multi-step decision-making.
Garr E, Cheng Y, Dong A … +1 more , Janak PH
Neuropharmacology · 2026 May · PMID 41619903 · Full text
It is commonly thought that drug addiction involves a transition to habitual control of action, where the choice to consume drugs becomes automatized and reflects a failure to deliberate over possible negative outcomes....
It is commonly thought that drug addiction involves a transition to habitual control of action, where the choice to consume drugs becomes automatized and reflects a failure to deliberate over possible negative outcomes. Determining whether the pursuit of addictive drugs is habitual is hampered by a lack of behavior assessments suitable for use during a bout of actual drug seeking. Therefore, to understand how variable histories of drug reinforcement might affect goal-directed and habitual pursuit of drug, we trained rats to perform a multi-step decision-making task to earn oral fentanyl and sucrose rewards following extensive pretraining with either fentanyl or sucrose. Importantly, this task allowed for independent measurements of goal-directed and habitual choice characteristics during online pursuit of rewards, and habitual choice could be further categorized into perseverative and reward-guided components. Chronic fentanyl led to a bias for reward-guided habitual choice specifically in females, and a high degree of perseveration in both sexes. These behavioral changes after chronic fentanyl pretraining generalized across fentanyl and sucrose seeking. In contrast, acute fentanyl selectively increased perseveration in females, and blunted the gradual within-session improvement in goal-directed choice in both sexes. These results show that chronic fentanyl reinforcement promotes habits that generalize across drug and non-drug reward seeking, and that female rats are especially susceptible to habitual control induced by both chronic and acute fentanyl reinforcement.
The potent and selective adenosine AR antagonists P400 and P625 protect against symptoms in autoimmune experimental encephalomyelitis by attenuating neuroinflammation and demyelination.
Morozzi M, Borgonetti V, Sasia C … +6 more , Videtta G, Calenda S, Catarzi D, Varano F, Colotta V, Galeotti N
Neuropharmacology · 2026 May · PMID 41610910 · Publisher ↗
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 t...
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 receptor (AR), the inflammatory and immune response. The aim of this study is to investigate the therapeutic potential of new selective AR 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&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 AR antagonists in ameliorating EAE symptoms by attenuating neuroinflammation and demyelination. These findings further highlight AR blocking as a promising perspective to control neurological disturbances in MS patients.
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.
Acosta-Vargas JS, de Las Heras-Martínez N, Marcos A … +4 more , Nozal L, Crego AL, Ucha M, Higuera-Matas A
Neuropharmacology · 2026 May · PMID 41580119 · Publisher ↗
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 i...
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 Δ-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.
Psilocin mediates long-term synaptic depression in the prelimbic cortex through 5-HT receptor-independent mechanisms.
Domi A, Lucente E, Cadeddu D … +3 more , Bengtsson N, Smedler E, Adermark L
Neuropharmacology · 2026 May · PMID 41577180 · Publisher ↗
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 actio...
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 and metabotropic glutamatergic receptor group 2 and mediated through enhanced GABAergic tone. The effect was partially inhibited by 5-HT 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 receptor activation, may be associated with the reduced prefrontal connectivity reported in humans after psilocin administration and could have implications for cognitive function.
Ivabradine reduces seizure susceptibility in a genetic model of mixed epilepsies.
Silva-Cardoso GK, N'Gouemo P
Neuropharmacology · 2026 May · PMID 41577179 · Full text
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 investigate...
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.
The novel PSD-95 inhibitor BXOS110 provides neuroprotection in acute ischemic stroke.
Zheng HY, Ding YR, Guo FY … +8 more , Lyu TJ, Feng BY, Li H, Li SY, Dong GH, Wang YJ, Li ZX, Han HM
Neuropharmacology · 2026 May · PMID 41571082 · Publisher ↗
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 b...
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 N-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.
The interaction between FLOT1 and FOSL2 promotes EphA2 transcription, regulating microglial polarization and affecting neuroinflammation in Alzheimer's disease.
Li B, Xu J, Zhu H … +4 more , Ren D, Xiao L, Zhang T, Li R
Neuropharmacology · 2026 May · PMID 41548752 · Publisher ↗
BACKGROUND: 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,...
BACKGROUND: 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. METHODS: 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. RESULTS: 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 in vivo and that targeting this pathway improved cognitive outcomes in AD models. CONCLUSION: 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.
The frequency of binge-like ethanol exposure bidirectionally regulates hippocampal mGlu-LTD via synaptic mechanisms and this effect is reversed by minocycline.
Debris M, Deschamps C, Martin M … +6 more , Zabijak L, Ouriemi M, Ropiquet M, Vilpoux C, Naassila M, Pierrefiche O
Neuropharmacology · 2026 Apr · PMID 41544755 · Publisher ↗
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 neuroinflammati...
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-LTD) were related to binge-like exposure frequency, with HF reducing mGlu-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 after HF. Moreover, LF decreased presynaptic GABA vesicular transporter and bicuculline replicated the increased mGlu-LTD after LF. Additionally, N-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-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.
Electrocorticographic, astrocytic and transcriptomic signatures in the triple transgenic mouse model of Alzheimer's disease submitted to stearoyl-CoA desaturase inhibition.
Hector A, Leduc T, da Costa Caiado MJ … +9 more , Delignat-Lavaud B, Dufort-Gervais J, Daneault C, Des Rosiers C, Bourguignon C, Lina JM, Fernandes K, Brouillette J, Mongrain V
Neuropharmacology · 2026 May · PMID 41539386 · Publisher ↗
Alzheimer's disease (AD) is associated with cognitive deficits and sleep disturbances. Research suggests the involvement of dysfunctions in lipid metabolism in the brain of AD patients and animal models. The inhibition o...
Alzheimer's disease (AD) is associated with cognitive deficits and sleep disturbances. Research suggests the involvement of dysfunctions in lipid metabolism in the brain of AD patients and animal models. The inhibition of stearoyl-CoA desaturase (SCD), a lipid-converting enzyme, was shown to restore memory in triple transgenic (3xTg)-AD mice. In the brain, astrocytes regulate the synthesis of specific lipids. This project tested whether the inhibition of SCD restores sleep in 3xTg-AD mice, and whether this associates with modifications in lipids, astrocytic function and the transcriptome. Wild-type (WT) and 3xTg-AD female mice received a SCD inhibitor (SCDi) or vehicle, which was followed by an electrocorticographic (ECoG) recording. Brain slices were stained for lipid droplets, astrocytic markers or processed for spatial transcriptomics. The reduced time spent awake (increased time spent in slow wave sleep) in 3xTg-AD mice was not restored by SCDi treatment. Rhythmic and scale-free ECoG activities were markedly altered in 3xTg-AD mice for all wake/sleep states, and SCDi changed these ECoG signatures differently in mutant in comparison to WT mice. GFAP-positive cell density and lipid droplet count were elevated in hippocampal CA1, and rescued by SCDi. The treatment also rescued the expression of several genes in a manner mainly overlapping between brain regions. The findings suggest that the multiple wake/sleep alterations in 3xTg-AD mice are not mitigated by SCD inhibition, but that this treatment can revert changes in hippocampal astrocytes, lipids and in the brain transcriptome. This work will benefit the understanding of the AD pathophysiology and associated sleep disturbances.
Lactate-driven H3K27 lactylation promotes Olig2-dependent remyelination and motor recovery after spinal cord injury.
Zhu Z, Chen X, Zhang H … +9 more , Miao R, Yu H, Zhao S, Zhang Y, Yu T, Zhang D, Zhou Y, Zhang X, Zhang W
Neuropharmacology · 2026 Apr · PMID 41525841 · Publisher ↗
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 a...
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.
Assessing the utility of the neurosteroid zuranolone to modify alcohol-related behaviours.
Ursich LT, Pearl AJ, Maddern XJ … +2 more , Lawrence AJ, Walker LC
Neuropharmacology · 2026 May · PMID 41520874 · Publisher ↗
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) receptors and influence al...
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) 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.
Brain-penetrant microtubule-stabilizer epothilone B delays isoflurane-induced unconsciousness in mice.
Huang Y, Qiu Z, Yu X … +4 more , Lee S, Zeng X, Chang A, Wiest MC
Neuropharmacology · 2026 Apr · PMID 41519196 · Publisher ↗
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. Inhal...
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 increased 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. 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.
Acetazolamide alleviates motion sickness by inhibiting inner ear carbonic anhydrase 2 and reducing endolymph volume.
Chen MM, Tian CY, Ge JG … +6 more , Li X, Peng B, Ji W, Cui L, Xu LH, Jiang ZL
Neuropharmacology · 2026 Apr · PMID 41512954 · Publisher ↗
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 ef...
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.
NLRP10 ablation alleviates neuropathic pain by inhibiting excessive NIX/LC3-dependent mitophagy in the spinal cord.
Zhang X, Sun J, Zhao F … +4 more , Liu T, Yu S, Zhang W, Tian X
Neuropharmacology · 2026 Apr · PMID 41506445 · Publisher ↗
OBJECTIVE: 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,...
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Nose-to-brain delivery of dopamine to the striatum of rats using neurotransmitter-loaded solid lipid nanoparticles: an in vivo study by brain microdialysis.
Dazzi L, Talani G, Trapani G … +6 more , Capasso L, Carbone A, Di Gioia S, Conese M, Trapani A, Sanna E
Neuropharmacology · 2026 Apr · PMID 41485518 · Publisher ↗
The intranasal route is a noninvasive method of delivering therapeutic compounds to the Central Nervous System (CNS). However, challenges associated with this method include reduced drug absorption, limited administered...
The intranasal route is a noninvasive method of delivering therapeutic compounds to the Central Nervous System (CNS). However, challenges associated with this method include reduced drug absorption, limited administered volume, insufficient nasal permeability, and enzymatic nasal metabolism. Nanotechnology-based delivery systems are being developed to overcome these limitations and improve drug availability and therapeutic effectiveness. In this regard, we recently developed dopamine (DA)-loaded solid lipid nanoparticles (DA-SLNs) using self-emulsifying Gelucire® 50/13 to form PEGylated SLNs for intranasal administration. To enhance mucoadhesion, we coated these lipid nanoparticles with the mucoadhesive cationic polymer glycolchitosan (GCS). In the present study, we performed microdialysis and electrophysiological experiments in a male rat model to evaluate the ability of GCS-DA-SLNs, when administered intranasally, to modify striatal extracellular DA concentrations and induce changes in the functional properties of striatal neurons. The results showed that intranasal administration of GCS-DA-SLNs at DA doses of 2.5 and 4 mg/kg significantly increased the extracellular concentration of DA (+130 ± 38 %) and the extracellular concentration of DOPAC (only at the lower dose of 1 mg/kg, by 70 ± 3 %). Ex vivo electrophysiological recordings in striatal neurons revealed that intranasal administration of GCS-DA-SLNs, at a DA dose of 4 mg/kg, but not 2.5, mg/kg, enhanced HCN-mediated I current amplitude. A similar effect was also observed in vitro when striatal neurons were exposed to DA or the D1 receptor agonist SKF81297. Overall, our data underscore the significant potential of using GCS-DA-SLN nanocarriers to efficiently deliver DA and other therapeutic compounds via the nose-to-brain pathway.
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