Neuropharmacology[JOURNAL]
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200 papers
Antidepressant-like activity of JZ-1201 in male rodents: a novel selective 5-HT/NE reuptake inhibitor and 5-HT receptor partial agonist.
Gao H, Wang S, Liu Q … +3 more , Jia J, Yang Y, Jin Z
Neuropharmacology · 2026 May · PMID 42107524 · Publisher ↗
Depression has become a significant public health issue, highlighting the need for novel antidepressants. Based on the monoaminergic mechanisms of classical antidepressant drugs and the therapeutic potential of 5-HT rece...
Depression has become a significant public health issue, highlighting the need for novel antidepressants. Based on the monoaminergic mechanisms of classical antidepressant drugs and the therapeutic potential of 5-HT receptor activation, we designed a novel compound, JZ-1201, which acts as a selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor and 5-HT receptor partial agonist. This study aimed to evaluate its antidepressant-like effects and explore the underlying mechanisms involving 5-HT receptor activation and enhanced neuroplasticity. The results demonstrated that JZ-1201 exhibited high affinity for the serotonin transporter (SERT) and norepinephrine transporter (NET), and 5-HT receptors, inhibited 5-HT and NE reuptake. It enhanced the 5-hydroxytryptophan (5-HTP)-induced head-twitch response (HTR) and inhibited forskolin-stimulated cAMP formation. In male ICR mice, acute administration of JZ-1201 reduced immobility time in the tail suspension test (TST) and forced swim test (FST), an effect that was attenuated by the selective 5-HT receptor antagonist WAY-100635. Chronic administration of JZ-1201 significantly ameliorated depressive-like behaviors in male Wistar rats subjected to chronic unpredictable mild stress (CUMS). In CUMS rats, JZ-1201 increased dendritic spine density and the expression of PACAP/mTOR/BDNF signaling pathway proteins in the hippocampus. These findings indicate that JZ-1201 is a triple-target antidepressant compound and modulates hippocampal PACAP-related neuroplasticity. Thus, JZ-1201 could be developed as a novel therapeutic agent for the treatment of depression.
Paraprobiotics attenuate oxidative stress, dopaminergic neuron loss, and gut microbiome imbalance in an intranasal MPTP rat model of Parkinson's disease.
Gomes J, Rodrigues ES, Carvalhinho-Lopes PS … +12 more , Comis-Neto AA, Pujol Arena RV, Birmann PT, Fidelis EM, Meus SS, Rodrigues BG, Alves de Jesus GF, Ávila DS, Pesarico AP, Ribeiro AM, Rosa SG, Pinton S
Neuropharmacology · 2026 Sep · PMID 42105976 · Publisher ↗
Intestinal dysbiosis may contribute to the progression of Parkinson's disease (PD) by promoting inflammation and oxidative stress. Paraprobiotics, defined as non-viable microbial cells, have emerged as a promising therap...
Intestinal dysbiosis may contribute to the progression of Parkinson's disease (PD) by promoting inflammation and oxidative stress. Paraprobiotics, defined as non-viable microbial cells, have emerged as a promising therapeutic strategy. This study evaluated the neuroprotective, gastroprotective, and microbiota-modulating effects of a paraprobiotic blend comprising Lactobacillus casei CCT 7859, Bifidobacterium lactis CCT 7858, and Streptococcus thermophilus ATCC 19258 in a murine PD model induced via intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Seventy female Wistar rats received either intranasal MPTP or saline, followed 24 h later by 14 days of paraprobiotic treatment (100 mg/kg/day, intragastrically). Fecal and tissue samples were collected for microbiota, oxidative stress, dopaminergic neurodegeneration, and physiological parameter analyses. Antioxidant enzymes (superoxide dismutase and catalase), oxidative damage markers (malondialdehyde, reactive oxygen and nitrogen species), gut microbiota composition, immunohistochemistry for tyrosine hydroxylase, and physiological variables such as body weight, intestinal length, fecal water content, and ash levels were assessed. Paraprobiotic administration enhanced antioxidant defenses, reduced oxidative damage in brain and intestinal tissues, preserved dopaminergic neurons within the nigrostriatal pathway, improved fecal hydration (indicating constipation relief), and decreased fecal mineral content, suggesting improved nutrient absorption. Notably, modulation of gut microbiota, including an increased abundance of beneficial families (Lactobacillaceae and Sutterellaceae) and a reduced abundance of potentially harmful families (Clostridiaceae and Peptostreptococcaceae), may have contributed to oxidative stress attenuation, preservation of gut health, and prevention of dopaminergic neuron loss. Collectively, these findings suggest that paraprobiotics may modulate microbiota composition and oxidative stress in both intestinal and brain tissues, and may attenuate dopaminergic neurodegeneration in an experimental model of PD.
Corrigendum to "Role of PPAR-β/δ/miR-17/TXNIP pathway in neuronal apoptosis after neonatal hypoxic-ischemic injury in rats" [Neuropharmacology 140 (2018) 150-161].
Gamdzyk M, Doycheva DM, Malaguit J … +3 more , Enkhjargal B, Tang J, Zhang JH
Neuropharmacology · 2026 Sep · PMID 42103493 · Publisher ↗
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Olfactory bulb circuits drive ketamine-enhanced high-frequency oscillations via kainate and GABAergic mechanisms.
Prosvirova T, Podolecka W, Wrobel J … +1 more , Hunt MJ
Neuropharmacology · 2026 Sep · PMID 42103276 · Publisher ↗
Ketamine produces rapid antidepressant effects accompanied by marked changes in fast brain rhythms. High-frequency oscillations (HFO; 130-180 Hz) are an increasingly recognized signature of ketamine across species. Howev...
Ketamine produces rapid antidepressant effects accompanied by marked changes in fast brain rhythms. High-frequency oscillations (HFO; 130-180 Hz) are an increasingly recognized signature of ketamine across species. However, their relationship to classical gamma activity and their circuit-level organization remain unclear. Using simultaneous multiregion recordings in freely moving male Wistar rats, we show that ketamine differentially reorganizes fast oscillations across cortical networks: neocortical gamma power increased broadly, whereas the olfactory bulb (OB) showed suppressed gamma alongside robust, highly coherent HFO. Local OB infusion of the non-NMDA ionotropic glutamate receptor antagonists CNQX or NBQX suppressed ketamine-enhanced HFO both locally and in ventral striatum and prefrontal cortex without affecting neocortical gamma, indicating dissociable circuit mechanisms. Within the OB, the kainate receptor antagonist UBP310 markedly reduced HFO, whereas AMPA receptor blockade with IEM-1925 had minimal effect. Local GABA-A receptor blockade with bicuculline significantly reduced HFO power while increasing gamma power, demonstrating that intact fast inhibition is required for HFO expression. Based on these findings and known receptor kinetics, we propose that tonic kainate-dependent depolarization recruits interneurons to generate an inhibitory network rhythm, producing synchronized bursts that modulate mitral cell dendrites and drive HFO propagation through olfactory-limbic circuits.
Corrigendum to "Omega-3-Enriched Fish oil reduces the chemotherapy-induced peripheral neuropathy in mice" [Neuropharmacology (2025) 271 110384 doi: 10.1016/j.neuropharm.2025.110384].
Melato J, Goldoni FC, Benvenutti L … +12 more , Corrêa TP, Remor AP, Varela KG, Stoeberl LC, Fernandes GG, de Lima Rasga G, Passos GF, Apel MA, Klein-Junior LC, Santin JR, da Costa R, Quintão NLM
Neuropharmacology · 2026 Sep · PMID 42097954 · Publisher ↗
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PPAR-α activation in a model of autism modulates social reward and endocannabinoid signaling selectively in male rats.
Salviati S, Braccagni G, Corridori E … +7 more , Sabatini G, Fanti F, Guzzi F, Parenti M, Battista N, Scheggi S, Gambarana C
Neuropharmacology · 2026 Sep · PMID 42097455 · Publisher ↗
Social difficulties in autism spectrum disorder (ASD), including reduced sensitivity and responsiveness to the rewarding value of social stimuli (social anhedonia), may arise from dysregulation of dopaminergic and endoca...
Social difficulties in autism spectrum disorder (ASD), including reduced sensitivity and responsiveness to the rewarding value of social stimuli (social anhedonia), may arise from dysregulation of dopaminergic and endocannabinoid (eCB) pathways. We examined whether social reward processing was restored in male and female rats prenatally exposed to valproic acid (VPA) by PPARαs activation which modulates dopaminergic and eCB transmission. After 4-week administration of the PPARα agonist fenofibrate (FBR), social interaction and social reward sensitivity were assessed, and levels of eCBs and related markers measured in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). In VPA-exposed male rats, FBR administration reinstated social behavior, increased N-palmitoyl ethanolamine (PEA) levels in the NAc and normalized fatty-acid amide hydrolase (FAAH) levels in the NAc and mPFC. In contrast, VPA-exposed female rats showed very subtle ASD-like social deficits, different patterns of eCB alterations, with decreased N-oleoyl ethanolamine (OEA) levels in both regions, and divergent responses to FBR. Overall, these findings suggest that FBR modulation of the eCB system contribute to improving social behavior in VPA-exposed male rats. Moreover, differences in eCB signaling in male and female rats may play a role in the development of sex-divergent phenotype following prenatal VPA exposure.
Sex-dependent effects of vasopressin microinjections in CA3 on nucleus accumbens neurochemical modulation and amphetamine-induced behavior.
Cáceres-Vergara D, Bahamonde T, Gárate-Pérez MF … +7 more , Sanhueza C, Meneses-Pacheco J, González-Ortega C, Guzmán F, Sotomayor-Zárate R, Hinostroza F, Renard GM
Neuropharmacology · 2026 Sep · PMID 42070767 · Publisher ↗
Addiction to psychostimulants, such as amphetamine (AMPH), disrupts mesolimbic dopaminergic circuits, and effective pharmacological treatments remain limited. AMPH enhances dopamine (DA) release in the nucleus accumbens...
Addiction to psychostimulants, such as amphetamine (AMPH), disrupts mesolimbic dopaminergic circuits, and effective pharmacological treatments remain limited. AMPH enhances dopamine (DA) release in the nucleus accumbens (NAc), a process tightly linked to context-dependent reinforcement. Emerging evidence implicates the dorsal CA3 subregion of the hippocampus (CA3d) in modulating reward-related processes through its interactions with limbic and mesolimbic circuits. While vasopressin (AVP) signaling has been shown to regulate addictive-like behaviors via extra-hypothalamic regions, its functional role within hippocampal circuits remains poorly understood. Here we investigated whether AVP modulates reward-related processes through actions in the CA3d and whether such modulation differs between sexes. We show that microinjection of AVP into the CA3d significantly attenuates AMPH-induced conditioned place preference (CPP) in both male and female rats. Neurochemical analyses revealed sex-dependent downstream effects in the NAc. In males, AVP administration resulted in a sustained reduction in accumbal DA levels. In contrast, females exhibited a pronounced phasic increase in DA accompanied by a marked reduction in glutamate levels. Despite these divergent neurochemical profiles, behavioral sensitivity to AMPH was similarly reduced across sexes, indicating that distinct neurochemical mechanisms converge on a shared behavioral outcome. Together, these findings identify hippocampal AVP signaling within the CA3d as a critical modulator of mesolimbic function and drug-associated contextual learning. Our results further demonstrate that sex-dependent neurochemical pathways can support equivalent behavioral effects, underscoring the importance of considering sex as a biological variable when investigating the neurobiological mechanisms underlying psychostimulant addiction.
BBB permeable selective HDAC3 inhibitor SP108 restores hippocampal plasticity and learning in a MAM-induced model of schizophrenia.
Ghosh A, Ambati H, Regula S … +7 more , Tashildar M, Kalita A, Ganorkar A, Anne A, Mohan KN, Kulkarni OP, Ghosh B
Neuropharmacology · 2026 Sep · PMID 42069333 · Publisher ↗
Schizophrenia is a complex neurodevelopmental disorder with cognitive impairment being one of the core features that remains largely unresponsive to current antipsychotic treatments. Histone deacetylase 3 (HDAC3), a nega...
Schizophrenia is a complex neurodevelopmental disorder with cognitive impairment being one of the core features that remains largely unresponsive to current antipsychotic treatments. Histone deacetylase 3 (HDAC3), a negative regulator of memory and synaptic plasticity, has been implicated in neurodegenerative conditions, but its role remains underexplored in psychosis. Here, we hypothesized that aberrant HDAC3 activity contributes to hippocampal dysfunction and learning deficits in schizophrenia. Pregnant SD rats were administered methylazoxymethanol (MAM; 20 mg/kg) and vehicle on GD 17. We characterized the pharmacokinetic profile of selective HDAC3 inhibitor, SP108, to ensure adequate BBB penetration and systemic exposure. Next, adult male offspring were administered SP108 (25 mg/kg, i.p.) and vehicle every day for 3 weeks, followed by behavioral analysis. The MAM-exposed group showed schizophrenia-like behavioral patterns with increased hippocampal HDAC3 expression and activity. HDAC3 inhibitor treatment selectively ameliorated avoidance learning and MK801-induced hyperlocomotion. At the molecular level, HDAC3 inhibition elevated hippocampal H3K9 acetylation and increased the expression of synaptic plasticity markers BDNF and PSD95. To establish a neurodevelopmental link, HDAC3 knockdown was performed in differentiating neurons from mouse embryonic stem cells (mESCs) exposed to MAM at the early differentiating phase in vitro. HDAC3 knockdown in MAM-exposed differentiating neurons enhanced MAP2 intensity and neurite length with improved levels of MAP2, NeuN, TUBB3 (neuronal differentiation and maturation markers), BDNF, and PSD95 (neuroplasticity markers). Collectively, these findings identify HDAC3 as an important regulator of hippocampal dysfunction and cognitive impairment in a schizophrenia-like preclinical model, highlighting its potential to augment the therapeutic outcomes beyond current antipsychotic treatments.
Substance P innervation of the nucleus accumbens mediates alcohol consumption following chronic social stress.
Decker Ramirez EB, Beugelsdyk LA, Arnold-Tolbert ME … +6 more , Jiang DQ, Patel K, Harber CE, Nguyen A, Pendela S, Schank JR
Neuropharmacology · 2026 Sep · PMID 42069332 · Publisher ↗
Social defeat stress (SDS) is a rodent model used to assess the effect of chronic stress on depressive-like behavior and alcohol consumption. Our previous studies have indicated that the neurokinin-1 receptor (NK1R) medi...
Social defeat stress (SDS) is a rodent model used to assess the effect of chronic stress on depressive-like behavior and alcohol consumption. Our previous studies have indicated that the neurokinin-1 receptor (NK1R) mediates the behavioral responses to this stressor, especially through its actions in the nucleus accumbens (NAc). The NK1R is the high affinity, endogenous target of the neuropeptide substance P (SP). In the experiments presented here, we first infused a cre-dependent, retrogradely transported virus into the NAc of Tac1-cre mice (Tac1 is the gene for SP) to identify brain regions that send SP-expressing inputs to the NAc. We found that significant SP projections originated in the paraventricular nucleus of the thalamus (PVT). Next, we used this same tracing strategy, exposed mice to SDS or control conditions, and assessed Fos expression in the PVT. This experiment confirmed that SP projections from the PVT to the NAc are activated by SDS. To chemogenetically manipulate SP innervation of the NAc, we bilaterally infused a cre-dependent, retrogradely transported virus that expresses an inhibitory DREADD receptor into the NAc of Tac1-cre mice and delivered the DREADD actuator clozapine-n-oxide (CNO) prior to each defeat exposure. We found that this treatment had no effect on SDS-induced social avoidance, but did reduce alcohol consumption after stress. In a following experiment, CNO was administered just prior to behavioral testing, as opposed to during stress. In line with the previous experiment, chemogenetic inhibition affected post-stress drinking, but not social interaction. Conversely, chemogenetic activation of these inputs acutely increased alcohol consumption without affecting social behavior. Together, these results show that SP projections from the PVT to the NAc are activated by SDS exposure, and suggest that SP innervation of the NAc, possibly from the PVT, mediates post-stress alcohol consumption.
Cell type specific targeting of nicotinic receptor activity with tethered ligand viral vectors.
Yan Y, Olyha LN, Tucker BR … +1 more , Drenan RM
Neuropharmacology · 2026 Sep · PMID 42069331 · Publisher ↗
Heteromeric β2-containing nicotinic acetylcholine receptors (nAChRs) regulate diverse neural processes, yet their study in native circuits has been limited by the inability to manipulate receptor function with cell-type...
Heteromeric β2-containing nicotinic acetylcholine receptors (nAChRs) regulate diverse neural processes, yet their study in native circuits has been limited by the inability to manipulate receptor function with cell-type specificity, without transgenics, and across species. Existing tethered-ligand approaches, including photoswitchable and knock-in-based systems, provide valuable control of engineered receptors but do not readily integrate with Cre-driver lines and cannot be used in rats, where many nicotine-related behaviors are more robust. To address these limitations, we developed Cre-dependent adeno-associated viral (AAV) vectors expressing the β2 E61C nAChR subunit, a cysteine-bearing variant that enables covalent antagonism by the maleimide-PEG4-choline tethered ligand MPEGCh. We generated AAVs encoding either β2 E61C or hypersensitive β2Leu9'Ser E61C subunits and validated their functional incorporation into native nAChR pentamers in mouse and rat ventral tegmental area (VTA) neurons. Patch-clamp recordings demonstrated that MPEGCh produced strong, long-lasting, and E61C-dependent suppression of ACh-evoked currents, with near-complete blockade following prolonged ligand exposure. The system performed robustly in both DAT-Cre mice and rats receiving co-infused AAV-Cre, establishing effective cross-species use. From our results, we infer that any heteromeric receptor containing ≥1 engineered β2 subunit becomes ligand-sensitive, and that viral expression efficiently converts the endogenous β2 receptor pool without increasing total receptor abundance. This AAV-based, Cre-dependent E61C system provides a practical, optics-free, and species-flexible platform for cell-type-specific silencing of β2-containing nAChRs. Its compatibility with widely used Cre lines and suitability for rat behavioral paradigms-including nicotine self-administration and sustained-attention tasks-positions it as a versatile tool for dissecting nicotinic signaling in intact neural circuits.
Rosuvastatin attenuates blood-brain barrier dysfunction after ICH through modulation of CXCL12-associated VEGFR2/p38 MAPK signaling.
Yuan M, Zhou H, Pan H … +3 more , Xiao Z, Wu H, Wu W
Neuropharmacology · 2026 Sep · PMID 42066986 · Publisher ↗
BACKGROUND: Blood-brain barrier (BBB) disruption is a major driver of secondary injury after intracerebral hemorrhage (ICH), yet no approved therapy specifically targets post-ICH BBB damage. Rosuvastatin has pleiotropic...
BACKGROUND: Blood-brain barrier (BBB) disruption is a major driver of secondary injury after intracerebral hemorrhage (ICH), yet no approved therapy specifically targets post-ICH BBB damage. Rosuvastatin has pleiotropic vascular protective actions beyond lipid lowering, but its role in hemorrhagic BBB injury remains unclear. This study examined whether rosuvastatin attenuates BBB dysfunction after ICH and explored involvement of CXCL12-associated VEGFR2/p38 MAPK signaling. METHODS: ICH was induced in rats by autologous blood injection, followed by daily rosuvastatin for 7 days. Neurological deficits, Evans blue leakage, inflammatory markers, CXCL12 localization, and BBB-related proteins were assessed in vivo. Hemin-injured hCMEC/D3 cells were used to evaluate endothelial viability, migration, tight-junction expression, and signaling changes. CXCL12 siRNA was applied to determine pathway involvement. RESULTS: Rosuvastatin significantly improved neurological outcomes and reduced Evans blue extravasation after ICH. It lowered serum and brain IL-6 and TNF-α levels, reduced perihematomal microglial activation, restored Occludin and ZO-1 expression, and modulated ICAM-1 and p38 MAPK signaling in perihematomal tissue. CXCL12/CD31 co-localization in perihematomal vasculature increased after ICH and was attenuated by rosuvastatin. In hemin-exposed hCMEC/D3 cells, rosuvastatin improved viability and migration, restored tight-junction protein expression, and modulated CXCL12 together with changes in VEGFR2 and p38 MAPK signaling. CXCL12 silencing partially attenuated rosuvastatin's protective effects. CONCLUSIONS: Rosuvastatin attenuates BBB dysfunction and neuroinflammatory injury after ICH and improves endothelial injury responses in vitro. These protective effects were associated, partly, with restoration of dysregulated CXCL12-associated VEGFR2/p38 MAPK signaling, highlighting the therapeutic potential of rosuvastatin for neurovascular protection after hemorrhagic stroke.
Unexpected mechanisms of repurposed drugs in the pathogenic pathways of neurodegenerative diseases. Discovering new neuroprotective therapies in cellular models.
Arasmou-Idrovo MS, Marín-Rodríguez B, Gironda-Martínez A … +4 more , García AG, León R, Pascual-Guerra J, Torres-Rico M
Neuropharmacology · 2026 Sep · PMID 42061810 · Publisher ↗
Advances in biomedicine have increased life expectancy, leading to a growing prevalence of age-related neurodegenerative diseases such as Alzheimer's and Parkinson's disease, alongside disorders of genetic or environment...
Advances in biomedicine have increased life expectancy, leading to a growing prevalence of age-related neurodegenerative diseases such as Alzheimer's and Parkinson's disease, alongside disorders of genetic or environmental origin including multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis. Despite their diverse etiologies, these conditions share convergent pathogenic mechanisms-calcium overload, neuroinflammation, and oxidative stress-that drive neuronal apoptosis and progressive neurodegeneration. Developing therapies that effectively target these interconnected pathways remains a major challenge. Here, we applied a drug-repurposing pipeline integrating computational chemistry, calcium channel affinity prediction, and in vitro validation in SH-SY5Y and HEK293 cells. Eight clinically approved CNS drugs were screened for activity against Caᵥ1, Orai1, and P2X7 channels, and subsequently evaluated in neuroprotection assays. Several compounds demonstrated significant efficacy, with chlorpromazine showing broad-spectrum activity (neuroprotection, Caᵥ1.2 and P2X7 antagonism, anti-inflammatory effects), trimipramine emerging as a potent antioxidant, and vilazodone displaying synergistic neuroprotection in combination with procyclidine. These findings reveal multi-target pharmacological profiles in well-tolerated drugs not currently used for neurodegenerative indications. By highlighting both individual and combinatorial strategies, this work provides a foundation for translational studies aimed at repurposing approved agents for complex neurological disorders, with particular relevance to Parkinson's disease.
GRK5 in dorsolateral septal somatostatin neurons mediates chronic stress-induced depression via the AKT-mTORC1 pathway.
Wei Y, Liu L, Gao A … +8 more , Ji X, Kang Q, Ding X, Guo J, Wang Z, Da J, Zhang L, Wang H
Neuropharmacology · 2026 Sep · PMID 42061809 · Publisher ↗
Depression is a complex mental disorder with a poorly understood pathogenesis and often unsatisfactory treatment options. We have previously demonstrated that dorsolateral septum (DLS) somatostatin (SST)-positive GABAerg...
Depression is a complex mental disorder with a poorly understood pathogenesis and often unsatisfactory treatment options. We have previously demonstrated that dorsolateral septum (DLS) somatostatin (SST)-positive GABAergic neurons play a role in the pathogenesis of depression. However, no DLS-specific therapeutic targets have been established in clinical practice. Here, using single-cell RNA sequencing with molecular validation, we report that chronic restraint stress (CRS) induces depression-like behaviors in mice and downregulates G protein-coupled receptor kinase 5 (GRK5) specifically in DLS SST neurons. This downregulation was also observed in a chronic social defeat stress model. Functionally, genetic knockdown of GRK5 in DLS SST neurons of naïve mice was sufficient to induce depression-like behaviors, whereas GRK5 overexpression in these neurons exerted robust antidepressant-like effects in both naïve and CRS-exposed mice. Mechanistically, GRK5 knockdown suppressed, while its overexpression activated, the AKT-mTORC1 signaling pathway in the DLS. Moreover, the antidepressant-like effects of GRK5 overexpression were completely blocked by knockdown of either AKT or mTORC1. In conclusion, chronic stress-induced downregulation of GRK5 in DLS SST neurons promotes depression-like behaviors by impairing the AKT-mTORC1 pathway. These results identify GRK5 within this specific DLS neuronal population as a promising target for developing novel antidepressants.
Region- and sex-dependent single-cell transcriptomic signatures of neurons and glia in the prefrontal cortex and nucleus accumbens in a rat model of alcohol relapse.
Rigat L, Appiah B, Hakus A … +4 more , Gül AZ, Winter C, Boerries M, Priller J
Neuropharmacology · 2026 Sep · PMID 42055213 · Publisher ↗
Alcohol use disorder (AUD) is characterized by problems controlling alcohol drinking despite adverse consequences, development of tolerance and/or withdrawal symptoms. Notably, sex differences in alcohol consumption patt...
Alcohol use disorder (AUD) is characterized by problems controlling alcohol drinking despite adverse consequences, development of tolerance and/or withdrawal symptoms. Notably, sex differences in alcohol consumption patterns and susceptibility to relapse are well documented but remain poorly understood at the molecular level. In this study, we performed single-nuclei RNA sequencing (snRNA-seq) of the medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc) from male and female outbred RccHan Wistar rats exposed to the alcohol deprivation effect (ADE) paradigm, a well-established model of relapse-like drinking behaviour. Comparing high-to low-drinking rats, we found pronounced transcriptional changes across different cell types, with the highest number of differentially expressed genes observed in GABAergic medium spiny neurons (MSNs) of the NAcc and glutamatergic neurons of the mPFC associated with relapse. Importantly, we also identified sex- and region-dependent transcriptional alterations, including differential expression of dopamine receptors and phosphodiesterase family genes, which have previously been associated with AUD in humans, as well as alterations in the transcription of genes associated with synaptic plasticity and neuroimmune signalling. Finally, we found induction of immune-related genes in microglia and sex-dependent activation of immune- and myelination-related genes in astrocytes and oligodendrocytes. These findings highlight cell type-, region-, and sex-dependent molecular signatures associated with alcohol relapse drinking, which may provide new therapeutic targets for AUD.
Paeoniflorin mitigates hyperoxia-induced cognitive deficits in neonatal mice by modulating p38/JNK signaling to reduce oxidative stress and neuroinflammation.
Huang C, Zhang X, Yu J … +5 more , Xuan C, Xu C, Li X, Cui H, Xu D
Neuropharmacology · 2026 Sep · PMID 42055212 · Publisher ↗
Hyperoxia is a common environmental condition associated with oxygen therapy in neonatal intensive care units. This may lead to developmental damage to the hippocampus and long-term impairments in learning and memory. De...
Hyperoxia is a common environmental condition associated with oxygen therapy in neonatal intensive care units. This may lead to developmental damage to the hippocampus and long-term impairments in learning and memory. Despite the fact that paeoniflorin (PF) is well-known for its anti-inflammatory and antioxidant qualities, there is still a dearth of systematic research on its ability to improve long-term cognitive deficits after neonatal hyperoxic brain injury, particularly with regard to its role in modulating the p38/JNK MAPK signaling pathway. In this study, the effects of PF on hippocampal injury and cognitive deficits were evaluated in a neonatal mouse hyperoxia exposure model, and its mechanism of action was investigated. Neonatal mice were exposed to hyperoxia (85% oxygen for 7 days) and concurrently received PF administration for 7 days.Compared to the Hyp group, PF significantly reduced oxidative stress in the hippocampus, inhibited microglial activation and the upregulation of inflammatory factors, and alleviated histological damage. In behavioral assessments, PF significantly improved spatial learning and memory deficits, as reflected by the Morris water maze, and increased recognition preference in the novel object recognition task. Further molecular analyses showed that PF significantly inhibited the phosphorylation and activation of p38 and JNK, suggesting that it may exert a neuroprotective effect by modulating the p38/JNK-related inflammation-oxidative stress pathway. These results support PF as a potential therapeutic candidate for hyperoxia-related neurodevelopmental injury and provide experimental evidence for mechanistic research and drug development targeting perinatal oxygen therapy-related brain injury.
Chronic p75 neurotrophin receptor modulation with LM11A-31 attenuates seizure progression and network hyperexcitability in pentylenetetrazol kindling.
Kabak E, Aydin-Abidin S, Göçmen AY … +4 more , Öztürk H, Köse D, Başoğlu H, Abidin İ
Neuropharmacology · 2026 Aug · PMID 42034162 · Publisher ↗
The proBDNF/p75 neurotrophin receptor (p75NTR) signaling pathway has been implicated in neuronal hyperexcitability, synaptic remodeling, and neuroinflammation during epileptogenesis. We investigated whether pharmacologic...
The proBDNF/p75 neurotrophin receptor (p75NTR) signaling pathway has been implicated in neuronal hyperexcitability, synaptic remodeling, and neuroinflammation during epileptogenesis. We investigated whether pharmacological modulation of p75NTR with the small-molecule ligand LM11A-31 attenuates seizure progression and network dysfunction, defined as increased ECoG power and RMS amplitude reflecting enhanced neuronal synchronization and hyperexcitability in a pentylenetetrazole (PTZ) kindling model. Male C57BL/6 mice were subjected to alternate-day PTZ injections (35 mg/kg, i.p.) for a total of eight injections to induce kindling. LM11A-31 (50 mg/kg, i.p.) treatment was initiated 7 days prior to the first PTZ injection and continued throughout the experimental period. Mice were divided into four groups: control (C, n = 10), LM11A-31 (L, n = 10), PTZ (P, n = 9), and PTZ + LM11A-31 (P + L, n = 9). Seizure severity was assessed using Racine scoring and cumulative seizure burden (AUC). Cortical electrocorticography (ECoG) recordings were performed to evaluate mean power and RMS amplitude. Synaptic proteins (PSD-95, synaptophysin), inflammatory markers (TNF-α, IL-6), and oxidative stress indices (TAS, TOS, TBARS) were quantified in cortical and hippocampal tissues. LM11A-31 significantly attenuated the progression of PTZ-induced seizure severity and reduced cumulative seizure burden compared with PTZ alone. PTZ kindling markedly increased cortical ECoG power and RMS amplitude, reflecting enhanced network hyperexcitability; these changes were significantly normalized by LM11A-31. PTZ induced substantial reductions in PSD-95 and synaptophysin levels in both cortex and hippocampus, which were restored by LM11A-31 treatment. TNF-α levels were robustly elevated following PTZ administration and were significantly reduced by LM11A-31, whereas IL-6 remained unchanged. In parallel, LM11A-31 partially restored antioxidant capacity and reduced oxidant load and lipid peroxidation. Pharmacological modulation of p75NTR signaling with LM11A-31 suppresses seizure progression and mitigates electrophysiological, synaptic, inflammatory, and oxidative alterations associated with PTZ kindling.
Broad glucagon-like peptide-1 (GLP-1) receptor distribution enhances glutamatergic transmission throughout the mouse cerebellar cortex.
Ritchey CR, Peterson B, Peters JH … +1 more , Rossi DJ
Neuropharmacology · 2026 Sep · PMID 42034161 · Publisher ↗
The gut hormone glucagon-like peptide 1 (GLP-1) is a key contributor to the controls of food intake and reward processing. GLP-1 receptors (GLP-1R) are widely expressed throughout the central nervous system where their s...
The gut hormone glucagon-like peptide 1 (GLP-1) is a key contributor to the controls of food intake and reward processing. GLP-1 receptors (GLP-1R) are widely expressed throughout the central nervous system where their signaling alters neuronal excitability, resulting in suppressed food intake and reward. Recent studies have shown GLP-1R expression in Purkinje cells (PCs) within the cerebellum, a region gathering increasing appreciation for its role in sensory processing and appetitive behaviors. Importantly, the cerebellum responds to feeding signals and directly projects to key mesolimbic nuclei that initiate appetitive behaviors, including food intake. What remains unknown is if GLP-1Rs are expressed in other cell types of the cerebellum and the extent to which their activation produces neurophysiological changes. Here we combined RT-qPCR, RNAscope and immunohistochemistry with functional electrophysiology to map GLP-1R expression and signaling across the lobes and cell types of the cerebellar cortex of male/female C57BL/6N mice. We found that GLP-1Rs were nearly evenly expressed across all cerebellar lobes at the level of the vermis, as well as densely expressed in the deep cerebellar nuclei. At the cellular level, we found significant GLP-1R expression in granule cells (GCs) and GC-innervating mossy fibers, in addition to the previously reported expression in the PCs. Functionally, application of the GLP-1R agonist exendin-4 increased the frequency of spontaneous glutamate release on to the majority of recorded GCs and enhanced action potential firing in PCs. Together these results demonstrate broad expression of functional GLP-1R across cerebellar lobes which enhance synaptic transmission through the cerebellar cortex.
Oxidative stress-induced mitochondrial fragmentation inhibits CREB-mediated PV regulation and facilitates caspase-3-mediated PV neuronal degeneration following status epilepticus.
Kim JE, Wang SH, Kang TC
Neuropharmacology · 2026 Aug · PMID 42031227 · Publisher ↗
Parvalbumin (PV)- expressing neurons (PV neurons) are a subpopulation of γ-aminobutyric acid (GABA)-ergic interneurons that are highly vulnerable to oxidative stress. Although mitochondrial homeostasis is an essential ho...
Parvalbumin (PV)- expressing neurons (PV neurons) are a subpopulation of γ-aminobutyric acid (GABA)-ergic interneurons that are highly vulnerable to oxidative stress. Although mitochondrial homeostasis is an essential housekeeping function for maintaining PV expression level, the underlying mechanisms of PV downregulation caused by aberrant mitochondrial dynamics are largely unknown. In this study, using an in vivo male rat model, we found that oxidative stress induced by L-buthionine sulfoximine (BSO) reduced PV expression and cAMP-response-element-binding protein (CREB) serine (S) 133 phosphorylation through cyclin-dependent kinase 5 (CDK5)-dynamin-related protein 1 (DRP1)-mediated mitochondrial fission within hippocampal PV neurons under normal control conditions. These effects were ameliorated by roscovitine (a CDK5 inhibitor) or mitochondrial division inhibitor-1 (Mdivi-1, an inhibitor of mitochondrial fission). Similar to BSO, WY14643-induced mitochondrial fission decreased PV expression and CREB S133 phosphorylation in PV neurons. Furthermore, CREB knockdown also led to PV downregulation without altering CDK5 activity or mitochondrial dynamics. Notably, these treatments did not lead to PV neuronal degeneration. In a pilocarpine-induced status epilepticus (SE) model, however, massive PV neuronal degeneration was observed accompanied by decreased CREB S133 phosphorylation and excessive mitochondrial fragmentation. N-acetylcysteine (NAC), roscovitine and Mdivi-1 attenuated SE-induced PV neuronal degeneration by preserving CREB S133 phosphorylation and mitochondrial integrity. These findings indicate that the CDK5-DRP1-CREB pathway may evoke PV downregulation under sublethal oxidative stress and lead to irreversible PV neuronal degeneration under severe pathological conditions such as SE. Therefore, our findings suggest that this signaling pathway may be a therapeutic target to preserve PV neurons in neurological and psychiatric diseases.
Sevoflurane-induced neurotoxicity in neonatal mice is driven by microglial ferroptosis via MSTRG.7388-dependent NCOA4/STING axis.
Zhang Q, Ma J, Gao Y … +5 more , Zhang J, Cai Z, Shi L, Li Y, Hou Z
Neuropharmacology · 2026 Aug · PMID 42009246 · Publisher ↗
Preclinical investigations have indicated that recurrent sevoflurane exposure induces long-term cognitive deficits in neonatal mice while the effects of inhalational anesthetics on children remain ambiguous. In the curre...
Preclinical investigations have indicated that recurrent sevoflurane exposure induces long-term cognitive deficits in neonatal mice while the effects of inhalational anesthetics on children remain ambiguous. In the current study, Our comprehensive analysis of single-nucleus transcriptomics-guided competing endogenous RNA (ceRNA) networks revealed long-stranded ncRNA (lncRNA) MSTRG.7388 as a pivotal modulator in sevoflurane-mediated cognitive impairment, regulating microglial activation through the inhibition of microRNA miR-410-3p and the promotion of nuclear receptor coactivator 4 (NCOA4) expression. Furthermore, we elucidated that mutual binding of NCOA4 and stimulator of interferon genes (STING) dimers induced microglial ferroptosis independent of the ubiquitination pathway and long-term cognitive impairment in mice exposed to sevoflurane. Notably, either the knockdown of NCOA4 or the administration of Fe2+ scavengers (iron chelators) reversed these effects. Collectively, these findings demonstrate that repeated sevoflurane exposure leads to long-term cognitive impairment in neonatal mice by aggravating microglial ferroptosis via the MSTRG.7388/miR-410-3p/NCOA4/STING signaling axis.
IL-1 receptor antagonist attenuates inflammatory injury and improves structural and functional outcomes in the fetal somatosensory cortex after TLR-4 mediated inflammation.
Kelly SB, Cho SX, Zahra V … +8 more , Menyen M, Hunt RW, Nold-Petry CA, Gunn AJ, Polglase GR, Hooper SB, Nold MF, Galinsky R
Neuropharmacology · 2026 Sep · PMID 42002096 · Publisher ↗
Perinatal inflammation, often caused by bacterial infection, is strongly linked with lifelong disability. We tested the hypothesis that IL-1 is a key mediator of inflammatory injury and evaluated whether systemic adminis...
Perinatal inflammation, often caused by bacterial infection, is strongly linked with lifelong disability. We tested the hypothesis that IL-1 is a key mediator of inflammatory injury and evaluated whether systemic administration of IL-1 receptor antagonist (IL-1Ra) could attenuate cortical inflammation and improve neuronal development in late gestation fetal sheep exposed to TLR-4 mediated inflammation with lipopolysaccharide (LPS). Fetal sheep of both sexes, instrumented for continuous EEG, were randomised to: (1) saline infusion, (2) repeated intravenous LPS + vehicle infusions or (3) the same LPS regimen plus intravenous IL-1Ra infusions 1 h after each LPS dose. Four days later, brains were examined using RNA-seq, Golgi staining and immunohistochemistry. On EEG, LPS-exposure reduced relative beta power (high frequency EEG activity) compared to control, particularly in rapid eye movement sleep. In the somatosensory cortex, LPS-exposure decreased expression of genes involved in dendritogenesis and synaptogenesis, and increased genes involved in immune activation via LPS and IL-1 signalling. LPS-exposed fetuses had increased microglial activation and reduced neuronal arborisation. IL-1Ra treatment improved relative beta power, upregulated expression of genes involved in synaptogenesis, dendritogenesis and immune activation, reduced microglial activation, and improved neuronal arborisation. In summary, these findings indicate that IL-1 is a key driver of cortical neuronal injury associated with fetal inflammation and that IL-1Ra may improve neurodevelopmental outcomes following perinatal infection/inflammation.
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