Neuropharmacology最新文献

{"title":"Effect of two novel GABAA receptor positive allosteric modulators on neuropathic and inflammatory pain in mice","authors":"Chu Xu ,&nbsp;Jian-Hong Wu ,&nbsp;Hui Yu ,&nbsp;Chun-Ge ,&nbsp;Yun-Xin Liu ,&nbsp;Jian-Jun Zou ,&nbsp;Jun Li","doi":"10.1016/j.neuropharm.2025.110317","DOIUrl":"10.1016/j.neuropharm.2025.110317","url":null,"abstract":"<div><div>Loss of GABAergic inhibition in the spinal dorsal horn (SDH) is implicated in central sensitization and chronic pain. Both agonists and positive allosteric modulators (PAMs) of GABAA receptor are found to be effective in the management of chronic pain. In addition to benzodiazepines, neuroactive steroids (NASs) also act as PAMs through binding to unique sites of GABAA receptors. Thus, it is worth investigating whether these NASs can attenuate chronic pain. This study tested the antinociceptive properties of two novel NAS PAMs, ganaxolone and zuranolone, in segmental spinal nerve ligation (SNL)-induced neuropathic pain and complete Freund's adjuvant (CFA)-induced inflammation pain models. Spinally administered ganaxolone and zuranolone both exhibited dose-dependent analgesic effects but with quite different durations. This antinociceptive effect might be generated from elevated GABAergic inhibition, as the PAMs both enhanced GABA-evoked currents in SDH neurons, and the K⁺-Cl^- cotransporter isoform 2 (KCC2) antagonist reversed the analgesic effect of the PAMs. Different from ganaxolone, zuranolone produced a durable increase in the surface expression of GABAA receptors and of the amplitude of spontaneous inhibitory currents, which may contribute to the long-lasting analgesic effect. Furthermore, the PAMs alleviated SNL-induced mechanical allodynia synergistically with diazepam or GABAA receptor activator muscimol at inactive doses, consistent with the non-competitive activity and distinct binding sites from benzodiazepines. In summary, our findings suggest that NASs may not only acutely modulate GABA receptor activity but also induce sustained metabotropic effects on GABAA receptors and thus exert long-lasting antinociceptive effects.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"269 ","pages":"Article 110317"},"PeriodicalIF":4.6,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067007","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 role of fear and dopamine-striatal pathways in grooming","authors":"Lior Givon ,&nbsp;Shahaf Edut ,&nbsp;Oded Klavir","doi":"10.1016/j.neuropharm.2025.110323","DOIUrl":"10.1016/j.neuropharm.2025.110323","url":null,"abstract":"<div><div>Fear is a fundamental emotion that triggers rapid and automatic behavioral response. Fear is known to suppress reward-seeking behaviors, interrupt previous activities to prioritize defensive responses and lead to rapid switch to defensive reactions. Dopamine (DA) plays a complicated role in the choice and performance of actions and it has a potential interaction of innate actions with the presence of fear. Here, in a series of experiments we explore the role of the different DA striatal pathways in mediating grooming, an innate behavior comprised of a structured sequence of repetitive actions, with or without the presence of fear. Using chemogenetics, we specifically inhibited the DA pathways projecting to the dorsolateral striatum (DLS), dorsomedial striatum (DMS), and ventral striatum (VS), while mice were engaged in a behavioral paradigm inducing grooming during the presentation of a fear related cue. We found that fear related cues consistently reduced grooming proportions and shortened induced grooming bouts, regardless of DA manipulation, indicating prioritization of freezing behavior in fearful contexts. This also suggests that fear responses may be mediated through pathways independent of DA-based action selection. The role of DA, however, varies depending on the specific striatal pathway. Inhibiting DLS DA input delayed grooming initiation and reduced grooming when competing with freezing. In contrast, DMS DA input had no effect on grooming, while inhibition of VS mesolimbic DA input increased grooming proportions and duration. These findings underscore the distinct and sometimes opposing roles of different DA-striatal pathways in modulating innate behaviors. We discuss potential implications of this duality in DA function for both theoretical and clinical fields.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"269 ","pages":"Article 110323"},"PeriodicalIF":4.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of G protein gated inwardly rectifying potassium (GIRK) channels in keratinocytes mediates peripheral kappa opioid receptor-mediated antinociception","authors":"Miryam M. Pando,&nbsp;Emily K. Debner,&nbsp;Blaine A. Jacobs,&nbsp;Raehannah J. Jamshidi,&nbsp;Elaine M. Jennings,&nbsp;William P. Clarke,&nbsp;Kelly A. Berg","doi":"10.1016/j.neuropharm.2025.110326","DOIUrl":"10.1016/j.neuropharm.2025.110326","url":null,"abstract":"<div><div>Kappa opioid receptors (KOR) expressed by peripheral pain-sensing neurons (nociceptors) are a promising target for development of effective and safer analgesics for inflammatory pain that are devoid of central nervous system adverse effects. Here we sought to delineate the signaling pathways that underlie peripheral KOR-mediated antinociception in adult male and female Sprague-Dawley rats. In an inflammatory model of pain, local intraplantar (i.pl.) injection of pertussis toxin prevented antinociception induced by the KOR agonist, U50488, indicating that members of the Gi/o family mediate the antinociceptive response. Furthermore, i.pl. injection of the G protein-coupled inward-rectifying potassium (GIRK) channel blocker, TPNQ, as well as GIRK2 subunit-targeted siRNA abolished U50488-mediated antinociceptive behavioral responses in both male and female rats. Consistent with these data, i.pl. injection of ML297, a direct activator of GIRK1 subunit-containing channels, elicited peripheral antinociceptive behavior. It is well known that intraepidermal nerve fibers (IENF) that innervate the hindpaw propagate nociceptive signals to the spinal cord. However, recent studies suggest that keratinocytes, the major cell type in the epidermis, also play an active role in pain and sensory processing. Results from RT-qPCR, RNAscope and immunohistochemistry experiments confirmed that both KOR and GIRK are expressed in keratinocytes in the epidermal layer of the rat hindpaw. Knockdown of either KOR or GIRK2 subunits selectively in keratinocytes by i.pl. injection of shRNA plasmids, prevented the antinociceptive response to U50488. Taken together, these data suggest that KOR-mediated activation of GIRK channels in keratinocytes is required for peripherally-mediated antinociception.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"268 ","pages":"Article 110326"},"PeriodicalIF":4.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067005","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":"Neurobiology, molecular pathways, and environmental influences in antisocial traits and personality disorders","authors":"Patryk M. Adamczyk ,&nbsp;Andrew Shaw ,&nbsp;Ilaria M. Morella ,&nbsp;Lorenzo More","doi":"10.1016/j.neuropharm.2025.110322","DOIUrl":"10.1016/j.neuropharm.2025.110322","url":null,"abstract":"<div><div>Personality disorders (PDs) are psychiatric conditions characterized by enduring patterns of cognition, emotion, and behaviour that deviate significantly from cultural norms, causing distress or impairment. The aetiology of PDs is complex, involving both genetic and environmental factors. Genetic studies estimate the heritability of PDs at 30%–60%, implicating genes involved in neurotransmitter regulation, such as those for serotonin transporters and dopamine receptors. Environmental factors, including childhood trauma and chronic stress, interact with genetic predispositions to induce epigenetic modifications like DNA methylation and histone modifications, contributing to PD development.</div><div>Neurobiological research has identified structural and functional abnormalities in brain regions related to emotional regulation and social cognition, such as the amygdala, prefrontal cortex, and limbic system. These abnormalities are linked to impaired emotion processing and interpersonal functioning in PDs. This review focuses on how environmental factors shape maladaptive behaviours and endophenotypes central to many PDs. It explores the interaction between the Ras-ERK, p38, and mTOR molecular pathways in response to environmental stimuli, and examines the role of oxidative stress and mitochondrial metabolism in these processes.</div><div>Also reviewed are various types of PDs and existing animal models that replicate key endophenotypes, highlighting changes in neurotransmitters and neurohormones. Identifying molecular biomarkers can lead to the development of “enviromimetic” drugs, which mimic environmental influences to activate molecular pathways, facilitating targeted, personalized treatments based on the molecular profiles of individuals with PDs. Ultimately, understanding the molecular mechanisms of PDs promises to enhance diagnostic accuracy, prognosis, and therapeutic outcomes for affected individuals.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"269 ","pages":"Article 110322"},"PeriodicalIF":4.6,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-specific alterations in emotional behavior and neurotransmitter systems in LPA1 receptor-deficient mice","authors":"Laura Sánchez-Marín ,&nbsp;Violeta Jiménez-Castilla ,&nbsp;María Flores-López ,&nbsp;Juan A. Navarro ,&nbsp;Ana Gavito ,&nbsp;Eduardo Blanco-Calvo ,&nbsp;Luis J. Santín ,&nbsp;Francisco J. Pavón-Morón ,&nbsp;Fernando Rodríguez de Fonseca ,&nbsp;Antonia Serrano","doi":"10.1016/j.neuropharm.2025.110325","DOIUrl":"10.1016/j.neuropharm.2025.110325","url":null,"abstract":"<div><div>Lysophosphatidic acid (LPA) and the endocannabinoid system (ECS) are critical lipid signaling pathways involved in emotional regulation and behavior. Despite their interconnected roles and shared metabolic pathways, the specific contributions of LPA signaling through the LPA₁ receptor to stress-related disorders remain poorly understood. This study investigates the effects of LPA₁ receptor deficiency on emotional behavior and neurotransmitter-related gene expression, with a focus on sex-specific differences, using maLPA₁-null mice of both sexes. We hypothesized LPA₁ receptor loss disrupts the interplay between LPA and the endocannabinoid 2-arachidonoylglycerol (2-AG) signaling, resulting in distinct behavioral and molecular alterations. maLPA₁-null mice exhibited increased anxiety-like behaviors and altered stress-coping responses compared to wild-type counterparts, with more pronounced effects observed in females. Female mice also displayed higher corticosterone levels, though no genotype-related differences were observed. Plasma analyses revealed elevated LPA levels in maLPA₁-null mice, suggesting a compensatory mechanism, and reduced 2-AG levels, indicating impaired ECS signaling. Gene expression profiling in the amygdala and medial prefrontal cortex showed significant alterations in the gene expression of key components of LPA and 2-AG signaling pathways, as well as neuropeptide systems such as corticotropin-releasing hormone (CRH) and neuropeptide Y (NPY). Glutamatergic signaling components also exhibited sex-specific variations. These findings suggest that LPA₁ receptor deficiency impacts behavioral response and disrupts sex-specific neurotransmitter signaling, emphasizing the importance of LPA-ECS crosstalk in emotional regulation. This study provides insights into the molecular mechanisms underlying stress-related disorders such as depression and anxiety, which may inform the development of sex-specific therapeutic approaches.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"268 ","pages":"Article 110325"},"PeriodicalIF":4.6,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047259","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":"Pharmacological characterization of the novel selective kappa opioid receptor agonists 10-Iodo-Akuammicine and 10-Bromo-akuammicine in mice","authors":"Kathryn Bland ,&nbsp;Chongguang Chen ,&nbsp;Peng Huang ,&nbsp;Conrad Ho ,&nbsp;Theodora Howe ,&nbsp;Katrina Ocampo ,&nbsp;Pingwei Zhao ,&nbsp;Simone Creed ,&nbsp;Joseph Noel-Torres ,&nbsp;Andrew P. Riley ,&nbsp;Lee-Yuan Liu-Chen","doi":"10.1016/j.neuropharm.2025.110316","DOIUrl":"10.1016/j.neuropharm.2025.110316","url":null,"abstract":"<div><div>Akuammicine (AKC), an indole alkaloid, is a kappa opioid receptor (KOR) full agonist with a moderate affinity. 10-Iodo-akuammicine (I-AKC) and 10-Bromo-akuammicine (Br-AKC) showed higher affinities for the KOR with K_i values of 2.4 and 5.1 nM, respectively, and high selectivity for the KOR over other opioid receptors. Both were KOR full agonists. As AKC and derivatives have distinctly different chemical structures from other KOR agonists, herein we investigated whether Br-AKC and I-AKC produced similar pharmacological effects as typical KOR agonists. Br-AKC and I-AKC inhibited compound 48/80-induced scratching in a dose-dependent manner, with ED₅₀ values of 3.0 and 1.3 mg/kg (s.c.), respectively, indicating anti-pruritic activities. Side effects of I-AKC and Br-AKC and their promotion of KOR phosphorylation and internalization were examined using doses in the effective anti-scratch dose range, at 1.9-3.8x ED₅₀ and 1.7-3.3x ED₅₀, respectively. At 5 mg/kg, Br-AKC and I-AKC produced profound conditioned place aversion (CPA). Br-AKC (10 mg/kg), but not I-AKC (5 mg/kg), reduced novelty-induced hyperlocomotion, and Br-AKC impaired rotarod performance more profoundly than I-AKC. Br-AKC, but not I-AKC, caused KOR phosphorylation at S369 in the mouse brain and KOR internalization in the ventral tegmental area. These results indicate that Br-AKC and I-AKC produce anti-scratch effect and CPA, similar to typical KOR agonists. However, there are some differences between the two. In addition, KOR phosphorylation and internalization in mouse brains are not associated with CPA but may be related to hypolocomotion and impaired rotarod performance. This is the first <em>in vivo</em> pharmacological characterization of AKC derivatives.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"268 ","pages":"Article 110316"},"PeriodicalIF":4.6,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040578","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":"Antisocial personality disorder:Failure to balance excitation/inhibition?","authors":"Klaus-Peter Lesch ,&nbsp;Nikita Gorbunov","doi":"10.1016/j.neuropharm.2025.110321","DOIUrl":"10.1016/j.neuropharm.2025.110321","url":null,"abstract":"<div><div>While healthy brain function relies on a dynamic but tightly regulated interaction between excitation (E) and inhibition (I), a spectrum of social cognition disorders, including antisocial behavior and antisocial personality disorder (ASPD), frequently ensuing from irregular neurodevelopment, may be associated with E/I imbalance and concomitant alterations in neural connectivity. Technological advances in the evaluation of structural and functional E/I balance proxies in clinical settings and in human cell culture models provide a general basis for identification of biomarkers providing a powerful concept for prevention and intervention across different dimensions of mental health and disease. In this perspective we outline a framework for research to characterize neurodevelopmental pathways to antisocial behavior and ASPD driven by (epi)genetic factors across life, and to identify molecular targets for preventing the detrimental effects of cognitive dysfunction and maladaptive social behavior, considering psychosocial experience; to validate signatures of E/I imbalance and altered myelination proxies as biomarkers of pathogenic neural circuitry mechanisms to determine etiological processes in the transition from mental health to antisocial behavior and ASPD and in the switch from prevention to treatment; to develop a neurobiologically-grounded integrative model of antisocial behavior and ASPD resultant of disrupted E/I balance, allowing to establish objective diagnoses and monitoring tools, to personalize prevention and therapeutic decisions, to predict treatment response, and thus counteract relapse; and finally, to promote transformation of dimensional disorder taxonomy and to enhance societal awareness and reception of the neurobiological basis of antisocial behavior and ASPD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"268 ","pages":"Article 110321"},"PeriodicalIF":4.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040542","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":"In vivo calcium extrusion from accumbal astrocytes reduces anxiety-like behaviors but increases compulsive-like responses and compulsive ethanol drinking in mice","authors":"Lee Peyton ,&nbsp;Humza Haroon ,&nbsp;Anthony Umpierre ,&nbsp;Hesham Essa ,&nbsp;Robert Bruce ,&nbsp;Long-Jun Wu ,&nbsp;Doo-Sup Choi","doi":"10.1016/j.neuropharm.2025.110320","DOIUrl":"10.1016/j.neuropharm.2025.110320","url":null,"abstract":"<div><div>The ventral striatum is crucially involved in reward processing. The present study investigates the behavioral effects of astrocyte-specific calcium extrusion virus “CalEx” on perseverative responses in the operant five-choice serial reaction time task and ethanol-conditioned place preference. Mice were injected with CalEx via the GfaABC₁D promoter to extrude cytosolic calcium from astrocytes within the ventral striatum. We found that CalEx transfection in the ventral striatum reduced evoked response duration, the maximum amplitude, and the response frequency to 500 μM ATP as measured by ΔF/F fluorescence intensity of the genetically encoded calcium indicator targeting astrocytes GCaMP6f. During the five-choice serial reaction time task, CalEx mice persisted in perseverative responses compared to their counterparts. Additionally, during ethanol-conditioned place preference, CalEx mice showed increased place preference for a low ethanol concentration compared to control group. Furthermore, we found that accumbal astrocytic calcium extrusion increased quinine adulterated ethanol drinking. Our findings suggest that diminishing ventral striatum astrocyte calcium activity contributes to compulsive behaviors, ethanol drinking, and enhanced ethanol drug reward.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"268 ","pages":"Article 110320"},"PeriodicalIF":4.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024209","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":"MK-801 attenuates one-trial tolerance in the elevated plus maze via the thalamic nucleus reuniens","authors":"Xue Xu ,&nbsp;Qian Gong ,&nbsp;Xiao-Dong Wang","doi":"10.1016/j.neuropharm.2025.110318","DOIUrl":"10.1016/j.neuropharm.2025.110318","url":null,"abstract":"<div><div>Anxiety, a future-oriented negative emotional state, is characterized by heightened arousal and vigilance. The elevated plus maze (EPM) test is a widely used assay of anxiety-related behaviors in rodents and shows a phenomenon where animals with prior test experience tend to avoid open arms in retest sessions. While this one-trial tolerance (OTT) phenomenon limits the reuse of the EPM test, the potential mechanisms remain unsolved. Here, we found that neither anxiogenic factors like acute restraint stress nor anxiolytic factors like diazepam (2 mg/kg) influenced the emergence of the OTT phenomenon in mice in the EPM test. In contrast, OTT was markedly attenuated by MK-801 (0.1 mg/kg), a non-competitive N-methyl-D-aspartate receptor antagonist. Through the use of c-fos mapping, MK-801 was found to increase neuronal activation in the thalamic nucleus reuniens (Re). Moreover, chemogenetic inactivation of Re neurons could prevent the effects of MK-801. Our findings suggest the Re as a crucial brain region in emotional adaptation in the EPM and shed light on the experimental design optimization and mechanistic investigation of anxiety-related behaviors.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"268 ","pages":"Article 110318"},"PeriodicalIF":4.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024210","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 class-IIa HDAC inhibitor TMP269 promotes BMP-Smad signalling and is neuroprotective in in vitro and in vivo 6-hydroxydopamine models of Parkinson's disease","authors":"Adam G. O'Mahony ,&nbsp;Martina Mazzocchi ,&nbsp;Alex Morris ,&nbsp;Noelia Morales-Prieto ,&nbsp;Caitriona Guinane ,&nbsp;Sean L. Wyatt ,&nbsp;Louise M. Collins ,&nbsp;Aideen M. Sullivan ,&nbsp;Gerard W. O'Keeffe","doi":"10.1016/j.neuropharm.2025.110319","DOIUrl":"10.1016/j.neuropharm.2025.110319","url":null,"abstract":"<div><div>Degeneration of midbrain nigrostriatal dopaminergic neurons is a pathological hallmark of Parkinson's disease (PD). Peripheral delivery of a compound(s) to arrest or slow this dopaminergic degeneration is a key therapeutic goal. Pan-inhibitors of histone deacetylase (HDAC) enzymes, key epigenetic regulators, have shown therapeutic promise in PD models. However as there are several classes of HDACs (ClassI-IV), class-specific inhibition will be important to ensure target specificity. Here we examine the neuroprotective potential of the Class-IIa HDAC inhibitor, TMP269. We show that TMP269 protected against 6-hydroxydopamine (6-OHDA)-induced neurite injury in SH-SY5Y cells and cultured rat ventral mesencephalic dopaminergic neurons. We find that TMP269 upregulated the neurotrophic factor BMP2 and BMP-Smad dependent transcription signalling in SH-SY5Y cells, which was necessary for its neuroprotective effect against 6-OHDA-induced injury. Furthermore, peripheral continuous infusion of 0.5 mg/kg of TMP269 for 7 days via a mini-osmotic pump, reduced forelimb impairments induced by striatal 6-OHDA administration. TMP269 also protected dopaminergic neurons in the substantia nigra and their striatal terminals from striatal 6-OHDA-induced neurodegeneration and prevented the 6-OHDA-induced increases in the numbers of IBA1-positive microglia in the striatum and substantia nigra <em>in vivo</em>. TMP269 also prevented 6-OHDA-induced decreases in BMP2, pSmad1/5 and acetylated histone 3 levels, and it reversed 6-OHDA-induced increase in nuclear HDAC5 in dopaminergic neurons in the substantia nigra. These data add to the growing body of evidence that Class-IIa specific HDAC inhibitors may be pharmacological agents of interest for peripheral delivery with the goal of neuroprotection in PD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"268 ","pages":"Article 110319"},"PeriodicalIF":4.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}