Neuropharmacology最新文献

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Reversal of a synthetic opioid overdose: Insights from a validated translational model 逆转合成阿片类药物过量:从一个有效的转化模型的见解。
IF 4.6 2区 医学
Neuropharmacology Pub Date : 2025-06-06 DOI: 10.1016/j.neuropharm.2025.110546
Celine M. Laffont , Prasad Purohit , Amparo de la Peña , Phil Skolnick
{"title":"Reversal of a synthetic opioid overdose: Insights from a validated translational model","authors":"Celine M. Laffont ,&nbsp;Prasad Purohit ,&nbsp;Amparo de la Peña ,&nbsp;Phil Skolnick","doi":"10.1016/j.neuropharm.2025.110546","DOIUrl":"10.1016/j.neuropharm.2025.110546","url":null,"abstract":"<div><div>Synthetic opioids are linked to &gt;90 % of opioid overdose deaths in the United States. A FDA's validated translational model of synthetic opioid overdose, expanded to include intranasal reversal agents, was used to compare the effectiveness of FDA-approved intranasal naloxone (4 mg) and intranasal nalmefene (3 mg nalmefene hydrochloride, 2.7 mg base). In the absence of intervention, simulations using various intravenous doses of fentanyl and carfentanil predicted an incidence of cardiac arrest ranging from 18 % to 90 % in chronic opioid users and from 40 % to 96 % in opioid naïve subjects. Across dosing scenarios, intranasal nalmefene produced large and clinically meaningful reductions in the incidence of cardiac arrest compared to intranasal naloxone; the greatest differences in effectiveness were manifested at the higher doses of synthetic opioids. In the original publication describing FDA's model, the reversal agent was administered 1 min after ventilation was reduced to 40 % of baseline. Introducing further delays in intervention reduced the effectiveness of both reversal agents. Simulations showed intranasal nalmefene reduced the incidence of cardiac arrest compared to intranasal naloxone when intervention was delayed 2.5–3 min; delays ≥7.5 min abolished the effectiveness of both agents. The model was also used to predict the duration of brain hypoxia following a synthetic opioid overdose in a typical chronic opioid user. Across those simulations, intranasal nalmefene was generally more effective than intranasal naloxone in reducing brain hypoxia duration. These findings illustrate both the relative effectiveness of nalmefene and naloxone in reversing a synthetic opioid overdose and the importance of rapid intervention.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110546"},"PeriodicalIF":4.6,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248826","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}
引用次数: 0
Berberine's paradox in Neurodegeneration: Therapeutic promise and safety challenges in Parkinson's disease 小檗碱在神经退行性变中的悖论:帕金森病的治疗前景和安全性挑战。
IF 4.6 2区 医学
Neuropharmacology Pub Date : 2025-06-06 DOI: 10.1016/j.neuropharm.2025.110555
Sultan M. Alshahrani , Hayder M. Al-kuraishy , Ali I. Al-Gareeb , Ali K. Albuhadily , Mohamed N. Fawzy , Sultan F. Kadasah , Mubarak Alruwaili , Marios Papadakis , Athanasios Alexiou , Gaber El-Saber Batiha
{"title":"Berberine's paradox in Neurodegeneration: Therapeutic promise and safety challenges in Parkinson's disease","authors":"Sultan M. Alshahrani ,&nbsp;Hayder M. Al-kuraishy ,&nbsp;Ali I. Al-Gareeb ,&nbsp;Ali K. Albuhadily ,&nbsp;Mohamed N. Fawzy ,&nbsp;Sultan F. Kadasah ,&nbsp;Mubarak Alruwaili ,&nbsp;Marios Papadakis ,&nbsp;Athanasios Alexiou ,&nbsp;Gaber El-Saber Batiha","doi":"10.1016/j.neuropharm.2025.110555","DOIUrl":"10.1016/j.neuropharm.2025.110555","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). α-Synuclein (α-Syn) is a key protein implicated in PD pathogenesis, with its structural and biophysical properties widely investigated due to their role in disease mechanisms. The presence of Lewy bodies and Lewy neurites, pathological hallmarks of PD primarily composed of aggregated α-Syn, further underscores its critical involvement. This correlation has led to the hypothesis that α-Syn aggregation actively contributes to PD development. Recent studies have implicated oligomers formed during the initial phases of protein aggregation as the primary neurotoxic agents driving cellular degeneration in PD. This pathological process worsens mitochondrial dysfunction, oxidative stress, and microglial activation, ultimately contributing to SNpc degeneration and PD progression. Currently, available PD medications only provide symptomatic relief and do not address underlying neuropathological mechanisms such as oxidative stress, mitochondrial impairment, α-syn aggregation, or SNpc degeneration. Moreover, long-term use of anti-PD drugs like L-DOPA can lead to motor complications and systemic side effects. As a result, repurposing traditional herbal medicines with antioxidant and anti-inflammatory properties presents a promising therapeutic approach. Studies suggest that berberine (BBR) may mitigate PD-related neuropathology. However, the exact mechanisms by which BBR exerts its neuroprotective effects remain unclear. This review explores the potential molecular pathways through which BBR could alleviate PD pathology.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110555"},"PeriodicalIF":4.6,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248824","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}
引用次数: 0
Transient receptor potential vanilloid 2 (TRPV2) channels modulate the nigrostriatal dopaminergic activity in rats 瞬时受体电位香草样蛋白2 (TRPV2)通道调节大鼠黑质纹状体多巴胺能活性。
IF 4.6 2区 医学
Neuropharmacology Pub Date : 2025-06-03 DOI: 10.1016/j.neuropharm.2025.110545
Sumela Basu , Biru B. Dudhabhate , Saptarsi Mitra , Abhinav Srivastava , Pritiusha Pradhan , Chandan Goswami , Dadasaheb M. Kokare , Praful S. Singru
{"title":"Transient receptor potential vanilloid 2 (TRPV2) channels modulate the nigrostriatal dopaminergic activity in rats","authors":"Sumela Basu ,&nbsp;Biru B. Dudhabhate ,&nbsp;Saptarsi Mitra ,&nbsp;Abhinav Srivastava ,&nbsp;Pritiusha Pradhan ,&nbsp;Chandan Goswami ,&nbsp;Dadasaheb M. Kokare ,&nbsp;Praful S. Singru","doi":"10.1016/j.neuropharm.2025.110545","DOIUrl":"10.1016/j.neuropharm.2025.110545","url":null,"abstract":"<div><div>Thermosensitive TRPV1-4-channels have emerged as novel regulators of neuronal function and behaviour. In midbrain, while TRPV1/TRPV3 regulates ventral tegmental area dopamine (DA) (VTA<sup>DA</sup>) neurons, TRPV1/TRPV3/TRPV4 play a role in the modulation of substantia nigra DA (SN<sup>DA</sup>) neurons. Although TRPV2 is widely expressed in the brain, its significance in the regulation of VTA<sup>DA</sup>/SN<sup>DA</sup> neurons is unclear. Herein, we test the occurrence of TRPV2 in midbrain and probe its relevance in the modulation of the nigrostriatal-DAergic pathway in male rats. PCR analysis detected <em>Trpv2</em> mRNA expression in the midbrain and anti-TRPV2 specific antiserum distinctly labelled neurons in the VTA, SN-pars compacta (SNc), and other midbrain nuclei. Tyrosine hydroxylase (TH) and TRPV2 were co-expressed in the VTA and SNc neurons with the latter displaying especially high TRPV2-enrichment. The SNc TH neurons projecting to the dorsal striatum co-expressed TRPV2. While intra-SNc administration of TRPV2-agonist probenecid increased the locomotor activity, pre-treatment with intra-SNc TRPV2-antagonist SET2 or intra-dorsal striatum DA-D<sub>2</sub>-receptor antagonist, sulpiride blocked the probenecid-induced response. In <em>ex-vivo</em> midbrain slices, probenecid treatment enhanced TH-ir and [Ca<sup>2+</sup>]<sub>i</sub> levels in SNc. Pre-treatment with SET2 blocked probenecid-induced changes in TH-ir. We next examined whether probenecid alters the striatal DA-levels during progressive degeneration of the nigrostriatal-DAergic pathway. In 6-hydoxydopamine (6-OHDA)-treated rats, probenecid/SET2 were injected intra-SNc and the changes in striatal-DA levels were analyzed. While intra-SNc probenecid enhanced striatal-DA levels, pre-treatment with SET2 reduced PB-induced response. We suggest TRPV2 as a novel regulator of the nigrostriatal-DAergic pathway and a potential target for the treatment of Parkinson's disease.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110545"},"PeriodicalIF":4.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234633","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}
引用次数: 0
Beraprost sodium ameliorates cognitive impairment by promoting oligodendrocyte precursor cell proliferation and differentiation in vascular cognitive impairment mouse model 贝拉前列素钠通过促进血管性认知障碍小鼠少突胶质前细胞增殖和分化改善认知障碍。
IF 4.6 2区 医学
Neuropharmacology Pub Date : 2025-06-03 DOI: 10.1016/j.neuropharm.2025.110547
Mengsha Hu , Bingsong Xu , Linzhi Ge , Huijie Bian , Chao Zhou , Shengnan Xia , Haiyan Yang , Xinyu Bao , Hui Zhao , Yun Xu , Shu Shu
{"title":"Beraprost sodium ameliorates cognitive impairment by promoting oligodendrocyte precursor cell proliferation and differentiation in vascular cognitive impairment mouse model","authors":"Mengsha Hu ,&nbsp;Bingsong Xu ,&nbsp;Linzhi Ge ,&nbsp;Huijie Bian ,&nbsp;Chao Zhou ,&nbsp;Shengnan Xia ,&nbsp;Haiyan Yang ,&nbsp;Xinyu Bao ,&nbsp;Hui Zhao ,&nbsp;Yun Xu ,&nbsp;Shu Shu","doi":"10.1016/j.neuropharm.2025.110547","DOIUrl":"10.1016/j.neuropharm.2025.110547","url":null,"abstract":"<div><div>Chronic cerebral hypoperfusion (CCH) leads to white matter injury (WMI), a key contributor to the development of vascular cognitive impairment (VCI). Beraprost sodium (BPS) is a chemically stable and orally active prostaglandin I<sub>2</sub> (PGI<sub>2</sub>) analog, while the role and mechanism of BPS in VCI have not been well understood. In this study, we used a mouse model of bilateral carotid artery stenosis (BCAS mice) and demonstrated that BPS treatment facilitated the proliferation and differentiation of oligodendrocyte precursor cells (OPCs), potentially via PDGFR-α pathway modulation. This intervention promoted remyelination and attenuated WMI and cognitive dysfunction in BCAS mice. Collectively, our results suggested that BPS mitigates chronic ischemic WMI by targeting OPC development, providing a potential therapeutic avenue for VCI.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110547"},"PeriodicalIF":4.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234631","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}
引用次数: 0
Enhancement of ASIC currents by angiotensin II in rat dorsal root ganglion neurons 血管紧张素II对大鼠背根神经节神经元ASIC电流的增强作用。
IF 4.6 2区 医学
Neuropharmacology Pub Date : 2025-06-03 DOI: 10.1016/j.neuropharm.2025.110544
Zhong-Qing Xu, Huan Yuan, Fei Sun, Xue-Mei Li, Ting-Ting Liu, Chun-Yu Qiu, Wang-Ping Hu
{"title":"Enhancement of ASIC currents by angiotensin II in rat dorsal root ganglion neurons","authors":"Zhong-Qing Xu,&nbsp;Huan Yuan,&nbsp;Fei Sun,&nbsp;Xue-Mei Li,&nbsp;Ting-Ting Liu,&nbsp;Chun-Yu Qiu,&nbsp;Wang-Ping Hu","doi":"10.1016/j.neuropharm.2025.110544","DOIUrl":"10.1016/j.neuropharm.2025.110544","url":null,"abstract":"<div><div>Emerging findings indicate that angiotensin II (Ang II) and its receptors, namely type 1 (AT1R) and type 2 (AT2R), are expressed in dorsal root ganglion (DRG) and involved in the nociception of sensory neurons. However, the mechanisms remain unknown. The purpose of this investigation is to determine the role of Ang II in the regulation of ion channels in nociceptive DRG neurons. Herein, we found that the application of Ang II for 10 min enhanced the electrophysiological activity of acid-sensing ion channels (ASICs) in rat DRG neurons. Ang II increased acid-evoked ASIC currents in a concentration-dependent manner. Ang II increased the maximum response of ASICs to acidic stimuli without changing their sensitivity. Ang II enhanced ASIC currents through AT1R but not AT2R. The enhancing effect of Ang II on ASIC currents was prevented by either the PKC inhibitor GF109203x, or the ERK inhibitor U0126, but not by the p38 inhibitor SB202190 or the JNK inhibitor SP600125. Moreover, Ang II increased the action potentials triggered by acidic stimuli. Finally, intraplantar injection of Ang II dose-dependently exacerbated acid-induced nociceptive behavior in rats through local AT1R. These results indicated that Ang II enhanced the functional activity of ASICs through a mechanism that depended on AT1R, the intracellular PKC, and the ERK signaling pathway. Our findings provided evidence that Ang II is a promising target for developing new treatments for pain, at least for pain associated with tissue acidification.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110544"},"PeriodicalIF":4.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234632","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}
引用次数: 0
Neuropeptide S system mediates nicotine-induced reward-facilitatory behavior 神经肽S系统介导尼古丁诱导的奖励促进行为
IF 4.6 2区 医学
Neuropharmacology Pub Date : 2025-06-02 DOI: 10.1016/j.neuropharm.2025.110543
Harish M. Kawade , Utkarsh P. Patil , Deepali M. Pandhare , Nishikant K. Subhedar , Dadasaheb M. Kokare
{"title":"Neuropeptide S system mediates nicotine-induced reward-facilitatory behavior","authors":"Harish M. Kawade ,&nbsp;Utkarsh P. Patil ,&nbsp;Deepali M. Pandhare ,&nbsp;Nishikant K. Subhedar ,&nbsp;Dadasaheb M. Kokare","doi":"10.1016/j.neuropharm.2025.110543","DOIUrl":"10.1016/j.neuropharm.2025.110543","url":null,"abstract":"<div><div>Neuropeptide S (NPS), a 20-amino acid bioactive molecule has emerged as a promising treatment target for substance abuse in preclinical research. However, its role in nicotine reward, a major contributor to tobacco addiction, remains unexplored. This study investigated the involvement of the NPS system in reward-related effects of nicotine using the intracranial self-stimulation (ICSS) procedure in operant chamber. Adult male Wistar rats were implanted with bipolar electrode targeting the lateral hypothalamus-medial forebrain bundle and trained under a fixed-ratio 1 schedule across a range of brain stimulation frequencies (165-33 Hz). Under control conditions, the trained rats displayed a frequency-dependent increase in lever-press activity. Intracerebroventricular (i.c.v.) infusion of NPS (0.5–2 nmol) facilitated ICSS behaviour, while NPS receptor antagonist SHA-68 (0.1–10 nmol) was not effective. However, SHA-68 pretreatment (i.c.v.) dose dependently blocked the ICSS-facilitatory action of nicotine (0.25 mg/kg; subcutaneous, s.c.). A single nicotine injection (s.c.) activated NPS-containing neurons in the pericoerulear area (peri-LC), and increased NPS protein levels in the lateral hypothalamus (LH). Repeated nicotine administration (s.c.) elevated NPS mRNA expression in the peri-LC, and increased protein levels in the LH, paraventricular thalamus and peri-LC. However, these changes seem region specific since the nicotine treatment, in single or multiple doses, ensued no response in parabrachial nucleus, amygdala or ventral tegmental area. In sum, we suggest that the endogenous NPS system plays a critical role in reward-related effects of nicotine.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110543"},"PeriodicalIF":4.6,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223131","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}
引用次数: 0
Increased c-Fos immunoreactivity in anxiety-related brain regions following paroxetine discontinuation 帕罗西汀停药后焦虑相关脑区c-Fos免疫反应性增加。
IF 4.6 2区 医学
Neuropharmacology Pub Date : 2025-06-02 DOI: 10.1016/j.neuropharm.2025.110541
Helen M. Collins , L. Sophie Gullino , Cara Fuller , Raquel Pinacho , David M. Bannerman , Trevor Sharp
{"title":"Increased c-Fos immunoreactivity in anxiety-related brain regions following paroxetine discontinuation","authors":"Helen M. Collins ,&nbsp;L. Sophie Gullino ,&nbsp;Cara Fuller ,&nbsp;Raquel Pinacho ,&nbsp;David M. Bannerman ,&nbsp;Trevor Sharp","doi":"10.1016/j.neuropharm.2025.110541","DOIUrl":"10.1016/j.neuropharm.2025.110541","url":null,"abstract":"<div><div>Selective serotonin reuptake inhibitor (SSRI) therapy cessation often induces a disabling discontinuation syndrome, including increased anxiety. We recently reported that SSRI discontinuation induced behavioural changes in mice, which we hypothesise arose from activated anxiety circuitry. Here, we investigated the effect of discontinuation from the SSRI paroxetine on the expression of the activity-dependent gene <em>c-fos</em> in selected anxiety-related midbrain and forebrain regions. Male mice were injected daily with paroxetine (10 mg/kg) or saline for 12 days, then treatment was either continued or discontinued for two or five days. Mice were then tested on the elevated plus maze (EPM) and tissue collected 90 min later. Brain sections including the dorsal (DRN) and median raphe nucleus, periaqueductal grey, hippocampus, prefrontal cortex, and amygdala were processed for c-Fos immunoreactivity. Two days after paroxetine discontinuation, when mice showed elevated anxiety-like behaviour on the EPM, increased c-Fos immunoreactivity was evident in the DRN and ventral hippocampus, but not in any other region examined, compared to saline-treated controls. Increased c-Fos in the DRN was evident in TPH2-immunopositive neurons as well as neurons doubled-labelled for TPH2 and VGLUT3, suggesting activation of 5-HT-glutamate co-releasing neurons. Five days after paroxetine discontinuation, increased c-Fos immunoreactivity was evident in the DRN, but mice no longer exhibited increased anxiety. These findings suggest that, under the current conditions, paroxetine discontinuation is associated with a short-lasting activation of anxiety-promoting circuitry limited to DRN 5-HT neurons and the hippocampus. This circuitry may contribute to symptoms such as anxiety that are a feature of SSRI discontinuation syndrome.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110541"},"PeriodicalIF":4.6,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225994","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}
引用次数: 0
Reduced exosomal miR-215-5p activates the NEAT1/MAPK1/p-CRMP2 pathway and contributes to social dysfunction in a VPA-induced autism model 减少的外泌体miR-215-5p激活NEAT1/MAPK1/p-CRMP2通路,并在vpa诱导的自闭症模型中促进社交功能障碍。
IF 4.6 2区 医学
Neuropharmacology Pub Date : 2025-06-02 DOI: 10.1016/j.neuropharm.2025.110539
Lian Liu , Liang Xie , Yongchun Shen , Zijian Zeng , Dan Xu , Lin Bo , Lei Wu , Yaping Wu , Yi Zhang , Yinchan Wang , Jinkui Pi , Xiaoting Chen , Rui Wang , Xiaohui Yang , Xinchuan Wei , Hanmin Liu , Yuying Tang
{"title":"Reduced exosomal miR-215-5p activates the NEAT1/MAPK1/p-CRMP2 pathway and contributes to social dysfunction in a VPA-induced autism model","authors":"Lian Liu ,&nbsp;Liang Xie ,&nbsp;Yongchun Shen ,&nbsp;Zijian Zeng ,&nbsp;Dan Xu ,&nbsp;Lin Bo ,&nbsp;Lei Wu ,&nbsp;Yaping Wu ,&nbsp;Yi Zhang ,&nbsp;Yinchan Wang ,&nbsp;Jinkui Pi ,&nbsp;Xiaoting Chen ,&nbsp;Rui Wang ,&nbsp;Xiaohui Yang ,&nbsp;Xinchuan Wei ,&nbsp;Hanmin Liu ,&nbsp;Yuying Tang","doi":"10.1016/j.neuropharm.2025.110539","DOIUrl":"10.1016/j.neuropharm.2025.110539","url":null,"abstract":"<div><div>Autism is a prevalent neurodevelopmental disorder characterized by social deficits. Environmental factors, such as prenatal exposure to valproic acid (VPA), are major risk factors for the development of autism in offspring. Environmental epigenetics investigates how environmental factors influence gene expression and function. Exosomal miRNAs carry epigenetic information, but their role in autism remains unknown. Here, we found that prenatal VPA exposure reduced the majority of exosomal miRNA expressions in male newborn amygdala tissue, with exosomal miR-215-5p showing the highest decline. Reduced exosomal miR-215-5p increased neuronal lncRNA NEAT1 expression. Overexpressed neuronal NEAT1 increased the recruitment of the HSP90AB1-MAPK1-CRMP2 complex, which elevated phosphorylated CRMP2 (p-CRMP2) levels. Enhanced p-CRMP2 acted as an “eat me” signal to microglia, resulting in excessive synaptic pruning and aberrant synaptic maturation. Increasing neuronal p-CRMP2 levels via phosphorylation virus T514E or overexpression of MAPK1 promoted microglial synaptic pruning, leading to synaptic defects and social dysfunction. Furthermore, NEAT1 silencing or MAPK1 inhibition reversed the elevated p-CRMP2 levels in VPA-exposed offspring, hence preventing excessive synaptic pruning and social dysfunction. These findings suggested that prenatal VPA exposure reduced exosomal miR-215-5p and activated NEAT1/MAPK1/p-CRMP2 pathway, which resulted in abnormal synaptic development and social interaction disorders.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110539"},"PeriodicalIF":4.6,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225995","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}
引用次数: 0
Unlocking molecular secrets: The role of miRNAs in Parkinson's disease dynamics 解开分子秘密:mirna在帕金森病动力学中的作用
IF 4.6 2区 医学
Neuropharmacology Pub Date : 2025-06-02 DOI: 10.1016/j.neuropharm.2025.110542
Rehab A. Ismail , Mohamed Abobakr , Mostafa Mohamed , Ahmed Hussieny , Mohamed Alaa , Mostafa tarek , Shereen Saeid Elshaer
{"title":"Unlocking molecular secrets: The role of miRNAs in Parkinson's disease dynamics","authors":"Rehab A. Ismail ,&nbsp;Mohamed Abobakr ,&nbsp;Mostafa Mohamed ,&nbsp;Ahmed Hussieny ,&nbsp;Mohamed Alaa ,&nbsp;Mostafa tarek ,&nbsp;Shereen Saeid Elshaer","doi":"10.1016/j.neuropharm.2025.110542","DOIUrl":"10.1016/j.neuropharm.2025.110542","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a devastating neurological age-related ailment that causes dysfunction in the motor system, leading to symptoms such as involuntary shaking at rest, muscle stiffness with jerky movements, difficulty with walking, sluggish movement, and issues in sustaining posture. A state of insufficient dopamine in the striatum can be linked to a significant decrease in dopaminergic neurons within the substantia nigra pars compacta. Likewise, the formation of Lewy bodies is a distinctive pathogenic feature of PD. Although contemporary therapeutic strategies for PD focus on preserving dopaminergic neurons or restoring dopamine levels in the brain, it is crucial to recognize that achieving total remission of the illness is still inaccessible. MicroRNAs (miRNAs) are a group of tiny RNAs that do not code for proteins. They play a substantial role in controlling gene expression after the process of transcription. miRNAs have a pivotal role in the underlying pathological mechanisms of various neurodegenerative diseases, including PD. The objective of this research initiative is to create a molecular network in order to identify miRNAs that have significant impacts on the evolution of PD, with the intention of utilising them for instant diagnosis as well as prompt prognosis.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110542"},"PeriodicalIF":4.6,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223132","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}
引用次数: 0
Prolonged nicotine exposure, via electronic cigarette, selectively increases Bdnf/TrkB transcription, dynorphin peptide levels and OLIG2 in male rat VTA 通过电子烟长期暴露于尼古丁中,可选择性地增加雄性大鼠VTA中Bdnf/TrkB转录、肌啡肽水平和OLIG2。
IF 4.6 2区 医学
Neuropharmacology Pub Date : 2025-06-01 DOI: 10.1016/j.neuropharm.2025.110540
Laura Rullo , Camilla Morosini , Loredana Maria Losapio , Fabio Vivarelli , Moreno Paolini , Lucy C. Fairclough , Donatella Canistro , Patrizia Romualdi , Sanzio Candeletti
{"title":"Prolonged nicotine exposure, via electronic cigarette, selectively increases Bdnf/TrkB transcription, dynorphin peptide levels and OLIG2 in male rat VTA","authors":"Laura Rullo ,&nbsp;Camilla Morosini ,&nbsp;Loredana Maria Losapio ,&nbsp;Fabio Vivarelli ,&nbsp;Moreno Paolini ,&nbsp;Lucy C. Fairclough ,&nbsp;Donatella Canistro ,&nbsp;Patrizia Romualdi ,&nbsp;Sanzio Candeletti","doi":"10.1016/j.neuropharm.2025.110540","DOIUrl":"10.1016/j.neuropharm.2025.110540","url":null,"abstract":"<div><div>Different drugs of abuse affect the Central Nervous System (CNS) neuronal networks and reshape the expression of neuroplasticity-related genes in crucial parts of the mesocorticolimbic reward circuitry, such as the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Recent evidence suggests that neuronal activity and life experience, including repeated drug exposure, can modulate oligodendrogenesis thus altering neuronal myelination. This study aimed to investigate whether the prolonged exposure to nicotine, via electronic cigarettes, affects oligodendrocyte differentiation. Results showed that exposure to nicotine mainstream enhances the expression of OLIG2, a transcription factor essential for oligodendrocyte differentiation, in male rat VTA. This effect was associated with increased mRNA levels of the epigenetic enzyme <em>Kdm6b</em>, which is involved in regulating OLIG2 expression and synaptic plasticity. In the same brain region, nicotine increased <em>Bdnf</em> and <em>TrkB</em> gene expression as well as dynorphin peptide levels, which are positive regulators for oligodendroglial differentiation. Noteworthy, these molecular changes occurred alongside a reduction in neurofilament light levels, suggesting potential axonal remodelling associated with enhanced oligodendrogenesis. No significant changes in investigated parameters were detected in the NAc, thus suggesting that the reported molecular alterations selectively occurred in the VTA. Protein correlation analysis revealed that prolonged nicotine exposure primarily affects neuroplasticity-related protein networks within this area. Overall, these findings suggest that prolonged nicotine exposure, through electronic cigarettes, induces alterations of oligodendrogenesis modulators in the VTA. These molecular changes may impact axonal conduction velocity and reward circuitry connectivity, promoting neuronal adaptations that could be relevant for the development of addictive behaviour.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110540"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216339","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}
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