Neuropharmacology最新文献

{"title":"Artesunate demonstrates neuroprotective effect through activation of lysosomal function and inhibition of cGAS-STING pathway","authors":"Hongqiao Wei ,&nbsp;Yongxin Chen ,&nbsp;Zhenmin Qin ,&nbsp;Honglei Wang ,&nbsp;Yujia Liu ,&nbsp;Tang Song ,&nbsp;Yong Wu ,&nbsp;Wanxiang Hu ,&nbsp;Xiaowei Huang ,&nbsp;Guodong Lu ,&nbsp;Jing Zhou","doi":"10.1016/j.neuropharm.2025.110426","DOIUrl":"10.1016/j.neuropharm.2025.110426","url":null,"abstract":"<div><div>Artesunate, a derivative of artemisinin, has a variety of pharmacological effects. Its potential application in ischemic brain injury still largely unknown. This study investigated the therapeutic effect and pharmacological mechanism of artesunate in neuronal injury following cerebral ischemia, and explore the potential role of lysosomal function and cGAS-STING signaling pathway in ischemia injury and artesunate treatment. Studies in rat models have revealed that artesunate can ameliorate neuronal injury and improve learning and memory function following ischemic insults. Furthermore, both <em>in vivo</em> and <em>in vitro</em> studies have confirmed that artesunate can protect neural cells from ischemic injury-induced cell death. Mechanistically, artesunate appears to exert its neuroprotective actions by activating lysosomal function and inhibiting the cGAS-STING pathway-mediated inflammatory response. Our findings provide valuable insights into the therapeutic effects of artesunate exerting a neuroprotective role in chronic ischemic brain injury by activating lysosomal function, inhibiting the cGAS-STING pathway, and regulating the inflammatory response. This study offers a potential therapeutic strategy by regulating lysosome for the treatment of stroke and related neurological disorders.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"272 ","pages":"Article 110426"},"PeriodicalIF":4.6,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674333","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":"Unveiling the potential abuse liability of α-D2PV: A novel α-carbon phenyl-substituted synthetic cathinone","authors":"Núria Nadal-Gratacós ,&nbsp;Sandra Mata ,&nbsp;Pol Puigseslloses ,&nbsp;Morgane De Macedo ,&nbsp;Virginie Lardeux ,&nbsp;Stephanie Pain ,&nbsp;Fu-Hua Wang ,&nbsp;Liselott Källsten ,&nbsp;David Pubill ,&nbsp;Xavier Berzosa ,&nbsp;Jan Kehr ,&nbsp;Marcello Solinas ,&nbsp;Jordi Camarasa ,&nbsp;Elena Escubedo ,&nbsp;Raul López-Arnau","doi":"10.1016/j.neuropharm.2025.110425","DOIUrl":"10.1016/j.neuropharm.2025.110425","url":null,"abstract":"<div><div>Synthetic cathinones are emerging psychoactive substances designed to mimic the effects of classical psychostimulants. Among them, α-D2PV, a novel pyrrolidine-containing cathinone characterized by a phenyl group on the α-carbon atom, has gained significant attention. This study investigates the <em>in vitro</em> and <em>in silico</em> mechanism of action as well as the abuse liability of α-D2PV using rodent models. Dopamine (DA), noradrenaline (NE), and serotonin (5-HT) uptake inhibition assays were conducted in HEK293 cells expressing the corresponding human monoamine transporter, complemented by molecular docking studies at the DA transporter (DAT). Behavioral studies in male Swiss CD-1 mice assessed locomotor activity and conditioned place preference, while microdialysis and self-administration experiments were performed in male Sprague-Dawley rats. The findings reveal that α-D2PV is a potent DA and NE uptake inhibitor, with minimal activity at the 5-HT transporter (SERT). Docking studies showed that the benzene rings of α-PVP and α-D2PV align precisely in their most stable conformations at DAT. In vivo, α-D2PV elicited dose-dependent hyperlocomotion, thigmotaxis, and rewarding effects in mice, alongside increased extracellular DA levels in the nucleus accumbens of awake rats. Self-administration experiments confirmed α-D2PV's high reinforcing efficacy, indicating a significant risk of abuse in humans. Finally, these results underscore the necessity for continued surveillance of α-D2PV within the illicit drug market. Furthermore, novel synthetic cathinones incorporating a phenyl ring at the α-carbon side chain warrant proactive monitoring due to their potential to retain dopaminergic activity and evade initial legal controls.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"272 ","pages":"Article 110425"},"PeriodicalIF":4.6,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674307","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":"T-type calcium channels attenuate anxiety in MPTP-treated mice through modulating burst firing of dopaminergic neuron","authors":"Jihu Zhao ,&nbsp;Deyuan Zhu ,&nbsp;Yue Chen ,&nbsp;Pengju Ma ,&nbsp;Suya Li ,&nbsp;Shifei Ye ,&nbsp;Wei Cao ,&nbsp;Shuai Han ,&nbsp;Yibin Fang","doi":"10.1016/j.neuropharm.2025.110424","DOIUrl":"10.1016/j.neuropharm.2025.110424","url":null,"abstract":"<div><div>T-type calcium channel(T-VGCC) is a critical voltage-gated channel extensively involved in signal transmission and functional regulation of the nervous system. Recent studies have shown that T-VGCC exhibits low-threshold activation properties and generate high-frequency firing, making it essential in neuronal firing patterns. However, the effects of T-VGCC on dopaminergic (DAergic) neurons in the substantia nigra (SN) remain unclear. In the present study, we constructed Parkinson's disease (PD) model mice using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and we found that intracerebroventricular injection of T-VGCC blocker (Mibefradil) alleviates the anxiety behavior and the extent of damage to DAergic neurons in MPTP-treated mice. In vivo electrophysiological experiments demonstrated that T-VGCC directly regulates the burst firing of DAergic neurons. Correlation analysis suggested a strong association between DAergic neuron burst firing and anxiety-like behaviors in mice. Notably, calcium imaging experiments revealed that inhibiting T-VGCC significantly decreased calcium signal levels in DAergic neurons of MPTP-treated mice. To sum up, our research results for the first time reveal the crucial role that the burst firing of DAergic neurons in the SN mediated by T-VGCC plays in regulating anxiety behavior in PD. This discovery offers a potential therapeutic target for PD patients with anxiety.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"272 ","pages":"Article 110424"},"PeriodicalIF":4.6,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674339","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":"Target inhibition of NAT10-mediated ac4C modification prevents seizure behavior in mice","authors":"Aomei Zhang ,&nbsp;Jingwen Yang ,&nbsp;Meng Wang ,&nbsp;Yujia Li ,&nbsp;Tao Hu ,&nbsp;Jialing Xie ,&nbsp;Yang Xu ,&nbsp;Wenyu Cao","doi":"10.1016/j.neuropharm.2025.110415","DOIUrl":"10.1016/j.neuropharm.2025.110415","url":null,"abstract":"<div><div>N4-acetylation of Cytidine (ac4C), catalyzed by its only known enzyme N-acetyltransferase 10 (NAT10), facilitates cellular mRNA translation and stability, but its function in brain disorders especially epilepsy is poorly understood. By using pentylenetetrazole (PTZ) induced mouse model of epilepsy, we first displayed spatiotemporally expression of ac4C and NAT10 in the mouse brain. To corroborate the alteration of ac4C and NAT10 in epilepsy, we used acute PTZ, chronic PTZ and intrahippocampal kainic acid (IHKA) mouse model. We then utilized a combination of viral tool and pharmacological approaches to implicate NAT10 mediated ac4C modification in seizure behaviors. We found that the expression of ac4C was increased in epileptic brain tissues in mouse models of epilepsy, which might be due to the up-regulated NAT10. Block of NAT10 led to both reduced brain ac4C level and resistance to PTZ or KA-induced seizure behavior, while hippocampal over-expression of NAT10 causes exacerbated seizure behavior. In support of such a role, our data demonstrated that the loss or gains of ac4C modification could normalize or exacerbate neuronal over-activation in epileptic brain tissues, respectively. Mechanically, we observed that block the NAT10 or over-expression NAT10 lead to reduced or enhanced BDNF, respectively. While the BDNF pathway inhibitor rescued the hippocampal NAT10 over-expression induced aggravated seizure behavior in the chronic PTZ treated mice. Therefore, our work provides the first demonstration of the ac4C levels in an epilepsy mice model, targeted to prevent ac4C by NAT10 inhibition seems to be effective in preventing and treating epilepsy.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"272 ","pages":"Article 110415"},"PeriodicalIF":4.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663940","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":"Comparison of fentanyl-induced brain oxygen responses following intravenous and intraperitoneal injections in rats","authors":"Feonil G. Limiac,&nbsp;Michael R. Noya,&nbsp;Eugene A. Kiyatkin","doi":"10.1016/j.neuropharm.2025.110412","DOIUrl":"10.1016/j.neuropharm.2025.110412","url":null,"abstract":"<div><div>This study used oxygen sensors coupled with amperometry to examine changes in brain (nucleus accumbens) and peripheral (subcutaneous space) oxygen levels following intravenous (IV) and intraperitoneal (IP) fentanyl injections at different doses. To avoid stress associated with traditional IP injection, fentanyl was delivered via chronically implanted IP catheter. SC oxygen levels decreased in a dose-dependent monophasic manner, whereas brain oxygen responses were more complex, showing modest increases at low fentanyl doses (&lt;3 μg/kg for IV and &lt;10 μg/kg for IP) and biphasic effects (decrease followed by increase) at higher doses (≥10 μg/kg for IV and ≥270 μg/kg for IP). IV-delivered fentanyl elicited faster and stronger responses, with over 10-fold greater potency to induce brain hypoxia compared to IP-fentanyl. Although oxygen response patterns were similar between catheter-based and traditional needle IP injection, the latter caused an ultra-fast brain oxygen increase coupled with rapid oxygen decrease in SC space, suggesting stress as a contributing factor. Interestingly, low-dose, stress-free IP fentanyl administration also induced phasic brain oxygen increases coupled with robust but transient behavioral activation, the effect appears to be independent of drug action on opioid receptors. This effect was attributed to the acidity of fentanyl citrate solution (pH 4.8) and direct actions of H+ on receptive sites on afferents of sensory nerves innervating the abdominal cavity. These findings reveal distinct fentanyl-induced oxygen dynamics based on administration route and highlight the influence of injection stress and drug formulation on oxygen and behavioral responses.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"271 ","pages":"Article 110412"},"PeriodicalIF":4.6,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143628650","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":"Exogenous oral application of PYY and exendin-4 impacts upon taste-related behavior and taste perception in wild-type mice","authors":"Satya Iyer ,&nbsp;Jean-Pierre Montmayeur ,&nbsp;Sergei Zolotukhin ,&nbsp;Cedrick D. Dotson","doi":"10.1016/j.neuropharm.2025.110408","DOIUrl":"10.1016/j.neuropharm.2025.110408","url":null,"abstract":"<div><div>Several gut peptides have been implicated in feeding and body mass accumulation. Glucagon-like peptide 1 (GLP-1) and peptide tyrosine-tyrosine (PYY) have been shown to mediate satiety and reduce food intake. While systemic administration of such peptides has been explored as a therapy for metabolic disease, the effects of these hormones on taste signaling should also be considered given the importance of taste to feeding decisions and considering the fact that components of these signaling systems are expressed in cells of the peripheral gustatory system. We previously demonstrated that genetic disruption of PYY signaling in mice can impact on taste responsiveness and feeding and that viral expression of PYY in the salivary glands of PYY knockout mice can rescue responsiveness. The present work uses adeno-associated virus-mediated salivary gland treatment with both GLP-1 receptor agonist exendin-4 and/or PYY encoding vectors to explore the effect of stimulating these orally present signaling systems on taste-related behavioral responsiveness in male wild-type mice with intact peptide signaling systems. Results showed a significant effect of salivary gland treatment on responsiveness to multiple taste qualities. Data gathered from taste bud cells <em>in vitro</em> suggest that these peptides directly influence the responsiveness of these primary sensory cells. Collectively, these findings show that taste perception can be modulated by the exogenous application of satiety peptides in wild-type mice and suggest that the taste bud is a promising substrate for food intake modulation.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"272 ","pages":"Article 110408"},"PeriodicalIF":4.6,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630682","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":"Effects of nestorone, a progesterone receptor agonist, on neonatal hypoxic-ischemic brain injury and reproductive functions in male and female rats","authors":"Motoki Tanaka ,&nbsp;Masahiro Sokabe ,&nbsp;Keiko Nakanishi ,&nbsp;Masato Asai","doi":"10.1016/j.neuropharm.2025.110411","DOIUrl":"10.1016/j.neuropharm.2025.110411","url":null,"abstract":"<div><div>Perinatal hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of neonatal death and neurological disorders. We recently demonstrated the neuroprotective effects of nestorone, a progesterone receptor agonist, in adult male rats subjected to focal cerebral ischemia; however, its effects on neonatal ischemic brain injury and on sexual differentiation and reproductive functions remain unclear. Therefore, the present study investigated the effects of nestorone on neonatal hypoxic-ischemic brain injury and reproductive functions in rats of both sexes. Seven-day-old male and female rat pups were subjected to occlusion of the right carotid artery and then exposed to 8 % oxygen (hypoxic-ischemia, HI). Brain lesion sizes and the numbers of activated astrocytes and microglia in male and female rats were significantly lower after administrating 10 μg/kg nestorone than vehicle 48 h after HI. Furthermore, the post-HI administration of nestorone for 7 days (10 μg/kg, once a day) significantly improved motor coordination and tactile responses 28 days after HI and cognitive performance 4 months after HI in male and female rats. The administration of nestorone did not affect the delivery rates or number of weaned pups in HI and sham-operated female rats or in intact female rats mated with HI or sham-operated males. These results suggest that nestorone exerts persistent neuroprotective effects against neonatal HI brain injury without serious adverse effects on reproductive functions in male and female rats. Therefore, nestorone is a promising potent and safe therapeutic agent in newborn infants with HIE of both sexes.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"271 ","pages":"Article 110411"},"PeriodicalIF":4.6,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625418","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":"Neuronal and therapeutic perspectives on empathic pain: A rational insight","authors":"Punit Prasanna Kujur,&nbsp;Surendar Ellappan,&nbsp;Amal Chandra Mondal","doi":"10.1016/j.neuropharm.2025.110414","DOIUrl":"10.1016/j.neuropharm.2025.110414","url":null,"abstract":"<div><div>Empathy is the capacity to experience and understand the feelings of others, thereby playing a key role in a person's mental well-being essentially by promoting kindness and a sense of belongingness to the group. However, too much empathy may result in psychological problems such as empathic distress, compassion fatigue, and burnout, collectively termed empathic pain. Several brain regions are implicated in processing empathic pain perception. Neuroimaging investigations bring in the context of brain structures involved in this emotional exchange, pointing toward the anterior insula (AI) and anterior cingulate cortex (ACC), indicating an overlap between the neural representation of direct and simulative pain. To discern such overlaps, therapeutic techniques for managing empathic pain require understanding different brain regions and their respective neural networks. At the moment, empathic pain is being treated using various methods, including pharmacological treatments such as antidepressants and psychological treatments such as mindfulness or meditation. For instance, researchers have been exploring the modulatory effects of neurotransmitters like serotonin, norepinephrine, and oxytocin on individuals' responses to empathic pain experience. Importantly, this review focuses on the specific brain parts and their unique roles in neurobiological pathways associated with emphatic pain and how shared neural networks play into available treatment options, suggesting possible future health benefits. Such an understanding of empathy can lead to more efficient management of types of care, focusing on enhancing social connections and mental well-being.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"272 ","pages":"Article 110414"},"PeriodicalIF":4.6,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625425","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":"Modulation of dorsal raphe nucleus connectivity and serotonergic signalling to the insular cortex in the prosocial effects of chronic fluoxetine","authors":"Jennyfer M. Payet ,&nbsp;Michael V. Baratta ,&nbsp;John P. Christianson ,&nbsp;Christopher A. Lowry ,&nbsp;Matthew W. Hale","doi":"10.1016/j.neuropharm.2025.110406","DOIUrl":"10.1016/j.neuropharm.2025.110406","url":null,"abstract":"<div><div>Long-term exposure to fluoxetine and other selective serotonin reuptake inhibitors alters social and anxiety-related behaviours, including social withdrawal, which is a symptom of several neuropsychiatric disorders. Adaptive changes in serotonergic neurotransmission likely mediate this delayed effect, although the exact mechanisms are still unclear. Here we investigated the functional circuitry underlying the biphasic effects of fluoxetine on social approach-avoidance behaviour and explored the place of serotonergic dorsal raphe nucleus (DR) ensembles in this network, using c-Fos-immunoreactivity as a correlate of activity. Graph theory-based network analysis revealed changes in patterns of functional connectivity and identified neuronal populations in the insular cortex (IC) and serotonergic populations in the DR as central targets to the prosocial effects of chronic fluoxetine. To determine the role of serotonergic projections to the IC, a retrograde tracer was micro-injected in the IC prior to fluoxetine treatment and social behaviour testing. Chronic fluoxetine increased c-Fos immunoreactivity in insula-projecting neurons of the rostral, ventral part of the DR (DRV). Using a virally delivered Tet-Off platform for temporally-controlled marking of neuronal activation, we observed that chronic fluoxetine may affect social behaviour by influencing independent but interconnected populations of serotonergic DR ensembles. These findings suggest that sustained fluoxetine exposure causes adaptive changes in functional connectivity due to altered serotonergic neurotransmission in DR projection targets, and the increased serotonergic signalling to the IC likely mediates some of the therapeutic effects of fluoxetine on social behaviour.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"272 ","pages":"Article 110406"},"PeriodicalIF":4.6,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625421","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":"Multi-functional memantine nitrate attenuated cognitive impairment in models of vascular dementia and Alzheimer's disease through neuroprotection and increased cerebral blood flow","authors":"Guangying Chen ,&nbsp;Kexin Zhang ,&nbsp;Minghua Sun ,&nbsp;Ningqing Xie ,&nbsp;Liangmiao Wu ,&nbsp;Guiliang Zhang ,&nbsp;Baojian Guo ,&nbsp;Chunhui Huang ,&nbsp;Maggie Pui Man Hoi ,&nbsp;Gaoxiao Zhang ,&nbsp;Changzheng Shi ,&nbsp;Yewei Sun ,&nbsp;Zaijun Zhang ,&nbsp;Yuqiang Wang","doi":"10.1016/j.neuropharm.2025.110410","DOIUrl":"10.1016/j.neuropharm.2025.110410","url":null,"abstract":"<div><div>Alzheimer's disease (AD) and vascular dementia (VaD) are two prevalent forms of dementia. VaD is linked to cerebrovascular lesions, such as those from white matter ischemia and chronic cerebral hypoperfusion, which can also occur in AD. Nitric oxide (NO) regulates cerebral blood flow (CBF) in the central nervous system. Memantine is an NMDA receptor antagonist approved for AD treatment. This study investigated the efficacy and molecular mechanism of MN-08, a novel memantine nitrate, in one VaD model (2VO) and two AD models (APP/PS1 mice and Aβ1-42-induced mice). MN-08 increased CBF, ameliorated cognitive and memory functions in VaD and AD, and was more effective than memantine. MN-08 increased the survival rate of CA1 neurons and mitigated white matter lesions and axonal damage. Moreover, MN-08 protected neurons from OGD-induced loss and promoted axonal outgrowth in the hippocampus by upregulating phosphorylated Akt (p-Akt), glycogen synthase kinase-3β (p-GSK3β), and high-molecular-weight neurofilaments (p-NFH). The beneficial effects of MN-08 were attenuated by carboxy-PTIO, a potent NO scavenger, suggesting that MN-08-derived NO may alleviate cognitive impairment from cerebral hypoperfusion. Taken together, our studies demonstrate that MN-08 is a promising therapeutic agent for the treatment of dementia including VaD and AD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"272 ","pages":"Article 110410"},"PeriodicalIF":4.6,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625423","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}