Pub Date : 2025-10-14Epub Date: 2025-08-05DOI: 10.1016/j.neulet.2025.138337
Yan Fang Mao, Liang Chen, Jun Yu Liu, Zhang Yu Guo, Pei Lin Lu, Yan Xing Chen
Brain insulin signaling deficits contribute to multiple pathologicalfeatures of Alzheimer's disease (AD).Intranasal insulin has demonstrated therapeutic potential, but its underlying mechanisms remain unclear. This study investigated whether intranasal insulinmodulates tau pathology in early-stage APPswe/PS1dE9 (APP/PS1) mice.After six weeks of treatment, no significant changes in total or phosphorylated tau levels were observed. However, there was a trend toward improvement in dysregulated signaling pathways associated with tau kinases. These findings suggest that the protective effect of nasal insulin in early AD may not primarily be against tau-related neurotoxicity.
{"title":"Intranasal insulin administration shows limited tau-targeted effects in early-stage APP/PS1 Alzheimer's mice.","authors":"Yan Fang Mao, Liang Chen, Jun Yu Liu, Zhang Yu Guo, Pei Lin Lu, Yan Xing Chen","doi":"10.1016/j.neulet.2025.138337","DOIUrl":"10.1016/j.neulet.2025.138337","url":null,"abstract":"<p><p>Brain insulin signaling deficits contribute to multiple pathologicalfeatures of Alzheimer's disease (AD).Intranasal insulin has demonstrated therapeutic potential, but its underlying mechanisms remain unclear. This study investigated whether intranasal insulinmodulates tau pathology in early-stage APPswe/PS1dE9 (APP/PS1) mice.After six weeks of treatment, no significant changes in total or phosphorylated tau levels were observed. However, there was a trend toward improvement in dysregulated signaling pathways associated with tau kinases. These findings suggest that the protective effect of nasal insulin in early AD may not primarily be against tau-related neurotoxicity.</p>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":" ","pages":"138337"},"PeriodicalIF":2.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-14Epub Date: 2025-07-27DOI: 10.1016/j.neulet.2025.138332
Liquan Qiu, Licai Zhang, Bin Fan, Xue Luo
Background: Sevoflurane anesthesia, while widely used, is associated with several side effects including the potential for nerve damage. MicroRNAs are disrupted in patients with sevoflurane anesthesia, including miR-423-3p. However, the association between miR-423-3p and neurological damage remains to be elucidated.
Aim: To investigate the effect of miR-423-3p on the rats after sevoflurane anesthesia and related molecular mechanisms.
Methods: RT-qPCR was utilized to quantify the levels of miR-423-3p, GPX4 and oxidative stress indicators in rat hippocampus. Cognitive function was assessed through the Morris water maze and novel object recognition tests. ELISA was applied to detect the levels of inflammatory factors.
Results: In the Sev group, miR-423-3p expression was significantly elevated, while GPX4 expression was markedly reduced. Down-regulated miR-423-3p negatively regulated GPX4 to shorten escape latency while increasing crossing times of the platform, time spend in the target quadrant, relative occupancy of exploring new objects and time to explore new objects. Furthermore, down-regulated miR-423-3p reduced ROS and MDA levels and increased GSH levels in nerve-injured rats, which could be reversed by inhibited GPX4. miR-423-3p inhibition reduced the levels of NLRP3, Caspase-1, IL-8, and IL-1β, which could be rescued by inhibition of GPX4.
Conclusion: Down-regulation of miR-423-3p attenuated cognitive deficits in nerve-injured rats. Moreover, repressed miR-423-3p mitigated oxidative stress and inflammation by negatively regulating GPX4.
{"title":"miR-423-3p alleviates sevoflurane-induced learning and memory dysfunction and nerve damage via negative regulation of GPX4.","authors":"Liquan Qiu, Licai Zhang, Bin Fan, Xue Luo","doi":"10.1016/j.neulet.2025.138332","DOIUrl":"10.1016/j.neulet.2025.138332","url":null,"abstract":"<p><strong>Background: </strong>Sevoflurane anesthesia, while widely used, is associated with several side effects including the potential for nerve damage. MicroRNAs are disrupted in patients with sevoflurane anesthesia, including miR-423-3p. However, the association between miR-423-3p and neurological damage remains to be elucidated.</p><p><strong>Aim: </strong>To investigate the effect of miR-423-3p on the rats after sevoflurane anesthesia and related molecular mechanisms.</p><p><strong>Methods: </strong>RT-qPCR was utilized to quantify the levels of miR-423-3p, GPX4 and oxidative stress indicators in rat hippocampus. Cognitive function was assessed through the Morris water maze and novel object recognition tests. ELISA was applied to detect the levels of inflammatory factors.</p><p><strong>Results: </strong>In the Sev group, miR-423-3p expression was significantly elevated, while GPX4 expression was markedly reduced. Down-regulated miR-423-3p negatively regulated GPX4 to shorten escape latency while increasing crossing times of the platform, time spend in the target quadrant, relative occupancy of exploring new objects and time to explore new objects. Furthermore, down-regulated miR-423-3p reduced ROS and MDA levels and increased GSH levels in nerve-injured rats, which could be reversed by inhibited GPX4. miR-423-3p inhibition reduced the levels of NLRP3, Caspase-1, IL-8, and IL-1β, which could be rescued by inhibition of GPX4.</p><p><strong>Conclusion: </strong>Down-regulation of miR-423-3p attenuated cognitive deficits in nerve-injured rats. Moreover, repressed miR-423-3p mitigated oxidative stress and inflammation by negatively regulating GPX4.</p>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":" ","pages":"138332"},"PeriodicalIF":2.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144743337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-14Epub Date: 2025-08-06DOI: 10.1016/j.neulet.2025.138339
Yan Li, Qian Gao, Chenyu Zhuang, Yifan Zhou, Zixin Chang, Yingying Zhao, Shenfan Zhu, Yanqing Liu, Bo Zhang
Background: Alzheimer's disease (AD) is a neurodegenerative disorder that accounts for almost half of all dementia cases globally and is progressively increasing. Etiology includes heredity, genetic factors, aging, and nutrition, but sex hormones also play a key role. Reliable animal models of AD are the basis for gaining insight into the pathophysiological mechanisms of AD and for developing and evaluating novel therapeutic strategies for preclinical AD.
New method: This study described and evaluated a model mimicking features of late-onset AD by combining gonadectomy with bilateral hippocampal dentate gyrus Aβ injections in mice.
Results: As demonstrated by the Morris water maze test, Nissl staining, TUNEL, and EDU labeling, this method produced the mouse model of AD with decreased learning memory capacity accompanied by decreased neuronal function in the hippocampus, increased apoptotic neurons in hippocampus CA1 area and decreased regenerative neurons in hippocampus dentate gyrus area.
Comparison with existing methods: Existing AD models often overlook the physiological feature of sex hormone deficiency in late-onset AD and fail to fully account for the neuroprotective effects of sex hormones, which may lead to false-positive results in neuroprotection-related assessments. The model in this study simulates low sex hormone levels through gonadectomy and is combined with bilateral hippocampal dentate gyrus injection of Aβ1-42 oligomers, overcoming the limitations of single-factor models and more effectively simulating the pathophysiological characteristics of sex hormone deficiency and Aβ deposition in late-onset AD.
Conclusions: The model effectively simulated the pathophysiological state of late-onset AD. In both sexes, most of these indications of dysfunction were significantly more pronounced in gonadectomized animals compared to gonadally intact controls.
Significance statement: In this study, a mouse model of late-onset Alzheimer's disease, developed by combining gonadectomy with Aβ injection into the bilateral hippocampal dentate gyrus, accurately simulates the pathophysiological processes of sex hormone deficiency and Aβ deposition in patients, thereby providing a robust platform to explore nervous system structural and functional changes in late-onset AD and evaluate potential preventive drugs. Moreover, this dual-factor model provides novel insights into the synergistic interaction between sex hormone deficiency and Aβ pathology, offering a physiologically relevant platform for studying late-onset AD.
{"title":"Modeling Alzheimer's disease in mice: Gonadectomy combined with bilateral hippocampus dentate gyrus injection of Aβ<sub>1-42</sub> oligomers.","authors":"Yan Li, Qian Gao, Chenyu Zhuang, Yifan Zhou, Zixin Chang, Yingying Zhao, Shenfan Zhu, Yanqing Liu, Bo Zhang","doi":"10.1016/j.neulet.2025.138339","DOIUrl":"10.1016/j.neulet.2025.138339","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is a neurodegenerative disorder that accounts for almost half of all dementia cases globally and is progressively increasing. Etiology includes heredity, genetic factors, aging, and nutrition, but sex hormones also play a key role. Reliable animal models of AD are the basis for gaining insight into the pathophysiological mechanisms of AD and for developing and evaluating novel therapeutic strategies for preclinical AD.</p><p><strong>New method: </strong>This study described and evaluated a model mimicking features of late-onset AD by combining gonadectomy with bilateral hippocampal dentate gyrus Aβ injections in mice.</p><p><strong>Results: </strong>As demonstrated by the Morris water maze test, Nissl staining, TUNEL, and EDU labeling, this method produced the mouse model of AD with decreased learning memory capacity accompanied by decreased neuronal function in the hippocampus, increased apoptotic neurons in hippocampus CA1 area and decreased regenerative neurons in hippocampus dentate gyrus area.</p><p><strong>Comparison with existing methods: </strong>Existing AD models often overlook the physiological feature of sex hormone deficiency in late-onset AD and fail to fully account for the neuroprotective effects of sex hormones, which may lead to false-positive results in neuroprotection-related assessments. The model in this study simulates low sex hormone levels through gonadectomy and is combined with bilateral hippocampal dentate gyrus injection of Aβ<sub>1-42</sub> oligomers, overcoming the limitations of single-factor models and more effectively simulating the pathophysiological characteristics of sex hormone deficiency and Aβ deposition in late-onset AD.</p><p><strong>Conclusions: </strong>The model effectively simulated the pathophysiological state of late-onset AD. In both sexes, most of these indications of dysfunction were significantly more pronounced in gonadectomized animals compared to gonadally intact controls.</p><p><strong>Significance statement: </strong>In this study, a mouse model of late-onset Alzheimer's disease, developed by combining gonadectomy with Aβ injection into the bilateral hippocampal dentate gyrus, accurately simulates the pathophysiological processes of sex hormone deficiency and Aβ deposition in patients, thereby providing a robust platform to explore nervous system structural and functional changes in late-onset AD and evaluate potential preventive drugs. Moreover, this dual-factor model provides novel insights into the synergistic interaction between sex hormone deficiency and Aβ pathology, offering a physiologically relevant platform for studying late-onset AD.</p>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":" ","pages":"138339"},"PeriodicalIF":2.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-14Epub Date: 2025-08-08DOI: 10.1016/j.neulet.2025.138347
Hsien-Hui Chung
Maternal diabetes (MD) increases the risk for neurodevelopmental disorders and leads to neural tube defects (NTDs) which are severe anomalies of the nervous system. In order to elucidate the etiology and pathological mechanisms causing NTDs in MD and try to search for new therapeutic strategies as well, the exposure of induced pluripotency stem cell (iPSC)-neural stem cells (NSCs) to high glucose (HG) may be associated with fetal progressive deterioration of neuronal functions in utero ultimately leading to MD-related NTDs. In the present study, although HG (25 mM) had no effect on the viability of undifferentiated iPSC-NSCs compared with the positive control mannitol (25 mM), HG attenuated iPSC-NSCs cell proliferation and induced the presence of decreased βIII-tubulin and neurite network length during 7-day neuronal differentiation, resulting in the inability of nerve-to-nerve connections to communicate effectively. Compared with mannitol, HG actually reduced gene and protein expressions of iPSC-NSCs differentiation marker βIII-tubulin on day 7. Moreover, HG increased protein expressions of caspase-1 during 7-day neuronal differentiation compared with mannitol, indicating the critical role of caspase-1 in HG-mediated neuronal inflammation. Thus, the present study indicated that HG-induced impairment in iPSC-NSCs differentiation was mediated by decreased βIII-tubulin, shorter neurite network length and increased caspase-1 expressions, which provided a direction for the clarification of MD-induced NTDs.
产妇糖尿病（MD）增加了神经发育障碍的风险，并导致神经管缺陷（NTDs），这是神经系统的严重异常。为了阐明MD中NTDs的病因和病理机制，并试图寻找新的治疗策略，诱导多能干细胞(iPSC)-神经干细胞（NSCs）暴露于高糖（HG）可能与胎儿在子宫内神经元功能的进行性恶化有关，最终导致MD相关的NTDs。在本研究中，虽然HG（25 mM）与阳性对照甘露醇（25 mM）相比，对未分化iPSC-NSCs的活力没有影响，但在7天的神经元分化过程中，HG减弱了iPSC-NSCs细胞的增殖，诱导β iii -微管蛋白和神经突网络长度的减少，导致神经间连接无法有效沟通。与甘露醇相比，HG在第7天实际上降低了iPSC-NSCs分化标志物β iii -微管蛋白的基因和蛋白表达。此外，与甘露醇相比，HG在7天的神经元分化过程中增加了caspase-1的蛋白表达，这表明caspase-1在HG介导的神经元炎症中起着关键作用。因此，本研究表明，hg诱导的iPSC-NSCs分化障碍是通过β iii -微管蛋白减少、神经突网络长度缩短和caspase-1表达增加介导的，这为阐明md诱导的NTDs提供了方向。
{"title":"The dysregulation of high glucose-induced iPSC-neural stem cells differentiation by caspase-1.","authors":"Hsien-Hui Chung","doi":"10.1016/j.neulet.2025.138347","DOIUrl":"10.1016/j.neulet.2025.138347","url":null,"abstract":"<p><p>Maternal diabetes (MD) increases the risk for neurodevelopmental disorders and leads to neural tube defects (NTDs) which are severe anomalies of the nervous system. In order to elucidate the etiology and pathological mechanisms causing NTDs in MD and try to search for new therapeutic strategies as well, the exposure of induced pluripotency stem cell (iPSC)-neural stem cells (NSCs) to high glucose (HG) may be associated with fetal progressive deterioration of neuronal functions in utero ultimately leading to MD-related NTDs. In the present study, although HG (25 mM) had no effect on the viability of undifferentiated iPSC-NSCs compared with the positive control mannitol (25 mM), HG attenuated iPSC-NSCs cell proliferation and induced the presence of decreased βIII-tubulin and neurite network length during 7-day neuronal differentiation, resulting in the inability of nerve-to-nerve connections to communicate effectively. Compared with mannitol, HG actually reduced gene and protein expressions of iPSC-NSCs differentiation marker βIII-tubulin on day 7. Moreover, HG increased protein expressions of caspase-1 during 7-day neuronal differentiation compared with mannitol, indicating the critical role of caspase-1 in HG-mediated neuronal inflammation. Thus, the present study indicated that HG-induced impairment in iPSC-NSCs differentiation was mediated by decreased βIII-tubulin, shorter neurite network length and increased caspase-1 expressions, which provided a direction for the clarification of MD-induced NTDs.</p>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":" ","pages":"138347"},"PeriodicalIF":2.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The current study aims to evaluate any potential anxiolytic effects and the action mechanisms of ferulic acid, a phenolic phytochemical compound, in mice. The anxiolytic activity of ferulic acid at the doses of 0.1, 1, 10, and 100 mg/kg, p.o in female BALB/c mice was assessed by open field, hole-board and elevated plus maze tests. The possible roles of noradrenergic, serotonergic, and GABAergic modulation in the anxiolytic action of 100 mg/kg ferulic acid were also investigated by pretreatment with 5 mg/kg (i.p.) yohimbine, 1 mg/kg (i.p.) WAY-100635, and 3 mg/kg (i.p.) flumazenil, respectively, in the hole-board and open field tests. Similar to the positive standard diazepam (1 mg/kg, i.p); without altering the locomotor activity, 100 mg/kg ferulic acid significantly altered all the parameters related to anxiolytic activity, whereas 0.1 and 10 mg/kg doses were found to be effective in only some parameters in elevated plus-maze and open field tests, suggesting a U-shaped dose–response pattern. The anxiolytic effect of 100 mg/kg ferulic acid was significantly antagonized by the pretreatment with 5-HT1A receptor antagonist WAY-100635 and especially by α-2 adrenoceptor antagonist yohimbine while the anxiolytic action was not blocked by GABAA/BZ receptor antagonist flumazenil pretreatment. The findings imply that ferulic acid’s anxiolytic effect is mediated by the activation of α-2 adrenoceptors and 5-HT1A receptors. In conclusion, it is possible to say that ferulic acid can be a safe potential agent which that be used alone or in combination with current effective treatments for anxiety.
{"title":"Ferulic acid possesses anxiolytic activity: evidence for the involvement of serotonergic and noradrenergic systems","authors":"Ozlem Pınar Cetiner , Hazal Eken , Feyza Alyu Altınok , Rana Arslan , Nurcan Bektas","doi":"10.1016/j.neulet.2025.138416","DOIUrl":"10.1016/j.neulet.2025.138416","url":null,"abstract":"<div><div>The current study aims to evaluate any potential anxiolytic effects and the action mechanisms of ferulic acid, a phenolic phytochemical compound, in mice. The anxiolytic activity of ferulic acid at the doses of 0.1, 1, 10, and 100 mg/kg, <em>p.o</em> in female BALB/c mice was assessed by open field, hole-board and elevated plus maze tests. The possible roles of noradrenergic, serotonergic, and GABAergic modulation in the anxiolytic action of 100 mg/kg ferulic acid were also investigated by pretreatment with 5 mg/kg (<em>i.p.</em>) yohimbine, 1 mg/kg (<em>i.p.</em>) WAY-100635, and 3 mg/kg (<em>i.p.</em>) flumazenil, respectively, in the hole-board and open field tests. Similar to the positive standard diazepam (1 mg/kg, i.p); without altering the locomotor activity, 100 mg/kg ferulic acid significantly altered all the parameters related to anxiolytic activity, whereas 0.1 and 10 mg/kg doses were found to be effective in only some parameters in elevated plus-maze and open field tests, suggesting a U-shaped dose–response pattern. The anxiolytic effect of 100 mg/kg ferulic acid was significantly antagonized by the pretreatment with 5-HT<sub>1A</sub> receptor antagonist WAY-100635 and especially by α-2 adrenoceptor antagonist yohimbine while the anxiolytic action was not blocked by GABA<sub>A</sub>/BZ receptor antagonist flumazenil pretreatment. The findings imply that ferulic acid’s anxiolytic effect is mediated by the activation of α-2 adrenoceptors and 5-HT<sub>1A</sub> receptors. In conclusion, it is possible to say that ferulic acid can be a safe potential agent which that be used alone or in combination with current effective treatments for anxiety.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"869 ","pages":"Article 138416"},"PeriodicalIF":2.0,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145293055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Parkinson’s disease (PD) is characterized by progressive loss of dopaminergic neurons in the substantia nigra, where oxidative stress and apoptosis play central roles. Epidemiological evidence suggests that nicotine may exert neuroprotective effects, but the molecular mechanisms remain incompletely understood. This study investigated whether nicotine mitigates MPTP-induced neurotoxicity in mice through modulation of the BDNF/PI3K/AKT/Nrf2 signaling pathway.
Male BALB/c mice were divided into control, nicotine, MPTP, and MPTP + nicotine groups. Histological analysis revealed that nicotine significantly reduced MPTP-induced neuronal pyknosis and preserved tyrosine hydroxylase-positive dopaminergic neurons. Biochemical assays showed that nicotine attenuated MPTP-induced increases in malondialdehyde, lactate dehydrogenase, and lactate/pyruvate ratio, while restoring complex I activity and antioxidant enzyme activities (SOD, CAT, GPx, GR). Western blotting demonstrated that nicotine reversed MPTP-induced suppression of phosphorylated PI3K, AKT, and Nrf2, and shifted apoptotic signaling toward survival by increasing Bcl-2 and reducing Bax and Bad.
Importantly, nicotine restored BDNF levels in the substantia nigra, and ex vivo experiments confirmed that nicotine upregulated BDNF via α7 nicotinic acetylcholine receptor activation. These findings suggest that nicotine confers neuroprotection by enhancing BDNF-mediated activation of the PI3K/AKT/Nrf2 axis, leading to improved antioxidant defenses and anti-apoptotic signaling.
In conclusion, nicotine mitigates MPTP-induced dopaminergic neurodegeneration via BDNF/PI3K/AKT/Nrf2 signaling. While nicotine’s addictive properties limit its therapeutic use, selective targeting of nicotinic pathways may represent a promising strategy for disease-modifying interventions in PD.
{"title":"The role of BDNF/PI3K/AKT/Nrf2 signaling in nicotine’s protective effects against MPTP-induced Parkinson’s disease","authors":"Nikoloz Zhgenti , Ekaterine Bakuradze , Otar Bibilashvili , Nana Koshoridze","doi":"10.1016/j.neulet.2025.138412","DOIUrl":"10.1016/j.neulet.2025.138412","url":null,"abstract":"<div><div>Parkinson’s disease (PD) is characterized by progressive loss of dopaminergic neurons in the substantia nigra, where oxidative stress and apoptosis play central roles. Epidemiological evidence suggests that nicotine may exert neuroprotective effects, but the molecular mechanisms remain incompletely understood. This study investigated whether nicotine mitigates MPTP-induced neurotoxicity in mice through modulation of the BDNF/PI3K/AKT/Nrf2 signaling pathway.</div><div>Male BALB/c mice were divided into control, nicotine, MPTP, and MPTP + nicotine groups. Histological analysis revealed that nicotine significantly reduced MPTP-induced neuronal pyknosis and preserved tyrosine hydroxylase-positive dopaminergic neurons. Biochemical assays showed that nicotine attenuated MPTP-induced increases in malondialdehyde, lactate dehydrogenase, and lactate/pyruvate ratio, while restoring complex I activity and antioxidant enzyme activities (SOD, CAT, GPx, GR). Western blotting demonstrated that nicotine reversed MPTP-induced suppression of phosphorylated PI3K, AKT, and Nrf2, and shifted apoptotic signaling toward survival by increasing Bcl-2 and reducing Bax and Bad.</div><div>Importantly, nicotine restored BDNF levels in the substantia nigra, and ex vivo experiments confirmed that nicotine upregulated BDNF via α7 nicotinic acetylcholine receptor activation. These findings suggest that nicotine confers neuroprotection by enhancing BDNF-mediated activation of the PI3K/AKT/Nrf2 axis, leading to improved antioxidant defenses and anti-apoptotic signaling.</div><div>In conclusion, nicotine mitigates MPTP-induced dopaminergic neurodegeneration via BDNF/PI3K/AKT/Nrf2 signaling. While nicotine’s addictive properties limit its therapeutic use, selective targeting of nicotinic pathways may represent a promising strategy for disease-modifying interventions in PD.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"868 ","pages":"Article 138412"},"PeriodicalIF":2.0,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-10DOI: 10.1016/j.neulet.2025.138413
Caifeng Shao , Jichao Wei , Hong-Yi Jia , Yu-Han Zhou , Mingwei Zhao , Kun Yang , Ming-Ming Zhang
Transient receptor potential (TRP) ion channels, including the thermoreceptor TRP vanilloid 1 (TRPV1) and innocuous warm detector TRP melastatin 8 (TRPM8), are widely expressed on the primary sensory neurons of the trigeminal ganglion (TG) and the dorsal root ganglion (DRG). By performing real-time quantitative PCR and immunostaining, we compared TRPV1 and TRPM8 gene expression and immunostaining in mouse DRG and TG neurons. Both TRPV1 and TRPM8 are widely expressed in the TG and DRG, but in different patterns: TRPV1 has relatively more abundant expression and immunostaining in the DRG, whereas TRPM8 has higher levels in the TG. Double-staining for TRPV1 and TRPM8 revealed very little coexpression in either the TG or the DRG. These results suggest that TRPV1 and TRPM8 are differentially expressed in TG and DRG, and this significant variation may underlie the different temperature sensory properties of the skin and oral cavity.
{"title":"Differential expression of TRPV1 and TRPM8 in the mouse trigeminal ganglion and spinal dorsal root ganglion","authors":"Caifeng Shao , Jichao Wei , Hong-Yi Jia , Yu-Han Zhou , Mingwei Zhao , Kun Yang , Ming-Ming Zhang","doi":"10.1016/j.neulet.2025.138413","DOIUrl":"10.1016/j.neulet.2025.138413","url":null,"abstract":"<div><div>Transient receptor potential (TRP) ion channels, including the thermoreceptor TRP vanilloid 1 (TRPV1) and innocuous warm detector TRP melastatin 8 (TRPM8), are widely expressed on the primary sensory neurons of the trigeminal ganglion (TG) and the dorsal root ganglion (DRG). By performing real-time quantitative PCR and immunostaining, we compared TRPV1 and TRPM8 gene expression and immunostaining in mouse DRG and TG neurons. Both TRPV1 and TRPM8 are widely expressed in the TG and DRG, but in different patterns: TRPV1 has relatively more abundant expression and immunostaining in the DRG, whereas TRPM8 has higher levels in the TG. Double-staining for TRPV1 and TRPM8 revealed very little coexpression in either the TG or the DRG. These results suggest that TRPV1 and TRPM8 are differentially expressed in TG and DRG, and this significant variation may underlie the different temperature sensory properties of the skin and oral cavity.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"868 ","pages":"Article 138413"},"PeriodicalIF":2.0,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-10DOI: 10.1016/j.neulet.2025.138415
Frida Stam , Sara Bjurling , Erik Nylander , Esther Olaniran Håkansson , Johan Gising , Mats Larhed , Luke R. Odell , Alfhild Grönbladh , Mathias Hallberg
Insulin-regulated aminopeptidase (IRAP) is emerging as a pharmaceutical target for treatment of neurotoxic- and neurodegenerative symptoms commonly seen in cognitive impairments. Ligands of IRAP, such as Angiotensin IV and similar analogues, bind to the active site of IRAP and causes an inhibition of its enzymatic activity, which is suggested to improve cognitive functions. Opioids are widely used in the clinic to treat for example pain and opioid use disorder, however opioid use have been associated with cognitive impairments, impaired neuronal development, and neuronal damage. To evaluate the potential of the macrocyclic IRAP inhibitor compound 9 (C9), the present study examined the restorative effects of C9 after opioid-induced cell toxicity. The toxic impact of the commonly used opioids methadone and buprenorphine was determined in rat primary hippocampal and cortical cells, along with the effects on various viability markers after subsequent treatment with C9. The metabolism of tetrazolium bromide salt (MTT) was measured to assess mitochondrial activity, and the level of membrane damage was assessed by measuring lactate dehydrogenase (LDH) in the cell media. Fluorescent calcein dye was used to evaluate intracellular esterase activity. In conclusion, this study demonstrate that methadone and buprenorphine induce toxic effects in primary hippocampal and cortical cell cultures and that IRAP inhibitor C9 has a restorative effect on intracellular esterase activity in methadone-damaged cells.
{"title":"Insulin-regulated aminopeptidase inhibitor C9 restores cellular activity in methadone-damaged primary cell cultures","authors":"Frida Stam , Sara Bjurling , Erik Nylander , Esther Olaniran Håkansson , Johan Gising , Mats Larhed , Luke R. Odell , Alfhild Grönbladh , Mathias Hallberg","doi":"10.1016/j.neulet.2025.138415","DOIUrl":"10.1016/j.neulet.2025.138415","url":null,"abstract":"<div><div>Insulin-regulated aminopeptidase (IRAP) is emerging as a pharmaceutical target for treatment of neurotoxic- and neurodegenerative symptoms commonly seen in cognitive impairments. Ligands of IRAP, such as Angiotensin IV and similar analogues, bind to the active site of IRAP and causes an inhibition of its enzymatic activity, which is suggested to improve cognitive functions. Opioids are widely used in the clinic to treat for example pain and opioid use disorder, however opioid use have been associated with cognitive impairments, impaired neuronal development, and neuronal damage. To evaluate the potential of the macrocyclic IRAP inhibitor compound 9 (C9), the present study examined the restorative effects of C9 after opioid-induced cell toxicity. The toxic impact of the commonly used opioids methadone and buprenorphine was determined in rat primary hippocampal and cortical cells, along with the effects on various viability markers after subsequent treatment with C9. The metabolism of tetrazolium bromide salt (MTT) was measured to assess mitochondrial activity, and the level of membrane damage was assessed by measuring lactate dehydrogenase (LDH) in the cell media. Fluorescent calcein dye was used to evaluate intracellular esterase activity. In conclusion, this study demonstrate that methadone and buprenorphine induce toxic effects in primary hippocampal and cortical cell cultures and that IRAP inhibitor C9 has a restorative effect on intracellular esterase activity in methadone-damaged cells.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"869 ","pages":"Article 138415"},"PeriodicalIF":2.0,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study explores the relationship between personality traits and visual homeostatic plasticity, a neural mechanism maintaining stable the brain activity. Actually, personality may influence neuroplasticity, the general brain ability to adapt through experiences. Indeed, prior research links traits like openness to experience and neuroticism to Hebbian plasticity (experience-based synaptic strengthening), but any connections to homeostatic plasticity remain largely unexplored.
To probe homeostatic plasticity we tested the effect of short-term monocular deprivation in 24 healthy adults. Participants wore an eye patch for two hours, and underwent binocular rivalry tests measuring shifts in perceptual dominance. The deprivation index, reflecting homeostatic plasticity in the primary visual cortex, was analysed alongside personality traits assessed via the Big Five Questionnaire.
Results revealed a positive correlation between the deprivation index and conscientiousness but a negative correlation with emotional stability. Conscientious individuals, often goal-directed and self-regulated, showed reduced homeostatic plasticity, suggesting diminished mental flexibility. Conversely, higher emotional stability (lower neuroticism) enhanced homeostatic plasticity, aligning with findings that neuroticism reduces resilience, a potential link to impaired plasticity.
Overall, the study suggests that homeostatic plasticity, often limited to sensory adaptation, might reflect broader brain regulatory properties that appear to be linked to personality traits.
{"title":"Stable Traits, Adaptive Brains: links between Visual Homeostatic Plasticity and Personality","authors":"Marina Baroni , Valentina Cesari , Angelo Gemignani , Maria Concetta Morrone , Claudia Lunghi , Danilo Menicucci","doi":"10.1016/j.neulet.2025.138414","DOIUrl":"10.1016/j.neulet.2025.138414","url":null,"abstract":"<div><div>This study explores the relationship between personality traits and visual homeostatic plasticity, a neural mechanism maintaining stable the brain activity. Actually, personality may influence neuroplasticity, the general brain ability to adapt through experiences. Indeed, prior research links traits like openness to experience and neuroticism to Hebbian plasticity (experience-based synaptic strengthening), but any connections to homeostatic plasticity remain largely unexplored.</div><div>To probe homeostatic plasticity we tested the effect of short-term monocular deprivation in 24 healthy adults. Participants wore an eye patch for two hours, and underwent binocular rivalry tests measuring shifts in perceptual dominance. The deprivation index, reflecting homeostatic plasticity in the primary visual cortex, was analysed alongside personality traits assessed via the Big Five Questionnaire.</div><div>Results revealed a positive correlation between the deprivation index and conscientiousness but a negative correlation with emotional stability. Conscientious individuals, often goal-directed and self-regulated, showed reduced homeostatic plasticity, suggesting diminished mental flexibility. Conversely, higher emotional stability (lower neuroticism) enhanced homeostatic plasticity, aligning with findings that neuroticism reduces resilience, a potential link to impaired plasticity.</div><div>Overall, the study suggests that homeostatic plasticity, often limited to sensory adaptation, might reflect broader brain regulatory properties that appear to be linked to personality traits.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"868 ","pages":"Article 138414"},"PeriodicalIF":2.0,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The crucial influence of mitochondria in ischemic stroke pathophysiology presents many unexplored yet promising avenues for therapeutic strategies and clinical outcomes. Post-stroke mitochondrial dysfunction contributes to aggravated levels of calcium overload and apoptosis. This dysfunction is signified by disruption of the mitochondrial lipids such as cardiolipin, along with mitochondrial DNA mutation, leading to an imbalance in mitophagy. Calcium overload-mediated calcineurin overexpression has been reported to exacerbate mitochondrial damage and further contribute to neuronal apoptosis. In our study, we explored the alterations in the mitochondrial function following inhibition of the calcium-mediated calcineurin levels in post-stroke condition. In a rodent model of middle cerebral artery occlusion (MCAo), we observed that the inhibition of the calcium channels in post-stroke condition led to restored neuronal histology and viability following upregulation of the antioxidant levels. At the mitochondrial level, calcium channel inhibition downregulated calcineurin activation and normalized cardiolipin concentration, mitochondrial membrane potential, and respiratory control ratio in post-stroke condition. This inhibition also balanced the mitochondrial dynamics proteins and mitophagy towards neuronal recovery following ischemic stress. Moreover, it also normalized the expression of TERT, a key marker of mitochondrial health and aging. These findings highlight the role of calcium-mediated calcineurin in influencing mitochondrial dysfunction and aging in ischemic stroke. Thus, calcium channel inhibition offers a promising therapeutic strategy by preserving mitochondrial integrity and promoting neuroprotection following stroke.
{"title":"Mitochondrial dysfunction and aging can be alleviated by modulating calcineurin and cardiolipin dynamics following stroke","authors":"Pallab Bhattacharya , Shailendra Saraf , Anirban Barik , Bijoyani Ghosh , Aishika Datta , Davendra Singh Malik","doi":"10.1016/j.neulet.2025.138410","DOIUrl":"10.1016/j.neulet.2025.138410","url":null,"abstract":"<div><div>The crucial influence of mitochondria in ischemic stroke pathophysiology presents many unexplored yet promising avenues for therapeutic strategies and clinical outcomes. Post-stroke mitochondrial dysfunction contributes to aggravated levels of calcium overload and apoptosis. This dysfunction is signified by disruption of the mitochondrial lipids such as cardiolipin, along with mitochondrial DNA mutation, leading to an imbalance in mitophagy. Calcium overload-mediated calcineurin overexpression has been reported to exacerbate mitochondrial damage and further contribute to neuronal apoptosis. In our study, we explored the alterations in the mitochondrial function following inhibition of the calcium-mediated calcineurin levels in post-stroke condition. In a rodent model of middle cerebral artery occlusion (MCAo), we observed that the inhibition of the calcium channels in post-stroke condition led to restored neuronal histology and viability following upregulation of the antioxidant levels. At the mitochondrial level, calcium channel inhibition downregulated calcineurin activation and normalized cardiolipin concentration, mitochondrial membrane potential, and respiratory control ratio in post-stroke condition. This inhibition also balanced the mitochondrial dynamics proteins and mitophagy towards neuronal recovery following ischemic stress. Moreover, it also normalized the expression of TERT, a key marker of mitochondrial health and aging. These findings highlight the role of calcium-mediated calcineurin in influencing mitochondrial dysfunction and aging in ischemic stroke. Thus, calcium channel inhibition offers a promising therapeutic strategy by preserving mitochondrial integrity and promoting neuroprotection following stroke.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"868 ","pages":"Article 138410"},"PeriodicalIF":2.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号