Pub Date : 2025-10-01DOI: 10.1016/j.neulet.2025.138406
Cuirong Chen , Hong Han , Hongzhe Li , Zitan Zhang , Yingbing Lv
Background
Postoperative cognitive dysfunction (POCD) refers to postoperative neurological complications in patients, thus affecting patients’ normal daily life.
Purpose
Our study aimed to confirm whether Adrb2/Pkg are involved in the protective effect of Dexmedetomidine (Dex) against POCD in rats.
Methods
The targets for Dex against POCD were screened by online databases. An POCD rat model was constructed, and the Morris water maze tests were conducted to evaluate the cognitive function of POCD rats. The inflammatory markers (IL-6, TNF-α, and IL-13) were recorded, and the levels of Adrb2 and Pkg in hippocampus tissue were detected using RT-qPCR. The key targets Adrb2/Pkg were verified through the LPS-induced inflammatory BV-2 cell model.
Results
Network pharmacology analysis predicted that Adrb2 and Pkg were the key genes of Dex against POCD. Dex treatment improved learning and memory skills of POCD rats. In vitro and in vivo experiments showed that Dex treatment alleviated inflammation, and upregulated Adrb2 and Pkg mRNA levels of POCD rats and inflammatory BV-2 cell line. Silencing Adrb2/Pkg reversed the apoptosis suppression in LPS-induced inflammatory BV-2 cells caused by Dex.
Conclusion
The Adrb2/Pkg could potentially be the mechanism by which Dex protects POCD rats from cognitive impairment.
{"title":"Dexmedetomidine improves postoperative cognitive dysfunction via regulating Adrb2/Pkg","authors":"Cuirong Chen , Hong Han , Hongzhe Li , Zitan Zhang , Yingbing Lv","doi":"10.1016/j.neulet.2025.138406","DOIUrl":"10.1016/j.neulet.2025.138406","url":null,"abstract":"<div><h3>Background</h3><div>Postoperative cognitive dysfunction (POCD) refers to postoperative neurological complications in patients, thus affecting patients’ normal daily life.</div></div><div><h3>Purpose</h3><div>Our study aimed to confirm whether <em>Adrb2/Pkg</em> are involved in the protective effect of Dexmedetomidine (Dex) against POCD in rats.</div></div><div><h3>Methods</h3><div>The targets for Dex against POCD were screened by online databases. An POCD rat model was constructed, and the Morris water maze tests were conducted to evaluate the cognitive function of POCD rats. The inflammatory markers (IL-6, TNF-α, and IL-13) were recorded, and the levels of <em>Adrb2</em> and <em>Pkg</em> in hippocampus tissue were detected using RT-qPCR. The key targets <em>Adrb2/Pkg</em> were verified through the LPS-induced inflammatory BV-2 cell model.</div></div><div><h3>Results</h3><div>Network pharmacology analysis predicted that <em>Adrb2</em> and <em>Pkg</em> were the key genes of Dex against POCD. Dex treatment improved learning and memory skills of POCD rats. <em>In vitro</em> and <em>in vivo</em> experiments showed that Dex treatment alleviated inflammation, and upregulated <em>Adrb2</em> and <em>Pkg</em> mRNA levels of POCD rats and inflammatory BV-2 cell line. Silencing <em>Adrb2/Pkg</em> reversed the apoptosis suppression in LPS-induced inflammatory BV-2 cells caused by Dex.</div></div><div><h3>Conclusion</h3><div>The <em>Adrb2/Pkg</em> could potentially be the mechanism by which Dex protects POCD rats from cognitive impairment.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"868 ","pages":"Article 138406"},"PeriodicalIF":2.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225823","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 : 2025-09-30DOI: 10.1016/j.neulet.2025.138405
Bo Wang , YongPan Wen , Yonghong Tang , Min Li
Purpose
To explore the potential involvement of m6A methylation in the neuroprotective mechanism of H2S against hippocampus neuronal apoptosis in aged rats with POCD.
Methods
Sprague-Dawley rats (18–20 months) were subjected to anesthesia and laparotomy surgery to establish an animal model of POCD. The Open Field, Y-maze, and Novel Object Recognition tests assessed behavioral performance. Protein expression levels were analyzed using Western blot analysis, and neuronal apoptosis was analyzed using TUNEL staining.
Results
NaHS (100 μmol/kg) significantly increased the alternation ratio of the Y-maze test and the discrimination index of the NOR test, reduced hippocampal neuronal apoptosis, indicated by decreased TUNEL-positive neurons and modulated the expression of apoptosis-related protein markers (Bcl-2 was upregulated and Bax/Cleaved caspase-3 were downregulated). Furthermore, NaHS restored reduced m6A RNA methylation levels and corrected the disturbed expression of m6A-related enzymes (METTL3, METTL14, YTHDF1, YTHDF3, FTO, ALKBH5) in the hippocampus of aged rats with POCD.
Conclusion
H2S shows neuroprotective effects by mitigating hippocampal neuronal apoptosis and restoring m6A RNA methylation in the hippocampus of aged rats with POCD. These findings provide preclinical evidence that H2S may serve as a potential therapeutic agent for the prevention of POCD.
{"title":"Hydrogen sulfide protects against hippocampal neuronal apoptosis in aged rats with postoperative cognitive dysfunction by promoting m6A methylation","authors":"Bo Wang , YongPan Wen , Yonghong Tang , Min Li","doi":"10.1016/j.neulet.2025.138405","DOIUrl":"10.1016/j.neulet.2025.138405","url":null,"abstract":"<div><h3>Purpose</h3><div>To explore the potential involvement of m6A methylation in the neuroprotective mechanism of H<sub>2</sub>S against hippocampus neuronal apoptosis in aged rats with POCD.</div></div><div><h3>Methods</h3><div>Sprague-Dawley rats (18–20 months) were subjected to anesthesia and laparotomy surgery to establish an animal model of POCD. The Open Field, Y-maze, and Novel Object Recognition tests assessed behavioral performance. Protein expression levels were analyzed using Western blot analysis, and neuronal apoptosis was analyzed using TUNEL staining.</div></div><div><h3>Results</h3><div>NaHS (100 μmol/kg) significantly increased the alternation ratio of the Y-maze test and the discrimination index of the NOR test, reduced hippocampal neuronal apoptosis, indicated by decreased TUNEL-positive neurons and modulated the expression of apoptosis-related protein markers (Bcl-2 was upregulated and Bax/Cleaved caspase-3 were downregulated). Furthermore, NaHS restored reduced m<sup>6</sup>A RNA methylation levels and corrected the disturbed expression of m<sup>6</sup>A-related enzymes (METTL3, METTL14, YTHDF1, YTHDF3, FTO, ALKBH5) in the hippocampus of aged rats with POCD.</div></div><div><h3>Conclusion</h3><div>H<sub>2</sub>S shows neuroprotective effects by mitigating hippocampal neuronal apoptosis and restoring m<sup>6</sup>A RNA methylation in the hippocampus of aged rats with POCD. These findings provide preclinical evidence that H<sub>2</sub>S may serve as a potential therapeutic agent for the prevention of POCD.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"868 ","pages":"Article 138405"},"PeriodicalIF":2.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213220","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 : 2025-09-28DOI: 10.1016/j.neulet.2025.138391
Ya-Jie Zhao , Hong-Zhen Bai , Yi-Na Wang , Yu-Kun Liu , Long-Biao Zhao , Zhao Li , Hui-Zhou Li , Xiu-Li Wang , Peng Liu
Our previous study demonstrated that STING/ATG5-mediated autophagy in the spinal dorsal horn contributes to diabetic neuropathic pain (DNP), although the underlying mechanisms remained unclear. In this study, we investigated how STING-driven autophagy leads to impaired spinal inhibition via lysosomal degradation of GABA receptors. In a rat model of DNP, spinal levels of STING and ATG5 were elevated, while P62, GABAA receptor, and GABAB receptor expression were reduced. Behavioral tests showed that intrathecal administration of a STING inhibitor increased mechanical pain thresholds and upregulated P62 and GABA receptors. Conversely, treatment with a STING agonist worsened hyperalgesia and further suppressed GABA receptor expression. Knockdown of ATG5 via siRNA similarly alleviated pain and restored GABA receptor levels. Interestingly, although the mTOR inhibitor rapamycin alleviated neuropathic pain, it unexpectedly increased spinal P62 expression compared to the DNP group. Administration of leupeptin, a lysosomal protease inhibitor, significantly increased paw withdrawal thresholds on days 1–3 and elevated GABA receptor expression, whereas the proteasomal inhibitor MG132 had no effect. These results demonstrate that STING/ATG5-mediated autophagy promotes DNP through autophagic-lysosomal degradation of GABA receptors, highlighting this pathway as a promising therapeutic target for treating diabetic neuropathic pain.
{"title":"GABAergic disinhibition through the STING-dependent autophagic pathway in the dorsal horn underlies diabetic neuropathic pain pathogenesis","authors":"Ya-Jie Zhao , Hong-Zhen Bai , Yi-Na Wang , Yu-Kun Liu , Long-Biao Zhao , Zhao Li , Hui-Zhou Li , Xiu-Li Wang , Peng Liu","doi":"10.1016/j.neulet.2025.138391","DOIUrl":"10.1016/j.neulet.2025.138391","url":null,"abstract":"<div><div>Our previous study demonstrated that STING/ATG5-mediated autophagy in the spinal dorsal horn contributes to diabetic neuropathic pain (DNP), although the underlying mechanisms remained unclear. In this study, we investigated how STING-driven autophagy leads to impaired spinal inhibition via lysosomal degradation of GABA receptors. In a rat model of DNP, spinal levels of STING and ATG5 were elevated, while P62, GABA<sub>A</sub> receptor, and GABA<sub>B</sub> receptor expression were reduced. Behavioral tests showed that intrathecal administration of a STING inhibitor increased mechanical pain thresholds and upregulated P62 and GABA receptors. Conversely, treatment with a STING agonist worsened hyperalgesia and further suppressed GABA receptor expression. Knockdown of ATG5 via siRNA similarly alleviated pain and restored GABA receptor levels. Interestingly, although the mTOR inhibitor rapamycin alleviated neuropathic pain, it unexpectedly increased spinal P62 expression compared to the DNP group. Administration of leupeptin, a lysosomal protease inhibitor, significantly increased paw withdrawal thresholds on days 1–3 and elevated GABA receptor expression, whereas the proteasomal inhibitor MG132 had no effect. These results demonstrate that STING/ATG5-mediated autophagy promotes DNP through autophagic-lysosomal degradation of GABA receptors, highlighting this pathway as a promising therapeutic target for treating diabetic neuropathic pain.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"868 ","pages":"Article 138391"},"PeriodicalIF":2.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200469","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 : 2025-09-27DOI: 10.1016/j.neulet.2025.138393
Douglas Lamounier de Almeida , Walace Cássio Pinto Barra , Renata Cristina Mendes Ferreira , Flávia Cristina Fonseca , Daniel Portela Dias Machado , Danielle Diniz Aguiar , Francisco Silveira Guimaraes , Igor Dimitri Gama Duarte , Thiago Roberto Lima Romero
Cannabidiol (CBD) has been getting attention from the scientific community regarding its potential for the treatment of different conditions, such as epilepsy, anxiety, and pain. This potential can be useful in clinical practice as an alternative or as an adjuvant alongside conventional therapeutic approaches; however, its mechanisms of action should be best described for its more effective application. Thus, our study aimed to evaluate whether the peripheral opioid system is involved in the analgesic mechanism of cannabidiol administered systemically for the treatment of neuropathic pain. Male Swiss mice were subjected to the sciatic constriction injury, and their nociceptive threshold was evaluated using the mechanical paw pressure test. Cannabidiol 20 mg/Kg produced an antinociceptive effect. Bestatin (400 µg/paw), a selective aminopeptidase-N inhibitor, potentiates the intermediate analgesic response of CBD at the dose of 2 mg/Kg. Naloxone (50 µg/paw), a non-selective opioid receptor antagonist, reversed the CBD-mediated analgesia. CTOP (5, 10, and 20 µg/paw) and naltrindole (30, 60, and 120 µg/paw), μ and Δ opioid receptor antagonists, but not norBNI (200 µg/paw), a κ opioid receptor antagonist, partially reversed the CBD analgesia. Thus, our study shows that cannabidiol may induce activation of opioid receptors in the periphery as a part of its analgesic mechanism in neuropathic pain.
{"title":"Cannabidiol engages the peripheral endogenous opioid system to produce analgesia in neuropathic mice","authors":"Douglas Lamounier de Almeida , Walace Cássio Pinto Barra , Renata Cristina Mendes Ferreira , Flávia Cristina Fonseca , Daniel Portela Dias Machado , Danielle Diniz Aguiar , Francisco Silveira Guimaraes , Igor Dimitri Gama Duarte , Thiago Roberto Lima Romero","doi":"10.1016/j.neulet.2025.138393","DOIUrl":"10.1016/j.neulet.2025.138393","url":null,"abstract":"<div><div>Cannabidiol (CBD) has been getting attention from the scientific community regarding its potential for the treatment of different conditions, such as epilepsy, anxiety, and pain. This potential can be useful in clinical practice as an alternative or as an adjuvant alongside conventional therapeutic approaches; however, its mechanisms of action should be best described for its more effective application. Thus, our study aimed to evaluate whether the peripheral opioid system is involved in the analgesic mechanism of cannabidiol administered systemically for the treatment of neuropathic pain. Male <em>Swiss</em> mice were subjected to the sciatic constriction injury, and their nociceptive threshold was evaluated using the mechanical paw pressure test. Cannabidiol 20 mg/Kg produced an antinociceptive effect. Bestatin (400 µg/paw), a selective aminopeptidase-N inhibitor, potentiates the intermediate analgesic response of CBD at the dose of 2 mg/Kg. Naloxone (50 µg/paw), a non-selective opioid receptor antagonist, reversed the CBD-mediated analgesia. CTOP (5, 10, and 20 µg/paw) and naltrindole (30, 60, and 120 µg/paw), μ and Δ opioid receptor antagonists, but not norBNI (200 µg/paw), a κ opioid receptor antagonist, partially reversed the CBD analgesia. Thus, our study shows that cannabidiol may induce activation of opioid receptors in the periphery as a part of its analgesic mechanism in neuropathic pain.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"868 ","pages":"Article 138393"},"PeriodicalIF":2.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192180","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 : 2025-09-27DOI: 10.1016/j.neulet.2025.138395
Yumi Oboshi , Mitsuru Kikuchi , Yasuomi Ouchi
Introduction
In past research, we have examined the characteristics of brain activity caused by prefrontal task completion in healthy older adults in a simplified manner using a near-infrared spectroscopy device, with the aim of identifying methods of early intervention to prevent their cognitive decline. Previously, we reported that prefrontal oxygenation during pre-task preparation was greater in young adults than older adults, and that this greater activation was associated with better task performances in both groups. To extend this research, in the present study, we examined previous findings with task repetitions, as older adults take more time to become familiar new tasks.
Methods
We modified the working memory task with a clear task-set instruction and examined the change in the task-set and task-induced activation in 63 cognitively healthy older adults.
Results
Task-set activation did not increase even after three repetitions, and the task-induced activation was greater than task-set activation in most channels. The difference in degree between task-induced activation and task-set activation showed a reduction with task repetitions. Significant inverse correlations were observed between the prefrontal activation due to the task itself in the third session, i.e., after task repetitions and the reaction time of the Trail Making Test, which represents attentional function.
Discussion
These results indicate that continued activation by the task itself, which persists even after older adults become familiar with the task, may be associated with executive function decline.
{"title":"Relationship between prefrontal oxygenation during task-set period and executive function in healthy older people: A near-infrared spectroscopy study","authors":"Yumi Oboshi , Mitsuru Kikuchi , Yasuomi Ouchi","doi":"10.1016/j.neulet.2025.138395","DOIUrl":"10.1016/j.neulet.2025.138395","url":null,"abstract":"<div><h3>Introduction</h3><div>In past research, we have examined the characteristics of brain activity caused by prefrontal task completion in healthy older adults in a simplified manner using a near-infrared spectroscopy device, with the aim of identifying methods of early intervention to prevent their cognitive decline. Previously, we reported that prefrontal oxygenation during pre-task preparation was greater in young adults than older adults, and that this greater activation was associated with better task performances in both groups. To extend this research, in the present study, we examined previous findings with task repetitions, as older adults take more time to become familiar new tasks.</div></div><div><h3>Methods</h3><div>We modified the working memory task with a clear task-set instruction and examined the change in the task-set and task-induced activation in 63 cognitively healthy older adults.</div></div><div><h3>Results</h3><div>Task-set activation did not increase even after three repetitions, and the task-induced activation was greater than task-set activation in most channels. The difference in degree between task-induced activation and task-set activation showed a reduction with task repetitions. Significant inverse correlations were observed between the prefrontal activation due to the task itself in the third session, i.e., after task repetitions and the reaction time of the Trail Making Test, which represents attentional function.</div></div><div><h3>Discussion</h3><div>These results indicate that continued activation by the task itself, which persists even after older adults become familiar with the task, may be associated with executive function decline.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"868 ","pages":"Article 138395"},"PeriodicalIF":2.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192258","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 : 2025-09-25DOI: 10.1016/j.neulet.2025.138394
Jiaquan Wang , Xiao-kang Gong , Jing Yu , Liangwei Wu , Yuheng Zhang , Pan Li , Min Qin , Xiao-chuan Wang , Xi-ji Shu , Jian Bao
Post-traumatic stress disorder (PTSD) is a severe psychiatric disorder characterized by a complex interplay of genetic and environmental influences. Substantial evidence has demonstrated an intricate nexus between nicotine, the principal psychoactive constituent of cigarette smoke, and PTSD neuropathology. Nevertheless, the intricate mechanism underlying the relationship between nicotine consumption and PTSD has not yet been fully understood. Following two weeks of intraperitoneal nicotine administration at two doses (5 mg/kg and 1 mg/kg), we initiated behavioral testing. Our findings reveal that nicotine supplementation exacerbates fear and depression-like behaviors while promoting microglial phagocytosis of synaptic proteins. Moreover, we observed synaptic protein loss and microglial activation in both the hippocampus and cortex in the 5 mg/kg group. CX3CR1-Cre driven Cre recombinase (Cre) is a widely used genetic tool for enabling gene manipulation in microglia. Here, we investigated a genetic ablation method of the CX3CR1 using a Cre-responsive adeno-associated virus (AAV) vector expressing diphtheria toxin subunit-A (DTA). Conversely, microglial ablation via rAAV-EF1a-DIO-DTA-WPRE hGH pA injection in the ventral hippocampus CA1 region of CX3CR1-Cre mice appears to mitigate the pathologies and behavioral abnormalities induced by nicotine. Our results underscore the role of nicotine in the progression of PTSD and demonstrate that microglial depletion mitigates nicotine-induced pathologies and behavioral disturbances. Consequently, our findings suggest that nicotine enhances microglial phagocytosis of synaptic proteins in PTSD, thereby exacerbating fear and depressive symptoms.
{"title":"Nicotine exacerbates fear and depression-like behaviors by promoting microglial phagocytosis of synaptic protein in a mouse model of foot shock","authors":"Jiaquan Wang , Xiao-kang Gong , Jing Yu , Liangwei Wu , Yuheng Zhang , Pan Li , Min Qin , Xiao-chuan Wang , Xi-ji Shu , Jian Bao","doi":"10.1016/j.neulet.2025.138394","DOIUrl":"10.1016/j.neulet.2025.138394","url":null,"abstract":"<div><div>Post-traumatic stress disorder (PTSD) is a severe psychiatric disorder characterized by a complex interplay of genetic and environmental influences. Substantial evidence has demonstrated an intricate nexus between nicotine, the principal psychoactive constituent of cigarette smoke, and PTSD neuropathology. Nevertheless, the intricate mechanism underlying the relationship between nicotine consumption and PTSD has not yet been fully understood. Following two weeks of intraperitoneal nicotine administration at two doses (5 mg/kg and 1 mg/kg), we initiated behavioral testing. Our findings reveal that nicotine supplementation exacerbates fear and depression-like behaviors while promoting microglial phagocytosis of synaptic proteins. Moreover, we observed synaptic protein loss and microglial activation in both the hippocampus and cortex in the 5 mg/kg group. CX3CR1-Cre driven Cre recombinase (Cre) is a widely used genetic tool for enabling gene manipulation in microglia. Here, we investigated a genetic ablation method of the CX3CR1 using a Cre-responsive adeno-associated virus (AAV) vector expressing diphtheria toxin subunit-A (DTA). Conversely, microglial ablation via rAAV-EF1a-DIO-DTA-WPRE hGH pA injection in the ventral hippocampus CA1 region of CX3CR1-Cre mice appears to mitigate the pathologies and behavioral abnormalities induced by nicotine. Our results underscore the role of nicotine in the progression of PTSD and demonstrate that microglial depletion mitigates nicotine-induced pathologies and behavioral disturbances. Consequently, our findings suggest that nicotine enhances microglial phagocytosis of synaptic proteins in PTSD, thereby exacerbating fear and depressive symptoms.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"867 ","pages":"Article 138394"},"PeriodicalIF":2.0,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182020","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 : 2025-09-24DOI: 10.1016/j.neulet.2025.138392
Marie-Michèle Serghani , Sondos Kassem-Moussa , Rawan Makki , Abdallah Kurdi , Marawan Elbaset , Helene Hajjar , Reem El Jammal , Gabriel T. Flath-Everhard , Ishaan Prasad , Assaad Eid , Aida Habib , Eva Hamade , Fletcher A. White , Bassam Badran , Makram Obeid
Hypoxic encephalopathy of the newborn is associated with long-term neurodevelopmental behavioral deficits that lack a definitive “optimal” treatment approach. We previously demonstrated that periadolescent depressive-like behaviors occur in a rat model of early-life hypoxia. Here, we investigated the short-term effects of the selective serotonin reuptake inhibitor, sertraline, against later-life behavioral deficits. Rats were exposed to global hypoxia at postnatal day 10 (P10) and then received either sertraline or its vehicle (P24 to P30). Normoxic controls received sertraline or its vehicle. Depressive-like and anxiety-like behaviors were assessed using the forced swim test (FST) and open field test (OFT), respectively. The FST was conducted at P25-26 and the OFT at P27. Rats were sacrificed at P30 to assess hippocampal microRNA (miR) expression and to histologically evaluate hippocampal neuronal densities and synaptophysin (Syp) protein levels. Early-life hypoxic seizures resulted in increased immobility in the FST (p < 0.05) and decreased exploration in the OFT (p < 0.05). Hypoxia also resulted in chronic alterations in the expression of 25 miRs, 22 of which are known to modulate inflammatory responses and synaptic function. Sertraline treatment normalized hypoxia-induced increased immobility and reversed 17 out of 25 alterations in miR expression. However, sertraline potentiated hypoxia-induced exploratory deficits (p < 0.05). The drug treatment also resulted in OFT deficits in controls (p < 0.05) and 13 unique dysregulations in miR expression. Neuronal densities and Syp levels were comparable among all groups. We demonstrate that sertraline reverses hypoxia-induced depressive-like behaviors, possibly by targeting inflammation and synaptic remodeling. Sertraline-induced anxiety-like behaviors may reflect its known transient early side effects and warrant further research on long-term outcomes.
{"title":"Short-term effects of sertraline against depressive-like behaviors in a rat model of neonatal hypoxic encephalopathy","authors":"Marie-Michèle Serghani , Sondos Kassem-Moussa , Rawan Makki , Abdallah Kurdi , Marawan Elbaset , Helene Hajjar , Reem El Jammal , Gabriel T. Flath-Everhard , Ishaan Prasad , Assaad Eid , Aida Habib , Eva Hamade , Fletcher A. White , Bassam Badran , Makram Obeid","doi":"10.1016/j.neulet.2025.138392","DOIUrl":"10.1016/j.neulet.2025.138392","url":null,"abstract":"<div><div>Hypoxic encephalopathy of the newborn is associated with long-term neurodevelopmental behavioral deficits that lack a definitive “optimal” treatment approach. We previously demonstrated that periadolescent depressive-like behaviors occur in a rat model of early-life hypoxia. Here, we investigated the short-term effects of the selective serotonin reuptake inhibitor, sertraline, against later-life behavioral deficits. Rats were exposed to global hypoxia at postnatal day 10 (P10) and then received either sertraline or its vehicle (P24 to P30). Normoxic controls received sertraline or its vehicle. Depressive-like and anxiety-like behaviors were assessed using the forced swim test (FST) and open field test (OFT), respectively. The FST was conducted at P25-26 and the OFT at P27. Rats were sacrificed at P30 to assess hippocampal microRNA (miR) expression and to histologically evaluate hippocampal neuronal densities and synaptophysin (Syp) protein levels. Early-life hypoxic seizures resulted in increased immobility in the FST (p < 0.05) and decreased exploration in the OFT (p < 0.05). Hypoxia also resulted in chronic alterations in the expression of 25 miRs, 22 of which are known to modulate inflammatory responses and synaptic function. Sertraline treatment normalized hypoxia-induced increased immobility and reversed 17 out of 25 alterations in miR expression. However, sertraline potentiated hypoxia-induced exploratory deficits (p < 0.05). The drug treatment also resulted in OFT deficits in controls (p < 0.05) and 13 unique dysregulations in miR expression. Neuronal densities and Syp levels were comparable among all groups. We demonstrate that sertraline reverses hypoxia-induced depressive-like behaviors, possibly by targeting inflammation and synaptic remodeling. Sertraline-induced anxiety-like behaviors may reflect its known transient early side effects and warrant further research on long-term outcomes.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"867 ","pages":"Article 138392"},"PeriodicalIF":2.0,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176615","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 : 2025-09-22DOI: 10.1016/j.neulet.2025.138389
Alana Tercino Frias, Paloma Molina Hernandes, Helio Zangrossi Jr
Panic attacks, characterized by intense fear accompanied by autonomic and respiratory changes, can be experimentally modeled in humans and rodents by exposure to high concentrations of CO2. Acid-sensing ion channels (ASICs), particularly the ASIC1a subtype, are activated by decrease in pH and have been implicated in defensive responses triggered by hypercapnia. ASIC1a are found in key panic-associated areas such as the lateral wings of the dorsal raphe nucleus (lwDRN) and the dorsal periaqueductal gray (dPAG). Here, we first investigated whether ASIC1a channels in the lwDRN modulate the expression of panic-associated escape response in mice. C57BL/6 mice received intra-lwDRN injections of psalmotoxin-1 (Pstx-1; 12.5 or 25 ηg/50 ηL), a selective ASIC1a blocker, and were exposed to 20% CO2. ASIC1a blockade significantly reduced escape behavior without affecting baseline locomotion, suggesting a panicolytic-like effect. This effect was site-specific and abolished by intra-dPAG administration of WAY100635 (0.74 ηmol/50 ηL), a 5-HT1A receptor antagonist. Our study provides novel evidence that ASIC1a channels in the lwDRN contribute to CO2-evoked escape responses and that this modulation depends on serotonergic signaling via 5-HT1A receptors in the dPAG. These findings offer new insights into the neurobiology of panic attacks paving the way for the development of more precise treatments for PD.
{"title":"Blockade of acid-sensing ion channels 1a in the mice dorsal raphe nucleus inhibits panic-like responses: Role of 5-HT1A receptors in the dorsal periaqueductal gray","authors":"Alana Tercino Frias, Paloma Molina Hernandes, Helio Zangrossi Jr","doi":"10.1016/j.neulet.2025.138389","DOIUrl":"10.1016/j.neulet.2025.138389","url":null,"abstract":"<div><div>Panic attacks, characterized by intense fear accompanied by autonomic and respiratory changes, can be experimentally modeled in humans and rodents by exposure to high concentrations of CO<sub>2</sub>. Acid-sensing ion channels (ASICs), particularly the ASIC1a subtype, are activated by decrease in pH and have been implicated in defensive responses triggered by hypercapnia. ASIC1a are found in key panic-associated areas such as the lateral wings of the dorsal raphe nucleus (lwDRN) and the dorsal periaqueductal gray (dPAG). Here, we first investigated whether ASIC1a channels in the lwDRN modulate the expression of panic-associated escape response in mice. C57BL/6 mice received intra-lwDRN injections of psalmotoxin-1 (Pstx-1; 12.5 or 25 ηg/50 ηL), a selective ASIC1a blocker, and were exposed to 20% CO<sub>2</sub>. ASIC1a blockade significantly reduced escape behavior without affecting baseline locomotion, suggesting a panicolytic-like effect. This effect was site-specific and abolished by intra-dPAG administration of WAY100635 (0.74 ηmol/50 ηL), a 5-HT<sub>1A</sub> receptor antagonist. Our study provides novel evidence that ASIC1a channels in the lwDRN contribute to CO<sub>2</sub>-evoked escape responses and that this modulation depends on serotonergic signaling via 5-HT<sub>1A</sub> receptors in the dPAG. These findings offer new insights into the neurobiology of panic attacks paving the way for the development of more precise treatments for PD.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"867 ","pages":"Article 138389"},"PeriodicalIF":2.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138070","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 : 2025-09-22DOI: 10.1016/j.neulet.2025.138390
Bin Luo , Yu Zheng , Qi Miao , Yimin Zhang , Ye Lei , Qingyun Xu , Wenwu Li , Jingao Yu , Xiao Zhu , Jianlin Yuan , Huiyuan Zhu
Cerebral ischemia–reperfusion injury (CIRI) is a cerebrovascular disorder with high rates of incidence, disability, and death. It has been identified that Salvia miltiorrhiza and safflower have a protective effect in CIRI. However, the mechanisms of which remain to be elucidated. In this study, we investigated the protective mechanisms of the components of Salvia miltiorrhiza and safflower in CIRI, based on the TLR4/NF-κB signaling pathway. Sprague Dawley (SD) rats were used to establish the rat middle cerebral artery occlusion/reperfusion (MACO/R) model by the suture method. Drugs were injected intraperitoneally at 0 and 2 h, followed by once-daily treatment for 3 days. Neurological function and the volume of brain infarction were evaluated, and the pathological changes in brain tissue were examined using HE staining. ELISA kits were used to detect the concentrations of TNF-α and IL-6, while RT-qPCR, Western blot, and immunofluorescence were employed to evaluate the mRNA and protein expression in brain tissue. Following a combination of tanshinone IIA and hydroxy safflower yellow A treatment, our findings indicated that cerebral infarct volume and neurological deficits were reduced. The findings of HE staining revealed an improvement in cerebral histopathological damage in rats with MCAO/R. The levels of TNF-α and IL-6 in serum, as well as the expression of TLR4 and NF-κB in rat brains, were significantly reduced (P < 0.0001). Taken together, these results indicate that the combination of tanshinone ⅡA and hydroxyl safflower yellow A may exhibit a neuroprotective effect on cerebral I/R injury in rats by activating the TLR4/NF-κB signaling pathway.
{"title":"Tanshinone IIA and hydroxy safflower yellow A reduce cerebral injury via TLR4/NF-κB pathway in rats","authors":"Bin Luo , Yu Zheng , Qi Miao , Yimin Zhang , Ye Lei , Qingyun Xu , Wenwu Li , Jingao Yu , Xiao Zhu , Jianlin Yuan , Huiyuan Zhu","doi":"10.1016/j.neulet.2025.138390","DOIUrl":"10.1016/j.neulet.2025.138390","url":null,"abstract":"<div><div>Cerebral ischemia–reperfusion injury (CIRI) is a cerebrovascular disorder with high rates of incidence, disability, and death. It has been identified that Salvia miltiorrhiza and safflower have a protective effect in CIRI. However, the mechanisms of which remain to be elucidated. In this study, we investigated the protective mechanisms of the components of Salvia miltiorrhiza and safflower in CIRI, based on the TLR4/NF-κB signaling pathway. Sprague Dawley (SD) rats were used to establish the rat middle cerebral artery occlusion/reperfusion (MACO/R) model by the suture method. Drugs were injected intraperitoneally at 0 and 2 h, followed by once-daily treatment for 3 days. Neurological function and the volume of brain infarction were evaluated, and the pathological changes in brain tissue were examined using HE staining. ELISA kits were used to detect the concentrations of TNF-α and IL-6, while RT-qPCR, Western blot, and immunofluorescence were employed to evaluate the mRNA and protein expression in brain tissue. Following a combination of tanshinone IIA and hydroxy safflower yellow A treatment, our findings indicated that cerebral infarct volume and neurological deficits were reduced. The findings of HE staining revealed an improvement in cerebral histopathological damage in rats with MCAO/R. The levels of TNF-α and IL-6 in serum, as well as the expression of TLR4 and NF-κB in rat brains, were significantly reduced (P < 0.0001). Taken together, these results indicate that the combination of tanshinone ⅡA and hydroxyl safflower yellow A may exhibit a neuroprotective effect on cerebral I/R injury in rats by activating the TLR4/NF-κB signaling pathway.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"867 ","pages":"Article 138390"},"PeriodicalIF":2.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138080","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 : 2025-09-21DOI: 10.1016/j.neulet.2025.138385
Chunyu Zhou , Yulin Wang , Longfei Zuo , Yufan Miao , Wenjie Li , Xing Li , Yuan Xue , Mengxin Li
Alzheimer’s disease (AD) is the most common primary progressive neurodegenerative disorder, with inflammatory responses involved in its onset and progression. Vitamin D (VD) is known for its health benefits, including antioxidant effects. Recently, Deglycase protein 1 (DJ-1/PARK7) has been shown to potentially regulate in antioxidant activity and inflammation regulation. In this study, we investigated the therapeutic effects of VD3 (30 IU/g/w) in Dj-1 knockdown APPswe/PS1E9 (APP/PS1) mice. Pathological changes were assessed using the Morris water maze and Barnes maze, as well as immunofluorescence, thioflavin S staining, Nissl staining, TUNEL staining, Western blot, and RT-PCR. The results demonstrated that VD3 significantly ameliorated cognitive deficits and attenuated AD-like pathology in APP/PS1 mice. Moreover, VD3 upregulated DJ-1 expression and suppressed neuroinflammation and neuronal pyroptosis by modulating the NF-κB/NLRP3/caspase-1 and caspase-3/GSDME signaling pathways. Collectively, these findings suggest that DJ-1 mediate these protective effects, as its knockdown reversed VD3-induced improvements in neuroinflammation and neuronal pyroptosis, implicating that DJ-1 is a crucial modulator in the effects of VD3 on Alzheimer’s disease pathology.
{"title":"Vitamin D3 alleviates AD-like pathology in APP/PS1 mice by inhibiting pyroptosis and neuroinflammation via DJ-1/PARK7","authors":"Chunyu Zhou , Yulin Wang , Longfei Zuo , Yufan Miao , Wenjie Li , Xing Li , Yuan Xue , Mengxin Li","doi":"10.1016/j.neulet.2025.138385","DOIUrl":"10.1016/j.neulet.2025.138385","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) is the most common primary progressive neurodegenerative disorder, with inflammatory responses involved in its onset and progression. Vitamin D (VD) is known for its health benefits, including antioxidant effects. Recently, Deglycase protein 1 (DJ-1/<em>PARK7</em>) has been shown to potentially regulate in antioxidant activity and inflammation regulation. In this study, we investigated the therapeutic effects of VD<sub>3</sub> (30 IU/g/w) in <em>Dj-1</em> knockdown APPswe/PS1E9 (APP/PS1) mice. Pathological changes were assessed using the Morris water maze and Barnes maze, as well as immunofluorescence, thioflavin S staining, Nissl staining, TUNEL staining, Western blot, and RT-PCR. The results demonstrated that VD<sub>3</sub> significantly ameliorated cognitive deficits and attenuated AD-like pathology in APP/PS1 mice. Moreover, VD<sub>3</sub> upregulated DJ-1 expression and suppressed neuroinflammation and neuronal pyroptosis by modulating the NF-κB/NLRP3/caspase-1 and caspase-3/GSDME signaling pathways. Collectively, these findings suggest that DJ-1 mediate these protective effects, as its knockdown reversed VD<sub>3</sub>-induced improvements in neuroinflammation and neuronal pyroptosis, implicating that DJ-1 is a crucial modulator in the effects of VD<sub>3</sub> on Alzheimer’s disease pathology.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"867 ","pages":"Article 138385"},"PeriodicalIF":2.0,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131375","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}
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