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}
Pub Date : 2025-10-05DOI: 10.1016/j.neulet.2025.138409
Elliot Sommer , Heather K. Caldwell
There is mounting evidence that the oxytocin (Oxt) and vasopressin (Avp) systems contribute to early brain development. Work from transgenic mouse models as well as pharmacological manipulation of the Oxt and Avp systems suggests that signaling through the Oxt receptor (Oxtr) and the Avp 1a receptor (Avpr1a) during embryonic brain development affects behavior in adulthood. Unfortunately, at this time, very little is known or understood about where in the brain Oxtr and Avpr1a occurs during embryonic development or what the downstream consequences may be. To help provide some answers, Oxtr- and Avpr1a-stimulated G-protein coupled receptor binding assays were performed using guanosine 5′-(γ-thio)triphosphate, a non-hydrolyzable analog of guanosine triphosphate, to determine the functionality of the Oxtr and Avpr1a in both sexes at embryonic day (E) 14.5, E16.5, and E18.5. Based on previous work, we hypothesized that the Oxtr and Avpr1a would be functional in both sexes by E16.5 and activated by Oxt and Avp, respectively. The data suggest that while the Oxtr and Avpr1a are functional in both sexes starting at E16.5, where in the brain they are functional is not fully aligned with where there is known receptor binding. For the Oxtr, at E16.5, functional binding was observed in the ventricular and subventricular zones of the cortical and septal neuroepithelium and the amygdalar area, this shifted by E18.5 with functional binding observed only in the ventricular and subventricular septal neuroepithelium and the amygdalar area, with no functional binding observed in the ventricular and subventricular cortical neuroepithelium. For the Avpr1a, at E16.5, functional binding was only observed in the ventral hypothalamic area but by E18.5 functional binding was observed across numerous brain regions. Taken together, these data suggest that Oxtr and Avpr1a signaling is positioned to have site-specific effects on mouse brain development starting at E16.5.
{"title":"Regional differences in oxytocin and vasopressin 1a receptor functionality in mouse embryonic brain development","authors":"Elliot Sommer , Heather K. Caldwell","doi":"10.1016/j.neulet.2025.138409","DOIUrl":"10.1016/j.neulet.2025.138409","url":null,"abstract":"<div><div>There is mounting evidence that the oxytocin (Oxt) and vasopressin (Avp) systems contribute to early brain development. Work from transgenic mouse models as well as pharmacological manipulation of the Oxt and Avp systems suggests that signaling through the Oxt receptor (Oxtr) and the Avp 1a receptor (Avpr1a) during embryonic brain development affects behavior in adulthood. Unfortunately, at this time, very little is known or understood about where in the brain Oxtr and Avpr1a occurs during embryonic development or what the downstream consequences may be. To help provide some answers, Oxtr- and Avpr1a-stimulated G-protein coupled receptor binding assays were performed using guanosine 5′-(γ-thio)triphosphate, a non-hydrolyzable analog of guanosine triphosphate, to determine the functionality of the Oxtr and Avpr1a in both sexes at embryonic day (E) 14.5, E16.5, and E18.5. Based on previous work, we hypothesized that the Oxtr and Avpr1a would be functional in both sexes by E16.5 and activated by Oxt and Avp, respectively. The data suggest that while the Oxtr and Avpr1a are functional in both sexes starting at E16.5, where in the brain they are functional is not fully aligned with where there is known receptor binding. For the Oxtr, at E16.5, functional binding was observed in the ventricular and subventricular zones of the cortical and septal neuroepithelium and the amygdalar area, this shifted by E18.5 with functional binding observed only in the ventricular and subventricular septal neuroepithelium and the amygdalar area, with no functional binding observed in the ventricular and subventricular cortical neuroepithelium. For the Avpr1a, at E16.5, functional binding was only observed in the ventral hypothalamic area but by E18.5 functional binding was observed across numerous brain regions. Taken together, these data suggest that Oxtr and Avpr1a signaling is positioned to have site-specific effects on mouse brain development starting at E16.5.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"868 ","pages":"Article 138409"},"PeriodicalIF":2.0,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244732","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 : 2025-10-03DOI: 10.1016/j.neulet.2025.138408
Fernanda M. Tagliapietra, Maycon I.O. Milanez, Edina da Luz Abreu, Erika E. Nishi, Cássia T. Bergamaschi, Ruy R. Campos
Increased production of reactive oxygen species (ROS) in brain regions contributes to the sympathetic vasomotor overactivity in Goldblatt hypertension (2K1C). Previously, studies reported that overexpression of spinal angiotensin II (Ang II) type I (AT1) contributes to sympathetic vasomotor overactivation in 2K1C rats. Considering that Ang II leads to an imbalance of oxidative stress, the present study evaluated the role of spinal ROS in regulating the activity of sympathetic preganglionic neurons in 2K1C rats. Hypertension was induced by clipping the left renal artery. Six weeks after clipping, a catheter was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anaesthetized rats. The effects of intrathecal (i.t.) injection of Tempol on mean arterial pressure (MAP), heart rate (HR), renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively) were evaluated over 60 consecutive minutes. mRNA expression of enzymes involved in oxidative balance was analyzed in the spinal cord. In addition, spinal ROS abundance was quantified by the DHE fluorescence method. An increase in ROS production was observed in the thoracic region of 2K1C rats compared to the control group. I.t. administration of Tempol triggered a significant and preferential reduction in rSNA in the 2K1C but not in control rats. Thus, the data suggest that renal sympathoexcitation in 2K1C rats was associated with an increase in oxidative imbalance in the spinal cord, particularly in sympathetic preganglionic neurons that drive rSNA.
{"title":"Increased reactive oxygen species in the spinal cord drive renal sympathetic vasomotor activity in Goldblatt hypertensive rats","authors":"Fernanda M. Tagliapietra, Maycon I.O. Milanez, Edina da Luz Abreu, Erika E. Nishi, Cássia T. Bergamaschi, Ruy R. Campos","doi":"10.1016/j.neulet.2025.138408","DOIUrl":"10.1016/j.neulet.2025.138408","url":null,"abstract":"<div><div>Increased production of reactive oxygen species (ROS) in brain regions contributes to the sympathetic vasomotor overactivity in Goldblatt hypertension (2K1C). Previously, studies reported that overexpression of spinal angiotensin II (Ang II) type I (AT1) contributes to sympathetic vasomotor overactivation in 2K1C rats. Considering that Ang II leads to an imbalance of oxidative stress, the present study evaluated the role of spinal ROS in regulating the activity of sympathetic preganglionic neurons in 2K1C rats. Hypertension was induced by clipping the left renal artery. Six weeks after clipping, a catheter was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anaesthetized rats. The effects of intrathecal (<em>i.t.</em>) injection of Tempol on mean arterial pressure (MAP), heart rate (HR), renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively) were evaluated over 60 consecutive minutes. mRNA expression of enzymes involved in oxidative balance was analyzed in the spinal cord. In addition, spinal ROS abundance was quantified by the DHE fluorescence method. An increase in ROS production was observed in the thoracic region of 2K1C rats compared to the control group. <em>I.t.</em> administration of Tempol triggered a significant and preferential reduction in rSNA in the 2K1C but not in control rats. Thus, the data suggest that renal sympathoexcitation in 2K1C rats was associated with an increase in oxidative imbalance in the spinal cord, particularly in sympathetic preganglionic neurons that drive rSNA.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"868 ","pages":"Article 138408"},"PeriodicalIF":2.0,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233062","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 : 2025-10-02DOI: 10.1016/j.neulet.2025.138407
Abigail M. Lantry , Huy Lu , Matt Marion , John Hamilton , Brittany Richardson , Teresa Quattrin , Lucy D. Mastrandrea , Michael Hadjiargyrou , David Komatsu , Panayotis K. Thanos
Methylphenidate (MP) is a psychostimulant commonly prescribed for attention-deficit/hyperactivity disorder (ADHD), and Fluoxetine (FLX) is a selective serotonin reuptake inhibitor (SSRI) commonly prescribed to treat depression and anxiety disorders. Both are shown to impact neurochemistry and behavior, but little is known about their individual and combined impacts on the endocannabinoid system (ECS). We examined the effects of MP and FLX, both as separate treatments and in combination, on cannabinoid receptor type 1 (CB1) binding in several key brain regions of interest. Male rats were treated with either water, MP, FLX, or MP + FLX via a previously established drinking paradigm for three months. Brains were harvested, and [3H] SR141716A in vitro autoradiography was performed to quantify CB1 binding. The combined treatment of MP + FLX showed significantly higher [3H] SR141716A binding compared to the water, MP, and FLX groups in the somatosensory forelimb (S(FL)) region. This indicates an ability of the common co-usage of MP and FLX to increase CB1 levels in the somatosensory cortex: a region of the brain required for the processing of sensory information.
{"title":"Combined chronic oral methylphenidate and fluoxetine treatment increases CB1 receptor density in the somatosensory forelimb region","authors":"Abigail M. Lantry , Huy Lu , Matt Marion , John Hamilton , Brittany Richardson , Teresa Quattrin , Lucy D. Mastrandrea , Michael Hadjiargyrou , David Komatsu , Panayotis K. Thanos","doi":"10.1016/j.neulet.2025.138407","DOIUrl":"10.1016/j.neulet.2025.138407","url":null,"abstract":"<div><div>Methylphenidate (MP) is a psychostimulant commonly prescribed for attention-deficit/hyperactivity disorder (ADHD), and Fluoxetine (FLX) is a selective serotonin reuptake inhibitor (SSRI) commonly prescribed to treat depression and anxiety disorders. Both are shown to impact neurochemistry and behavior, but little is known about their individual and combined impacts on the endocannabinoid system (ECS). We examined the effects of MP and FLX, both as separate treatments and in combination, on cannabinoid receptor type 1 (CB1) binding in several key brain regions of interest. Male rats were treated with either water, MP, FLX, or MP + FLX via a previously established drinking paradigm for three months. Brains were harvested, and [<sup>3</sup>H] SR141716A <em>in vitro</em> autoradiography was performed to quantify CB1 binding. The combined treatment of MP + FLX showed significantly higher [<sup>3</sup>H] SR141716A binding compared to the water, MP, and FLX groups in the somatosensory forelimb (S(FL)) region. This indicates an ability of the common co-usage of MP and FLX to increase CB1 levels in the somatosensory cortex: a region of the brain required for the processing of sensory information.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"869 ","pages":"Article 138407"},"PeriodicalIF":2.0,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228286","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 : 2025-10-01DOI: 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}
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