Pub Date : 2025-01-15DOI: 10.1016/j.neuropharm.2025.110313
Kayla E. Rohr , Himanshu K. Mishra , Johansen Amin , Timothy Nakhla , Michael J. McCarthy
Bipolar disorder (BD) is a severe mental illness characterized by recurrent episodes of depression and mania. Lithium is the gold standard pharmacotherapy for BD, but outcomes are variable, and the relevant therapeutic mechanisms underlying successful treatment response remain uncertain. To identify synaptic markers of BD and lithium response, we measured the effects of lithium on induced pluripotent stem cell-derived neurons from BD patients and controls. We determined that baseline expression of synapsin I (SYN1) and PSD-95 is reduced in BD neurons compared to controls. In control neurons, lithium treatment had modest, transient effects increasing SYN1 and PSD-95 expression. In BD neurons, lithium increased SYN1 expression regardless of lithium response history. However, lithium only increased PSD-95 expression selectively in neurons from lithium-responders and not in neurons from lithium non-responders, leading to group differences in the colocalization of SYN1 and PSD-95. In conclusion, this preliminary work indicates synaptic protein markers are associated with BD pathology and correction of post-synaptic protein expression may be an important mechanism underlying lithium response.
{"title":"Synaptic protein expression in bipolar disorder patient-derived neurons implicates PSD-95 as a marker of lithium response","authors":"Kayla E. Rohr , Himanshu K. Mishra , Johansen Amin , Timothy Nakhla , Michael J. McCarthy","doi":"10.1016/j.neuropharm.2025.110313","DOIUrl":"10.1016/j.neuropharm.2025.110313","url":null,"abstract":"<div><div>Bipolar disorder (BD) is a severe mental illness characterized by recurrent episodes of depression and mania. Lithium is the gold standard pharmacotherapy for BD, but outcomes are variable, and the relevant therapeutic mechanisms underlying successful treatment response remain uncertain. To identify synaptic markers of BD and lithium response, we measured the effects of lithium on induced pluripotent stem cell-derived neurons from BD patients and controls. We determined that baseline expression of synapsin I (SYN1) and PSD-95 is reduced in BD neurons compared to controls. In control neurons, lithium treatment had modest, transient effects increasing SYN1 and PSD-95 expression. In BD neurons, lithium increased SYN1 expression regardless of lithium response history. However, lithium only increased PSD-95 expression selectively in neurons from lithium-responders and not in neurons from lithium non-responders, leading to group differences in the colocalization of SYN1 and PSD-95. In conclusion, this preliminary work indicates synaptic protein markers are associated with BD pathology and correction of post-synaptic protein expression may be an important mechanism underlying lithium response.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"268 ","pages":"Article 110313"},"PeriodicalIF":4.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-15DOI: 10.1016/j.neuropharm.2025.110312
Xinquan Song , Siwen Fan , Yuetong Gao, Anxin Ma, Xiashu Zhang, Zihui Zhou, Yijia Zheng, Lei Du, Xia Zhu
Oxidative stress and inflammation play important roles in diabetic-associated cognitive dysfunction (DACD). Swietenolide (Std), isolated from the fruit of Swietenia macrophylla King, exhibits various potent pharmacological activities, including antioxidant, anti-inflammatory, and anti-tumor properties. However, the effects of Std on DACD remains unexplored. We utilized diabetic db/db mice and the hippocampal cell line HT22 to evaluate the effects and underlying molecular mechanisms of Std on DACD. Molecular docking study, western blotting, immunohistochemistry, and enzyme-linked immunosorbent assay analyses were conducted to elucidate the molecular mechanisms involved. We found that Std significantly improved cognitive dysfunction in diabetic mice and increased cell viability in HT22 cells under high glucose condition. The reduction in superoxide dismutase (SOD) enzamy activity and glutathione (GSH) level, along with an increase in malondialdehyde (MDA) induced by high glucose in hippocampus, were reversed by Std treatment. Furthermore, Std effectively diminished the levels of proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Importantly, Std markedly activated the Nrf2 pathway to inhibit the thioredoxin-interacting protein/NOD-like receptor protein 3 (TXNIP/NLRP3) pathways. However, the neuroprotective effect of Std was significantly weakened by Nrf2 inhibitor ML385. These results indicate that Std provides substantial protection against high glucose-induced hippocampal injury by inhibiting the TXNIP/NLRP3 pathways dependent on Nrf2, which may serve as a promising agent for attenuating DACD.
{"title":"Swietenolide inhibits the TXNIP/NLRP3 pathways via Nrf2 activation to ameliorate cognitive dysfunction in diabetic mice","authors":"Xinquan Song , Siwen Fan , Yuetong Gao, Anxin Ma, Xiashu Zhang, Zihui Zhou, Yijia Zheng, Lei Du, Xia Zhu","doi":"10.1016/j.neuropharm.2025.110312","DOIUrl":"10.1016/j.neuropharm.2025.110312","url":null,"abstract":"<div><div>Oxidative stress and inflammation play important roles in diabetic-associated cognitive dysfunction (DACD). Swietenolide (Std), isolated from the fruit of Swietenia macrophylla King, exhibits various potent pharmacological activities, including antioxidant, anti-inflammatory, and anti-tumor properties. However, the effects of Std on DACD remains unexplored. We utilized diabetic <em>db/db</em> mice and the hippocampal cell line HT22 to evaluate the effects and underlying molecular mechanisms of Std on DACD. Molecular docking study, western blotting, immunohistochemistry, and enzyme-linked immunosorbent assay analyses were conducted to elucidate the molecular mechanisms involved. We found that Std significantly improved cognitive dysfunction in diabetic mice and increased cell viability in HT22 cells under high glucose condition. The reduction in superoxide dismutase (SOD) enzamy activity and glutathione (GSH) level, along with an increase in malondialdehyde (MDA) induced by high glucose in hippocampus, were reversed by Std treatment. Furthermore, Std effectively diminished the levels of proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Importantly, Std markedly activated the Nrf2 pathway to inhibit the thioredoxin-interacting protein/NOD-like receptor protein 3 (TXNIP/NLRP3) pathways. However, the neuroprotective effect of Std was significantly weakened by Nrf2 inhibitor ML385. These results indicate that Std provides substantial protection against high glucose-induced hippocampal injury by inhibiting the TXNIP/NLRP3 pathways dependent on Nrf2, which may serve as a promising agent for attenuating DACD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"267 ","pages":"Article 110312"},"PeriodicalIF":4.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-13DOI: 10.1016/j.neuropharm.2025.110302
Eleonora Corridori , Sara Salviati , Veronica Begni , Alessia Marchesin , Carla Gambarana , Marco Andrea Riva , Simona Scheggi
Anhedonia, a transdiagnostic symptom prevalent in depressive and psychotic disorders, poses a significant challenge for pharmacological intervention due to its association with impaired motivation. Understanding how psychotropic drugs can modulate this pathological domain and elucidating the molecular mechanisms underlying such effects are crucial endeavors in psychiatric research. In this study, we aimed to investigate the pro-motivational properties of lurasidone in a rat (Sprague Dawley males) model of anhedonia and to unravel the interplay between lurasidone and the brain regions critical for reward processing. Exposure to unpredictable chronic stress (UCS) led to a marked reduction in motivation, a deficit that was restored by lurasidone treatment at 3 mg/kg, but not at 10 mg/kg. Interestingly, the stress-induced decrease in reactivity to negative stimuli was reversed by both doses of lurasidone. At the molecular level, stressed animals exhibited reduced expression of neuroplastic markers, that was increased following lurasidone administration. Furthermore, UCS exposure impaired the activation of the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) in response to hedonic stimuli, an effect amended by lurasidone treatment. Additionally, lurasidone restored the impaired phosphorylation of DARPP-32, a key regulator of dopamine signaling, in mPFC and NAc of UCS rats exposed to a hedonic stimulus.
These findings underscore the potential of lurasidone in improving various psychopathological domains, like impaired motivation and emotional reactivity, core elements contributing to the disability associated with mental disorders. These effects highlight the therapeutic potential of lurasidone in addressing the intricate behavioral and neurochemical alterations associated with anhedonia and related mood disorders.
{"title":"Restorative properties of chronic lurasidone treatment on emotional dysfunction in rats exposed to chronic unavoidable stress: A role for medial prefrontal cortex - nucleus accumbens network","authors":"Eleonora Corridori , Sara Salviati , Veronica Begni , Alessia Marchesin , Carla Gambarana , Marco Andrea Riva , Simona Scheggi","doi":"10.1016/j.neuropharm.2025.110302","DOIUrl":"10.1016/j.neuropharm.2025.110302","url":null,"abstract":"<div><div>Anhedonia, a transdiagnostic symptom prevalent in depressive and psychotic disorders, poses a significant challenge for pharmacological intervention due to its association with impaired motivation. Understanding how psychotropic drugs can modulate this pathological domain and elucidating the molecular mechanisms underlying such effects are crucial endeavors in psychiatric research. In this study, we aimed to investigate the pro-motivational properties of lurasidone in a rat (Sprague Dawley males) model of anhedonia and to unravel the interplay between lurasidone and the brain regions critical for reward processing. Exposure to unpredictable chronic stress (UCS) led to a marked reduction in motivation, a deficit that was restored by lurasidone treatment at 3 mg/kg, but not at 10 mg/kg. Interestingly, the stress-induced decrease in reactivity to negative stimuli was reversed by both doses of lurasidone. At the molecular level, stressed animals exhibited reduced expression of neuroplastic markers, that was increased following lurasidone administration. Furthermore, UCS exposure impaired the activation of the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) in response to hedonic stimuli, an effect amended by lurasidone treatment. Additionally, lurasidone restored the impaired phosphorylation of DARPP-32, a key regulator of dopamine signaling, in mPFC and NAc of UCS rats exposed to a hedonic stimulus.</div><div>These findings underscore the potential of lurasidone in improving various psychopathological domains, like impaired motivation and emotional reactivity, core elements contributing to the disability associated with mental disorders. These effects highlight the therapeutic potential of lurasidone in addressing the intricate behavioral and neurochemical alterations associated with anhedonia and related mood disorders.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"267 ","pages":"Article 110302"},"PeriodicalIF":4.6,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-13DOI: 10.1016/j.neuropharm.2025.110301
Xinying Zhang , Zifeng Wu , Siqi Yang , Yuanyuan Wang , Suwan Hu , Yawei Ji , Qi Zhang , Yuchen Bu , Chenqi Jiang , Jingyao Huang , Haoran Wang , Di Wang , Chaoli Huang , Peng Jiang , Cunming Liu , Xiaolin Yang , Chun Yang , Ling Yang , Riyue Jiang
Empathy plays a crucial role in social communication and the perception of affective states and behavioral processes. In this study, we observed that empathic interaction with a mouse experiencing pain resulted in decreased mechanical pain thresholds and anxiety-like behaviors in its bystander, though the underlying mechanisms remain unknown. We demonstrated that CD38 expression in the paraventricular nucleus (PVN) was upregulated during empathic pain, and the pain and emotions of CD38 knockout (CD38KO) mice as bystanders were not affected. Furthermore, fiber photometry recordings indicated that calcium activities of PVN neurons were increased during empathic pain. Interestingly, direct chemogenetic inhibition of PVN neurons attenuated the hyperalgesia and anxiety-like behaviors associated with empathic pain. In contrast, activating PVN neurons through chemogenetics in CD38KO mice induced hyperalgesia and anxiety-like effects in empathic pain. Oxytocin levels in PVN were upregulated during empathic pain, while CD38KO mice inhibit the upregulation in OXT levels, confirming that CD38 is involved in releasing brain OXT and that the CD38-OXT system in the PVN plays a role in empathic pain. Collectively, CD38-mediated oxytocin signaling in PVN is closely linked to empathic pain through its effect on the activation of PVN neurons, and it could be viable targets for novel empathic behavior interventions.
{"title":"CD38-mediated oxytocin signaling in paraventricular nucleus contributes to empathic pain","authors":"Xinying Zhang , Zifeng Wu , Siqi Yang , Yuanyuan Wang , Suwan Hu , Yawei Ji , Qi Zhang , Yuchen Bu , Chenqi Jiang , Jingyao Huang , Haoran Wang , Di Wang , Chaoli Huang , Peng Jiang , Cunming Liu , Xiaolin Yang , Chun Yang , Ling Yang , Riyue Jiang","doi":"10.1016/j.neuropharm.2025.110301","DOIUrl":"10.1016/j.neuropharm.2025.110301","url":null,"abstract":"<div><div>Empathy plays a crucial role in social communication and the perception of affective states and behavioral processes. In this study, we observed that empathic interaction with a mouse experiencing pain resulted in decreased mechanical pain thresholds and anxiety-like behaviors in its bystander, though the underlying mechanisms remain unknown. We demonstrated that CD38 expression in the paraventricular nucleus (PVN) was upregulated during empathic pain, and the pain and emotions of CD38 knockout (CD38KO) mice as bystanders were not affected. Furthermore, fiber photometry recordings indicated that calcium activities of PVN neurons were increased during empathic pain. Interestingly, direct chemogenetic inhibition of PVN neurons attenuated the hyperalgesia and anxiety-like behaviors associated with empathic pain. In contrast, activating PVN neurons through chemogenetics in CD38KO mice induced hyperalgesia and anxiety-like effects in empathic pain. Oxytocin levels in PVN were upregulated during empathic pain, while CD38KO mice inhibit the upregulation in OXT levels, confirming that CD38 is involved in releasing brain OXT and that the CD38-OXT system in the PVN plays a role in empathic pain. Collectively, CD38-mediated oxytocin signaling in PVN is closely linked to empathic pain through its effect on the activation of PVN neurons, and it could be viable targets for novel empathic behavior interventions.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"267 ","pages":"Article 110301"},"PeriodicalIF":4.6,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-13DOI: 10.1016/j.neuropharm.2025.110303
Sudarat Nimitvilai-Roberts , Marcelo F. Lopez , John J. Woodward
Alcohol use disorder is associated with altered function of cortical-amygdala-striatal circuits such as the orbitofrontal cortex (OFC), basolateral amygdala (BLA) and their connections to the dorsal medial striatum (DMS) shown to be involved in goal-directed actions. Using retrobead tracing, we previously reported enhanced excitability of DMS-projecting OFC neurons in mice following 3-to-7-day withdrawal from chronic intermittent ethanol (CIE) exposure. In the same animals, spiking of DMS-projecting BLA neurons was decreased at 3-days post-withdrawal followed by an increase in firing at 7- and 14-days. In the current study, we used transsynaptic labeling and slice electrophysiology to investigate the effects of CIE exposure on DMS neurons that receive convergent inputs from the OFC and BLA. Mice were infused with anterograde transsynaptic AAVs in the OFC (AAV1-Cre) and BLA (AAV1-Flpo) and a Cre-On/Flp-On-YFP AAV in the DMS followed by 4 weekly cycles of Air or CIE vapor exposure. Current-clamp recordings of YFP + DMSOFC−BLA neurons showed three distinct patterns of firing: regular spiking, regular spiking followed by depolarization block and regular spiking with the appearance of broadened action potentials and plateau potentials at higher current steps (termed FANS). In both male and female mice, withdrawal from CIE exposure significantly increased the excitability of regular spiking neurons as compared to air controls. More subtle effects were observed on FANS neurons with both increases and decreases in firing that were current step and sex-dependent. These findings add to a growing literature demonstrating how neurons within cortical-amygdala-striatal circuits implicated in compulsive/habitual behaviors are impacted by chronic alcohol exposure.
{"title":"Effects of chronic ethanol exposure on dorsal medial striatal neurons receiving convergent inputs from the orbitofrontal cortex and basolateral amygdala","authors":"Sudarat Nimitvilai-Roberts , Marcelo F. Lopez , John J. Woodward","doi":"10.1016/j.neuropharm.2025.110303","DOIUrl":"10.1016/j.neuropharm.2025.110303","url":null,"abstract":"<div><div>Alcohol use disorder is associated with altered function of cortical-amygdala-striatal circuits such as the orbitofrontal cortex (OFC), basolateral amygdala (BLA) and their connections to the dorsal medial striatum (DMS) shown to be involved in goal-directed actions. Using retrobead tracing, we previously reported enhanced excitability of DMS-projecting OFC neurons in mice following 3-to-7-day withdrawal from chronic intermittent ethanol (CIE) exposure. In the same animals, spiking of DMS-projecting BLA neurons was decreased at 3-days post-withdrawal followed by an increase in firing at 7- and 14-days. In the current study, we used transsynaptic labeling and slice electrophysiology to investigate the effects of CIE exposure on DMS neurons that receive convergent inputs from the OFC and BLA. Mice were infused with anterograde transsynaptic AAVs in the OFC (AAV1-Cre) and BLA (AAV1-Flpo) and a Cre-On/Flp-On-YFP AAV in the DMS followed by 4 weekly cycles of Air or CIE vapor exposure. Current-clamp recordings of YFP + DMS<sup>OFC−BLA</sup> neurons showed three distinct patterns of firing: regular spiking, regular spiking followed by depolarization block and regular spiking with the appearance of broadened action potentials and plateau potentials at higher current steps (termed FANS). In both male and female mice, withdrawal from CIE exposure significantly increased the excitability of regular spiking neurons as compared to air controls. More subtle effects were observed on FANS neurons with both increases and decreases in firing that were current step and sex-dependent. These findings add to a growing literature demonstrating how neurons within cortical-amygdala-striatal circuits implicated in compulsive/habitual behaviors are impacted by chronic alcohol exposure.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"267 ","pages":"Article 110303"},"PeriodicalIF":4.6,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-10DOI: 10.1016/j.neuropharm.2025.110295
Shrouk M. Basiouny , Hala F. Zaki , Shimaa M. Elshazly , Ahmed F. Mohamed
Seizures can lead to cardiac dysfunction. Multiple pathways contribute to this phenomenon, of which the chaperone sigma-1 receptor (S1R) signaling represents a promising nexus between the abnormalities seen in both epilepsy and ensuing cardiac complications. The study explored the potential of Berberine (BER), a promising S1R agonist, in treating epilepsy and associated cardiac abnormalities in a pentylenetetrazol (PTZ) kindling rat model of epilepsy. Male Wistar albino rats received PTZ (35 mg/kg) every other day alone, with BER, with phenytoin (PHT), with both BER and PHT and with both BER and an S1R blocker (NE-100) over 27 days. BER decreased seizure severity and improved hemodynamic parameters. Histopathological abnormalities were more pronounced in the PTZ, and blocker group than in other groups, in heart tissue. In cardiac tissue, BER enhanced the AKT/eNOS signaling pathway and mitigated ferroptosis by boosting the cystine/glutamate transporter/Glutathione/Glutathione Peroxidase 4 (XCT/GSH/GPX4) system and ferritin heavy chain-1 (FTH-1) expression, while reducing iron and Transferrin receptor protein 1 (TFR1) levels. Such effects were largely negated by NE-100 pretreatment. In conclusion, BER shows protective effects on cardiac dysfunction induced by the PTZ kindling model by acting as an S1R agonist and influencing the AKT/eNOS signaling pathway and ferroptosis.
{"title":"Berberine ameliorates seizure activity and cardiac dysfunction in pentylenetetrazol-kindling seizures in rats: Modulation of sigma1 receptor, Akt/eNOS signaling, and ferroptosis","authors":"Shrouk M. Basiouny , Hala F. Zaki , Shimaa M. Elshazly , Ahmed F. Mohamed","doi":"10.1016/j.neuropharm.2025.110295","DOIUrl":"10.1016/j.neuropharm.2025.110295","url":null,"abstract":"<div><div>Seizures can lead to cardiac dysfunction. Multiple pathways contribute to this phenomenon, of which the chaperone sigma-1 receptor (S1R) signaling represents a promising nexus between the abnormalities seen in both epilepsy and ensuing cardiac complications. The study explored the potential of Berberine (BER), a promising S1R agonist, in treating epilepsy and associated cardiac abnormalities in a pentylenetetrazol (PTZ) kindling rat model of epilepsy. Male Wistar albino rats received PTZ (35 mg/kg) every other day alone, with BER, with phenytoin (PHT), with both BER and PHT and with both BER and an S1R blocker (NE-100) over 27 days. BER decreased seizure severity and improved hemodynamic parameters. Histopathological abnormalities were more pronounced in the PTZ, and blocker group than in other groups, in heart tissue. In cardiac tissue, BER enhanced the AKT/eNOS signaling pathway and mitigated ferroptosis by boosting the cystine/glutamate transporter/Glutathione/Glutathione Peroxidase 4 (XCT/GSH/GPX4) system and ferritin heavy chain-1 (FTH-1) expression, while reducing iron and Transferrin receptor protein 1 (TFR1) levels. Such effects were largely negated by NE-100 pretreatment. In conclusion, BER shows protective effects on cardiac dysfunction induced by the PTZ kindling model by acting as an S1R agonist and influencing the AKT/eNOS signaling pathway and ferroptosis.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"267 ","pages":"Article 110295"},"PeriodicalIF":4.6,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-09DOI: 10.1016/j.neuropharm.2025.110300
Shuwei Zhang , Chan Wang , Jianxing Liu , Liu Liu , Lin Miao , Haowei Wang , Yunqing Tian , Hao Cheng , Juan Li , Xiaofeng Zeng
Methamphetamine (METH) is a synthetic drug with potent addictive, relapse, and neurotoxic properties. METH abuse contributes to severe damage to the central nervous system, potentially causing cognitive impairments, behavioral changes, and neurodegenerative diseases. METH-induced neuronal damage is closely related to apoptosis and cell cycle abnormalities, while gene expression regulator microRNAs (miRNAs) may play extensive roles in this progress, but the specific mechanisms remain unclear. We found that the novel miRNA 146 (miR_146) was downregulated in METH-induced apoptosis and cell cycle arrest in tree shrew primary neurons, while the expression of its target gene Tfdp2 was increased after METH exposure. Overexpression of miR_146 or silencing of Tfdp2 significantly alleviated METH-induced cell cycle arrest and apoptosis in primary tree shrew neurons. These findings provide new insights into the role of the miR_146-Tfdp2 axis in METH-induced neurotoxic injury and offer a theoretical basis for miR_146 as potential therapeutic targets in drug abuse.
{"title":"The novel miR_146-Tfdp2 axis antagonizes METH induced neuron apoptosis and cell cycle abnormalities in tree shrew","authors":"Shuwei Zhang , Chan Wang , Jianxing Liu , Liu Liu , Lin Miao , Haowei Wang , Yunqing Tian , Hao Cheng , Juan Li , Xiaofeng Zeng","doi":"10.1016/j.neuropharm.2025.110300","DOIUrl":"10.1016/j.neuropharm.2025.110300","url":null,"abstract":"<div><div>Methamphetamine (METH) is a synthetic drug with potent addictive, relapse, and neurotoxic properties. METH abuse contributes to severe damage to the central nervous system, potentially causing cognitive impairments, behavioral changes, and neurodegenerative diseases. METH-induced neuronal damage is closely related to apoptosis and cell cycle abnormalities, while gene expression regulator microRNAs (miRNAs) may play extensive roles in this progress, but the specific mechanisms remain unclear. We found that the novel miRNA 146 (miR_146) was downregulated in METH-induced apoptosis and cell cycle arrest in tree shrew primary neurons, while the expression of its target gene <em>Tfdp2</em> was increased after METH exposure. Overexpression of miR_146 or silencing of <em>Tfdp2</em> significantly alleviated METH-induced cell cycle arrest and apoptosis in primary tree shrew neurons. These findings provide new insights into the role of the miR_146-<em>Tfdp2</em> axis in METH-induced neurotoxic injury and offer a theoretical basis for miR_146 as potential therapeutic targets in drug abuse.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"267 ","pages":"Article 110300"},"PeriodicalIF":4.6,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142966128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-09DOI: 10.1016/j.neuropharm.2025.110299
Johnathan M. Borland , Abigail L. Kohut-Jackson , Anna C. Peyla , Megan AL. Hall , Paul G. Mermelstein , Robert L. Meisel
Hypoactive sexual desire disorder (HSDD) is the most reported sexual dysfunction among premenopausal women worldwide. Bremelanotide, trade name Vyleesi, has been approved by the United States Food and Drug Administration to treat HSDD. However, despite approval, very little is known about its neurobiological mechanism of action. In this study, we utilized a female Syrian hamster model to investigate the effects of bremelanotide on melanocortin receptor expression in the mesolimbic dopamine system and sexual reward. We found that the majority of melanocortin 3 and 4 (MC4R) receptor mRNA is expressed in dopamine neurons in the ventral tegmental area (VTA). Fewer neurons express MC4R in the nucleus accumbens (NAc) or dorsal striatum, where they rarely colocalize with neurons expressing dopamine D1 or D2 receptors. Instead, MC4R mRNA is expressed in nucleus accumbens interneurons. Neither the low nor the high dose of bremelanotide had an effect on the expression of melanocortin receptor mRNA in the mesolimbic dopamine system. Finally, sexual experience resulted in a conditioned place preference (CPP) in female Syrian hamsters, though bremelanotide treatment failed to enhance sexual reward in this test. The results of this study are discussed in conjunction with similar studies in rats, with the conclusion that bremelanotide does not act on the VTA-NAc reward circuit and does not enhance the rewarding effects of sexual interactions.
{"title":"Female Syrian hamster analyses of bremelanotide, a US FDA approved drug for the treatment of female hypoactive sexual desire disorder","authors":"Johnathan M. Borland , Abigail L. Kohut-Jackson , Anna C. Peyla , Megan AL. Hall , Paul G. Mermelstein , Robert L. Meisel","doi":"10.1016/j.neuropharm.2025.110299","DOIUrl":"10.1016/j.neuropharm.2025.110299","url":null,"abstract":"<div><div>Hypoactive sexual desire disorder (HSDD) is the most reported sexual dysfunction among premenopausal women worldwide. Bremelanotide, trade name Vyleesi, has been approved by the United States Food and Drug Administration to treat HSDD. However, despite approval, very little is known about its neurobiological mechanism of action. In this study, we utilized a female Syrian hamster model to investigate the effects of bremelanotide on melanocortin receptor expression in the mesolimbic dopamine system and sexual reward. We found that the majority of melanocortin 3 and 4 (MC4R) receptor mRNA is expressed in dopamine neurons in the ventral tegmental area (VTA). Fewer neurons express MC4R in the nucleus accumbens (NAc) or dorsal striatum, where they rarely colocalize with neurons expressing dopamine D1 or D2 receptors. Instead, MC4R mRNA is expressed in nucleus accumbens interneurons. Neither the low nor the high dose of bremelanotide had an effect on the expression of melanocortin receptor mRNA in the mesolimbic dopamine system. Finally, sexual experience resulted in a conditioned place preference (CPP) in female Syrian hamsters, though bremelanotide treatment failed to enhance sexual reward in this test. The results of this study are discussed in conjunction with similar studies in rats, with the conclusion that bremelanotide does not act on the VTA-NAc reward circuit and does not enhance the rewarding effects of sexual interactions.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"267 ","pages":"Article 110299"},"PeriodicalIF":4.6,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142966129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-09DOI: 10.1016/j.neuropharm.2025.110296
Yufang Lu , Ruiying Zhou , Ruyi Zhu , Xue Wu , Jin Liu , Yue Ma , Xin Zhang , Yaling Zhang , Luting Yang , Yanhua Li , Yuan Zhang , Yaping Yan , Qian Zhang
This study aims to elucidate the target and mechanism of baicalin, a clinically utilized drug, in the treatment of neuroinflammatory diseases. Neuroinflammation, characterized by the activation of glial cells and the release of various pro-inflammatory cytokines, plays a critical role in the pathogenesis of various diseases, including spinal cord injury (SCI). The remission of such diseases is significantly dependent on the improvement of inflammatory microenvironment. Toll-like receptor 4/myeloid differentiation protein 2 (TLR4/MD2) complex plays an important role in pathogen recognition and innate immune activation. baicalin, a natural flavonoid, is renowned for its potent anti-inflammatory property. In this study, we discovered that baicalin significantly reduced the activation of glial cells and the levels of pro-inflammatory cytokines at the lesion site of SCI mice, thereby mitigating demyelination and neuronal damage. By directly occupying the active pocket of TLR4/MD2 complex on microglia, baicalin inhibited PI3K/AKT/NF-κB pathway, thereby exerting its anti-inflammatory effect. These findings were corroborated in mice induced by lipopolysaccharide, a TLR4 agonist. Furthermore, baicalin indirectly altered phenotype of astrocytes by reducing secretion of TNF-α, IL-1α, and C1q levels from microglia. Our work demonstrated that baicalin effectively alleviated neuroinflammation by directly targeting microglia and indirectly modulating astrocytes phenotype. As a natural flavonoid, baicalin holds significant potential as a therapeutic candidate for diseases characterized by neuroinflammation.
{"title":"Baicalin ameliorates neuroinflammation by targeting TLR4/MD2 complex on microglia via PI3K/AKT/NF-κB signaling pathway","authors":"Yufang Lu , Ruiying Zhou , Ruyi Zhu , Xue Wu , Jin Liu , Yue Ma , Xin Zhang , Yaling Zhang , Luting Yang , Yanhua Li , Yuan Zhang , Yaping Yan , Qian Zhang","doi":"10.1016/j.neuropharm.2025.110296","DOIUrl":"10.1016/j.neuropharm.2025.110296","url":null,"abstract":"<div><div>This study aims to elucidate the target and mechanism of baicalin, a clinically utilized drug, in the treatment of neuroinflammatory diseases. Neuroinflammation, characterized by the activation of glial cells and the release of various pro-inflammatory cytokines, plays a critical role in the pathogenesis of various diseases, including spinal cord injury (SCI). The remission of such diseases is significantly dependent on the improvement of inflammatory microenvironment. Toll-like receptor 4/myeloid differentiation protein 2 (TLR4/MD2) complex plays an important role in pathogen recognition and innate immune activation. baicalin, a natural flavonoid, is renowned for its potent anti-inflammatory property. In this study, we discovered that baicalin significantly reduced the activation of glial cells and the levels of pro-inflammatory cytokines at the lesion site of SCI mice, thereby mitigating demyelination and neuronal damage. By directly occupying the active pocket of TLR4/MD2 complex on microglia, baicalin inhibited PI3K/AKT/NF-κB pathway, thereby exerting its anti-inflammatory effect. These findings were corroborated in mice induced by lipopolysaccharide, a TLR4 agonist. Furthermore, baicalin indirectly altered phenotype of astrocytes by reducing secretion of TNF-α, IL-1α, and C1q levels from microglia. Our work demonstrated that baicalin effectively alleviated neuroinflammation by directly targeting microglia and indirectly modulating astrocytes phenotype. As a natural flavonoid, baicalin holds significant potential as a therapeutic candidate for diseases characterized by neuroinflammation.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"267 ","pages":"Article 110296"},"PeriodicalIF":4.6,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-06DOI: 10.1016/j.neuropharm.2025.110298
Adrianna Kirckof , Emma Kneller , Erika M. Vitale , Michael A. Johnson , Adam S. Smith
In humans, grief is characterized by intense sadness, intrusive thoughts of the deceased, and intense longing for reunion with the deceased. Human fMRI studies show hyperactivity in emotional pain and motivational centers of the brain when an individual is reminded of a deceased attachment figure, but the molecular underpinnings of these changes in activity are unknown. Prairie voles (Microtus ochrogaster), which establish lifelong social bonds between breeding pairs, also display distress and motivational shifts during periods of prolonged social loss, providing a model to investigate these behavioral and molecular changes at a mechanistic level. Here, a novel odor preference test was used to assess social vs non-social odor investigation, and a sucrose preference test was used to assess non-social, reward-driven motivation. Females that lost a male partner investigated partner- and food-associated cues significantly more than females that lost a female cagemate or remained intact with a male partner. However, females experiencing the loss of a male partner did not change investigation of stranger-associated cues. Western blotting revealed significant increases of dopamine receptor type 1 (DRD1) and oxytocin receptor protein content in specific brain regions in response to the loss of distinct social relationships. Such effects included an increase in DRD1 in the medial preoptic area of the hypothalamus (mPOA) in females experiencing loss of a male partner compared to all other conditions. Pharmacological antagonism of DRD1 in the mPOA blocked the loss-associated increase of investigation of the partner odor but did not affect investigation of food or stranger odors. This reveals a novel dopamine-mediated mechanism for partner-seeking behavior during periods of partner loss in female prairie voles.
{"title":"The effects of social loss and isolation on partner odor investigation and dopamine and oxytocin receptor expression in female prairie voles","authors":"Adrianna Kirckof , Emma Kneller , Erika M. Vitale , Michael A. Johnson , Adam S. Smith","doi":"10.1016/j.neuropharm.2025.110298","DOIUrl":"10.1016/j.neuropharm.2025.110298","url":null,"abstract":"<div><div>In humans, grief is characterized by intense sadness, intrusive thoughts of the deceased, and intense longing for reunion with the deceased. Human fMRI studies show hyperactivity in emotional pain and motivational centers of the brain when an individual is reminded of a deceased attachment figure, but the molecular underpinnings of these changes in activity are unknown. Prairie voles (<em>Microtus ochrogaster</em>), which establish lifelong social bonds between breeding pairs, also display distress and motivational shifts during periods of prolonged social loss, providing a model to investigate these behavioral and molecular changes at a mechanistic level. Here, a novel odor preference test was used to assess social vs non-social odor investigation, and a sucrose preference test was used to assess non-social, reward-driven motivation. Females that lost a male partner investigated partner- and food-associated cues significantly more than females that lost a female cagemate or remained intact with a male partner. However, females experiencing the loss of a male partner did not change investigation of stranger-associated cues. Western blotting revealed significant increases of dopamine receptor type 1 (DRD1) and oxytocin receptor protein content in specific brain regions in response to the loss of distinct social relationships. Such effects included an increase in DRD1 in the medial preoptic area of the hypothalamus (mPOA) in females experiencing loss of a male partner compared to all other conditions. Pharmacological antagonism of DRD1 in the mPOA blocked the loss-associated increase of investigation of the partner odor but did not affect investigation of food or stranger odors. This reveals a novel dopamine-mediated mechanism for partner-seeking behavior during periods of partner loss in female prairie voles.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"267 ","pages":"Article 110298"},"PeriodicalIF":4.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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