NeuropharmacologyPub Date : 2025-09-06DOI: 10.1016/j.neuropharm.2025.110673
Sneha Sujitkumar Kapse, Mattia M. Migliore
{"title":"Cytoprotective effects of Gymnemic Acid 1 in cellular models of neurodegeneration","authors":"Sneha Sujitkumar Kapse, Mattia M. Migliore","doi":"10.1016/j.neuropharm.2025.110673","DOIUrl":"10.1016/j.neuropharm.2025.110673","url":null,"abstract":"<div><div><em>Gymnema sylvestre</em> (<em>G. sylvestre</em>) is a traditional medicinal herb known for its anti-diabetic properties, yet its molecular mechanisms remain unknown. Growing evidence suggests a strong link between insulin resistance and neurodegeneration, mediated by impaired pro-survival signaling (e.g., PI3K/Akt), increased oxidative stress, and inflammation.</div><div>This study investigates the cytoprotective potential of Gymnemic Acid 1 (GA1), a key bioactive compound from <em>G. sylvestre</em>, in cellular models of neurodegeneration. Neurotoxicity was induced in SH-SY5Y cells using either 6-hydroxydopamine (6-OHDA) or streptozotocin (STZ), followed by treatment with increasing concentrations of GA1. GA1 treatment significantly increased cell viability and reduced malondialdehyde (MDA) levels, indicating antioxidant and cytoprotective effects.</div><div>To explore its mechanism of action, we assessed GA1 activity at the glucagon-like peptide-1 receptor (GLP-1R) using a reporter gene assay. GA1 exhibited agonistic activity at GLP-1R, and its protective effects are lost in the presence of a GLP-1R antagonist, further solidifying the involvement of GLP-1R in GA1's action. Further analysis revealed that GA1 treatment increased phosphorylation of PI3K and Akt proteins compared to toxin-only controls, suggesting activation of the GLP-1R/PI3K/Akt signaling pathway.</div><div>These findings demonstrate that GA1 confers protection against neurotoxic insults via antioxidant mechanisms and activation of GLP-1R-mediated pro-survival signaling. This study provides mechanistic insight into the neuroprotective potential of <em>G. sylvestre</em> and supports further exploration of GA1 as a candidate for therapeutic development in neurodegenerative diseases.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"280 ","pages":"Article 110673"},"PeriodicalIF":4.6,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145023839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Selective inhibition of histone deacetylase 3 (HDAC3) prevents vincristine-induced peripheral neuropathy via macrophage polarization","authors":"Sonam Dolma, Aaditi Karnik, Regula Sanjeev, Balaram Ghosh, Abhijeet R. Joshi","doi":"10.1016/j.neuropharm.2025.110678","DOIUrl":"10.1016/j.neuropharm.2025.110678","url":null,"abstract":"<div><div>Neuroinflammation is vital in vincristine-induced peripheral neuropathy (VIPN). Locally infiltrated macrophages polarize to pro-inflammatory M1-type, release inflammatory cytokines, and contribute to neuropathic pain. Histone deacetylase 3 (HDAC3) regulates macrophage polarization. In a mouse model of VIPN (0.5 mg/kg vincristine, i.p.), we observed increased HDAC3 activity in dorsal root ganglia (DRG). Therefore, we hypothesized that the selective HDAC3 inhibitor, PT3, would polarize macrophages from pro-inflammatory M-1 to anti-inflammatory M-2, reducing the inflammation-induced neuropathic pain in VIPN. Interestingly, co-treatment of vincristine and PT3 (15 mg/kg, i.p.) prevented the development of vincristine-induced mechanical allodynia and thermal hyperalgesia as assessed by pin-prick and hot plate methods, respectively. PT3 also preserved the sensory nerve conduction and reduced the loss of PGP9.5-positive intraepidermal nerve fibers in the paw skin. Additionally, vincristine-induced motor dysfunction, as assessed by open field test, paw print analysis, and motor nerve conduction studies, was also alleviated by HDAC3 inhibition. To investigate the underlying mechanism, we utilized immunoblotting and immunohistochemistry to determine the population of M1 and M2 macrophages using specific markers. We observed that the co-treatment with PT3 significantly reduced the number of infiltrated M1 macrophages (CD80<sup>+</sup>) and increased M2 macrophages (CD163+) in the sciatic nerves compared to the vincristine-treated group. Moreover, the quantitative cytokine profile revealed reduced expression of pro-inflammatory cytokines (IL-6, TNF-α) and increased expression of anti-inflammatory cytokine (IL-10) in both the sciatic nerve and DRG from the PT3-treated compared to the vincristine-treated group. Collectively, our data strongly demonstrated that selective HDAC3 inhibition is a promising target for the amelioration of VIPN.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"280 ","pages":"Article 110678"},"PeriodicalIF":4.6,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145004624","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}
NeuropharmacologyPub Date : 2025-09-04DOI: 10.1016/j.neuropharm.2025.110677
Ma Fuyun , Ye Yuhang , Han Qiuqin , Yang Yuewang , Gao Ce , Wang Yilin , Leng Xiaoru , Yao Jiacheng , Zhan wei , Hu Xiamin
{"title":"Effects of geniposide on cerebral ischemia/reperfusion-induced neuron damage by inhibiting autophagy via cGAS-STING","authors":"Ma Fuyun , Ye Yuhang , Han Qiuqin , Yang Yuewang , Gao Ce , Wang Yilin , Leng Xiaoru , Yao Jiacheng , Zhan wei , Hu Xiamin","doi":"10.1016/j.neuropharm.2025.110677","DOIUrl":"10.1016/j.neuropharm.2025.110677","url":null,"abstract":"<div><h3>Aim of the study</h3><div>This study aimed to investigate the protective effects of Geniposide (GEN) against cerebral ischemia-reperfusion injury by targeting the cGAS-STING pathway and modulating autophagy in neuronal cells.</div></div><div><h3>Materials and methods</h3><div><em>In vivo</em> middle cerebral artery occlusion/reperfusion (MCAO/R) model and an <em>in vitro</em> oxygen-glucose deprivation/reperfusion (OGD/R) model to mimic the pathology of cerebral ischemic stroke in humans. Behavioral tests, tissue staining to assess neurological deficits and tissue damage in mice. RNA-Seq analysis, molecular docking, immunofluorescence, western blotting, and transmission electron microscopy to verify the underlying autophagic molecular mechanisms.</div></div><div><h3>Results</h3><div>GEN significantly reduced cerebral infarction volume and neuronal apoptosis in MCAO/R mice. In OGD/R models, GEN improved cell viability and reduced apoptosis rates. Mechanistically, GEN inhibited cGAS-STING pathway activation, suppressing excessive autophagy observed during ischemia-reperfusion injury. RNA-Seq analysis and molecular docking supported these findings, indicating the involvement of autophagy and the cGAS-STING pathway in GEN-mediated neuroprotection.</div></div><div><h3>Conclusion</h3><div>GEN demonstrates potent neuroprotective effects against cerebral ischemia-reperfusion injury by mitigating neuronal apoptosis and improving neurological functions. These effects are attributed to their ability to modulate autophagy by inhibiting the cGAS-STING pathway. These findings highlight GEN as a promising therapeutic candidate for ischemic stroke treatment.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"280 ","pages":"Article 110677"},"PeriodicalIF":4.6,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008346","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}
NeuropharmacologyPub Date : 2025-09-03DOI: 10.1016/j.neuropharm.2025.110675
Sophia Draughon , Ali Idriss , Kylie Kealoha , Meira Gildin , Michael Lauber , Benjamin Carper , Lawrence Toll , Kelly M. Standifer , Andrea Cippitelli
{"title":"Testing the effect of the non-selective opioid PPL-138 in a model of alcohol relapse in the context of PTSD","authors":"Sophia Draughon , Ali Idriss , Kylie Kealoha , Meira Gildin , Michael Lauber , Benjamin Carper , Lawrence Toll , Kelly M. Standifer , Andrea Cippitelli","doi":"10.1016/j.neuropharm.2025.110675","DOIUrl":"10.1016/j.neuropharm.2025.110675","url":null,"abstract":"<div><div>Alcohol use disorder (AUD) is a frequent comorbidity in patients suffering from post-traumatic stress disorder (PTSD). Few therapeutic options are available for the individual disorders, and there are currently no drugs specifically shown to treat AUD in patients with comorbid PTSD. As PTSD has been associated with dysregulation of the brain's opioid system, our study aimed to examine the effects of a non-selective opioid compound, PPL-138, for use in co-morbid PTSD and AUD. Female and male Sprague-Dawley rats were trained to respond for alcohol in operant chambers. Following extinction, alcohol-seeking behavior was reinstated by cues previously associated with alcohol availability. All rats underwent Single Prolonged Stress (SPS) to induce PTSD-like manifestations, except for a male and female untraumatized group. Afterward, the anxiety-like behavior of all individual rats was assessed, and a second cue-induced reinstatement was conducted<strong>.</strong> Following subcutaneous PPL-138 testing (0.0, 0.1, 0.3, 1.0 mg/kg), female, but not male rats, who had escalated alcohol-seeking behavior after SPS, showed a reduction in their responses. Additionally, PPL-138 attenuated reinstatement in the subset of female rats that exhibited anxiety-like behavior. PPL-138 increased alcohol seeking in non-traumatized male rats, while leaving alcohol seeking of non-traumatized female rats unaltered. These results support the efficacy of pharmacological modulation of the opioid system in reducing both traumatic-like stress-induced escalation of alcohol-seeking behavior and cue-induced relapse associated with heightened anxiety, specifically in female rats. Classifying individuals based on traumatic stress-induced changes in alcohol-seeking behavior may provide a valuable model for evaluating pharmacological treatments for PTSD and AUD comorbidity.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"280 ","pages":"Article 110675"},"PeriodicalIF":4.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144997247","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}
NeuropharmacologyPub Date : 2025-09-01DOI: 10.1016/j.neuropharm.2025.110674
Yaozong Yu , Xiang liu , Ziyi Zang , Xuechong Zhao , Bo Zhao , Yahui Zhang , Junfang Niu , Qiujun Wang
{"title":"Enhanced meningeal lymphatic drainage alleviates cognitive dysfunction induced by anesthesia and surgery in aged mice","authors":"Yaozong Yu , Xiang liu , Ziyi Zang , Xuechong Zhao , Bo Zhao , Yahui Zhang , Junfang Niu , Qiujun Wang","doi":"10.1016/j.neuropharm.2025.110674","DOIUrl":"10.1016/j.neuropharm.2025.110674","url":null,"abstract":"<div><div>Postoperative cognitive dysfunction (POCD) occurs in elderly surgical patients as a common complication and manifests as cognitive decline. It is associated with neuroinflammation, microglial activation, and impaired metabolic waste clearance—key mechanisms underlying POCD. Meningeal lymphatic vessels (MLVs) facilitate the drainage of cerebrospinal fluid (CSF) and interstitial fluid (IF), regulating brain immune responses and clearing metabolic waste, immune cells, and antigens, thus modulating neuroinflammation. This study investigates whether enhancing meningeal lymphatic drainage mitigates POCD in aged mice. A POCD mouse model was established via tibial fracture surgery under general anesthesia. Meningeal lymphatic drainage was assessed using immunofluorescence, followed by intra-cisterna magna injection of adeno-associated virus (AAV)-vascular endothelial growth factor-c (AAV-VEGF-C) or AAV-mCherry. Cognitive performance, microglial activation, and pro-inflammatory cytokines were evaluated through behavioral tests, western blotting, and immunofluorescence. Anesthesia and surgery impair the function and morphology of MLVs, leading to reduced lymphatic drainage. These changes were associated with elevated hippocampal expression of microglial activation markers ionized calcium-binding adapter molecule 1 (Iba1) and cluster of differentiation 68 (CD68), as well as increased levels of Interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), which collectively contributed to cognitive impairment. In contrast, AAV-VEGF-C enhanced meningeal lymphatic drainage by promoting lymphangiogenesis and improving function, reduced microglial activation and neuroinflammation, and improved cognitive outcomes. These findings demonstrate that dysfunction of MLVs exacerbates POCD by amplifying neuroinflammation, while enhancing the function of MLVs mitigates these effects. MLVs represent a promising therapeutic target for managing POCD among the aged.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"280 ","pages":"Article 110674"},"PeriodicalIF":4.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144989012","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}
NeuropharmacologyPub Date : 2025-08-30DOI: 10.1016/j.neuropharm.2025.110655
Negin Mohammadmirzaei , Praveen Kulkarni , Matt Biddle , Xuezhu Cai , Khan Hekmatyar , Dayan Knox
{"title":"Using in vivo MRI to reveal circuits that are sensitive to traumatic stress in male and female rats","authors":"Negin Mohammadmirzaei , Praveen Kulkarni , Matt Biddle , Xuezhu Cai , Khan Hekmatyar , Dayan Knox","doi":"10.1016/j.neuropharm.2025.110655","DOIUrl":"10.1016/j.neuropharm.2025.110655","url":null,"abstract":"<div><h3>Background</h3><div>Post traumatic stress disorder (PTSD) is debilitating and more prevalent in women than men. While this suggests there are sex differences in the way neural systems respond to traumatic stress, identifying these systems are challenging. As such, studies designed to identify neural systems that are differentially sensitive to traumatic stress are needed.</div></div><div><h3>Methods</h3><div>We examined the impact of traumatic stress within a rat model (single prolonged stress (SPS)) on resting-state functional connectivity (rs-FC) and anatomical volume using in vivo MRI. Rs-FC and anatomical volume were measured before and after application of stress in male and female rats. Algorithmic, clustering, and GLM approaches were used to characterize how SPS changed rs-FC and volume across multiple neural systems.</div></div><div><h3>Results</h3><div>SPS decreased rs-FC within the DMN, within the hippocampus (Hipp), and increased rs-FC between the thalamus (th) and striatum. Changes in th-Hipp connectivity brought on by SPS were different in males and females, with decreased rs-FC between the mediodorsal thalamus (thMD) and ventral CA1 (vCA1) occurring in males, and increased rs-FC between the paraventricular thalamic nucleus (PV) and vCA1, and thMD and the dorsal dentate gyrus (dDG), occurring in female rats. In control rats dDG volume expanded from the pre-to post-stress scans and this expansion was inhibited in SPS animals.</div></div><div><h3>Conclusions</h3><div>The results of this study raise the possibility that sex differences in traumatic stress responsivity could manifest through thalamo-Hipp circuits. The results also raise the possibility that traumatic stress may inhibit natural volumetric expansions within the Hipp.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"280 ","pages":"Article 110655"},"PeriodicalIF":4.6,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962561","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}
NeuropharmacologyPub Date : 2025-08-30DOI: 10.1016/j.neuropharm.2025.110670
Carina Joy Donegan , Dimitri Daldegan-Bueno , Tehseen Noorani , Rachael Sumner , Anna Forsyth , William Evans , Todd Smith , Nicholas Hoeh , Frederick Sundram , David Menkes , Suresh Muthukumaraswamy , Lisa Reynolds
{"title":"Qualitative content analysis of expectations in participants with depression about to begin LSD microdosing treatment: Identifying the need for psychedelic expectancy measures","authors":"Carina Joy Donegan , Dimitri Daldegan-Bueno , Tehseen Noorani , Rachael Sumner , Anna Forsyth , William Evans , Todd Smith , Nicholas Hoeh , Frederick Sundram , David Menkes , Suresh Muthukumaraswamy , Lisa Reynolds","doi":"10.1016/j.neuropharm.2025.110670","DOIUrl":"10.1016/j.neuropharm.2025.110670","url":null,"abstract":"<div><div>Expectations can impact antidepressant treatment and psychedelic therapy, often enhancing placebo effects and influencing outcomes. However, research in this context is lacking. Our study explored the expectations of participants with major depressive disorder (MDD) before microdosing lysergic acid diethylamide (LSD) in an open-label trial. Twenty-three individuals with MDD completed a semi-structured interview about their expectations before commencing an LSD microdosing regimen. Interviews were transcribed and analysed using qualitative content analysis and compared with Credibility/Expectancy Questionnaire scores. Response categories were motivation, influence, expected effects, expected mechanisms, and hope. Over half of the participants (16/23 participants) cited previous treatment failure as a motivation for participating, with additional motivations including long-term depression (7/23), interest in psychedelics (9/23), desire for microdosing to be available to others (4/23) and recommendation by a professional (2/23). Media (12/23) and friends/family (5/23) were major influences on microdosing opinions, as was the desire to avoid influence (10/23). Participants expected various effects, including changes to consciousness (5/23), subtle effects (10/23) or had no expectations (12/23). Some participants were unsure about mechanisms (7/23), but others believed microdosing might cause neural rewiring (11/23) or changes to thought patterns (7/23). Participants were optimistic (8/23), cautious (11/23), and/or excited about the research (7/23). Our study highlights the role of media in shaping expectations and the extent to which participants expect healing through psychedelics. Hope acted as a motivator and a disappointment buffer. Future research should develop a psychedelic-specific expectancy measure covering additional factors not covered by current measures.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"280 ","pages":"Article 110670"},"PeriodicalIF":4.6,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962605","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}
NeuropharmacologyPub Date : 2025-08-29DOI: 10.1016/j.neuropharm.2025.110662
Zhenyu Huang , Jiawen Sun , Haokang Li , Zhuang Hu , Haibo Tan , Yuanfei Fu , Linchao Gao , Xin Peng , Hongkan Lou
{"title":"Microglial-derived nitric oxide regulates amygdala synaptic plasticity to drive chronic pain and depression induced by lumbar disc herniation","authors":"Zhenyu Huang , Jiawen Sun , Haokang Li , Zhuang Hu , Haibo Tan , Yuanfei Fu , Linchao Gao , Xin Peng , Hongkan Lou","doi":"10.1016/j.neuropharm.2025.110662","DOIUrl":"10.1016/j.neuropharm.2025.110662","url":null,"abstract":"<div><div>Lumbar disc herniation (LDH) is a major driver of chronic low back pain often accompanied by depression-like behaviors, yet the supraspinal mechanisms that link nociception to affective disturbance remain unclear. Here, we investigated the potential mechanisms by which microglia-derived nitric oxide (NO) modulates synaptic plasticity in the amygdala of a rat model of LDH. Behavioral assessments confirmed the presence of mechanical hyperalgesia and depression-like behaviors in LDH rats. Multi-omics profiling revealed increased L-arginine in CSF and enrichment of cGMP–PKG and glutamatergic, long-term potentiation pathways in the amygdala. Protein-level validation confirmed upregulation of iNOS, NO, cGMP, and PRKG2 in the amygdala. Concurrently, increased levels of IL-1β and TNF-α in both the amygdala and CSF, along with Iba1 and iNOS co-localization in microglia, confirmed a neuroinflammatory microenvironment. Enhanced expression of GRIA1, p-GRIA1, GRIN2B, and p-CaMKII indicated potentiation of excitatory synaptic transmission in the amygdala. In a microglia-neuron co-culture system, conditioned medium from CSF-activated BV2 cells upregulated PRKG2, cGMP, and synaptic plasticity markers in PC12 cells. These effects were abolished by the iNOS inhibitor 1400W and mimicked by the NO donor DETA-NONOate, confirming a mechanistic link between microglial NO and neuronal plasticity. These findings suggested that LDH-induced neuroinflammation activates microglial iNOS in the amygdala, leading to NO elevations that engage the cGMP/PRKG2 pathway and drive pathological excitatory synaptic plasticity. Targeting this neuroimmune pathway may offer novel therapeutic strategies for chronic pain and related depression induced by LDH.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"280 ","pages":"Article 110662"},"PeriodicalIF":4.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144933541","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}
NeuropharmacologyPub Date : 2025-08-28DOI: 10.1016/j.neuropharm.2025.110661
Lianmei Liu , Zhixin Li , Xuemei Qin , Lei Xu , Zhenyu Li , Shengnan Xiao
{"title":"Astragaloside Ⅳ improves neuroinflammation in Parkinson's disease by regulating amino acid metabolism and the PI3K-AKT signaling pathway","authors":"Lianmei Liu , Zhixin Li , Xuemei Qin , Lei Xu , Zhenyu Li , Shengnan Xiao","doi":"10.1016/j.neuropharm.2025.110661","DOIUrl":"10.1016/j.neuropharm.2025.110661","url":null,"abstract":"<div><h3>Objective</h3><div>Elucidation the pharmacological mechanism of AS-Ⅳ, providing a scientific basis for the development of AS-Ⅳ as a therapeutic agent for Parkinson's disease (PD).</div></div><div><h3>Methods</h3><div>An acute PD model was established in C57BL/6 mice through intraperitoneal injection of MPTP. A comprehensive multi-omics approach was employed for in-depth data analysis and processing. The effects of AS-Ⅳ on motor dysfunction and neuropathological changes were validated at both protein and mRNA levels using Western blotting and RT-qPCR, revealing its therapeutic potential and mechanisms of action in PD.</div></div><div><h3>Results</h3><div>AS-Ⅳ significantly improved behavioral parameters in PD mouse models, increased the population of dopaminergic neurons, and attenuated neuroinflammation. Metabolomic analysis revealed that AS-Ⅳ exerts <em>anti</em>-neuroinflammatory effects through modulation of amino acid metabolism. Further investigation demonstrated that AS-Ⅳ downregulates CCN3 gene expression, thereby enhancing PI3K-AKT phosphorylation and suppressing the expression of inflammatory factors.</div></div><div><h3>Conclusions</h3><div>In summary, this study elucidates a novel mechanism of AS-Ⅳ in PD treatment, providing a scientific foundation for the development of AS-Ⅳ drugs for PD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"280 ","pages":"Article 110661"},"PeriodicalIF":4.6,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144912684","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}
NeuropharmacologyPub Date : 2025-08-27DOI: 10.1016/j.neuropharm.2025.110660
Wen Kang , Kang Liu , Xia Pan , Yue le , Long Wang
{"title":"Epigallocatechin gallate ameliorates oxaliplatin-induced peripheral neuropathy via upregulation of IGF-1 signaling and suppression of neuroinflammation","authors":"Wen Kang , Kang Liu , Xia Pan , Yue le , Long Wang","doi":"10.1016/j.neuropharm.2025.110660","DOIUrl":"10.1016/j.neuropharm.2025.110660","url":null,"abstract":"<div><div>Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a severe neurological complication characterized by persistent pain and sensory dysfunction. This study investigated the role of Insulin-like Growth Factor-1 (IGF-1) signaling in the pathogenesis of oxaliplatin-induced CIPN and evaluated the therapeutic potential of Epigallocatechin gallate (EGCG). Using an oxaliplatin-induced CIPN mouse model, we examined IGF-1 expression in dorsal root ganglia (DRG) and spinal cord, and assessed the therapeutic effects of intraperitoneal EGCG (50 mg/kg/day) administration. Oxaliplatin induced mechanical hypersensitivity and significantly reduced IGF-1 protein levels, predominantly localized in neurons, within both DRG and spinal cord, while IGF-1 receptor (IGF1R) expression remained unchanged. Daily EGCG administration significantly attenuated oxaliplatin-induced mechanical hypersensitivity and restored neuronal IGF-1 expression in these tissues. These therapeutic effects were accompanied by robust <em>anti</em>-neuroinflammatory actions. EGCG treatment significantly reduced oxaliplatin-induced microglia/macrophage activation (Iba-1 positive cells) in both DRG and spinal dorsal horn (SDH). Furthermore, EGCG suppressed the phosphorylation of NFκB, p38 MAPK (notably in Iba-1 positive cells), and ERK, key inflammatory signaling molecules. EGCG also reversed the oxaliplatin-induced increase in phosphorylated CREB and diminished expression of the pain marker Calcitonin Gene-Related Peptide (CGRP). Interestingly, the phosphorylation of AKT, a common downstream effector of IGF-1, was not significantly altered by EGCG treatment in this model. In conclusion, our study demonstrates EGCG's therapeutic potential in CIPN by enhancing neuronal IGF-1 signaling and suppressing neuroinflammation through the modulation of NFκB, p38 MAPK, ERK, and CREB pathways. These findings highlight EGCG as a promising candidate for CIPN management, warranting further investigation.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"280 ","pages":"Article 110660"},"PeriodicalIF":4.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962597","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}