Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology最新文献

{"title":"Correction: Low-Dose Aspirin Upregulates Tyrosine Hydroxylase and Increases Dopamine Production in Dopaminergic Neurons: Implications for Parkinson's Disease.","authors":"Suresh B Rangasamy, Sridevi Dasarathi, Priyanka Pahan, Malabendu Jana, Kalipada Pahan","doi":"10.1007/s11481-025-10189-3","DOIUrl":"https://doi.org/10.1007/s11481-025-10189-3","url":null,"abstract":"","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"28"},"PeriodicalIF":6.2,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulating Multiple Molecular Trajectories by Nutraceuticals and/or Physical Activity in Attention-Deficit/Hyperactivity Disorder (ADHD)-Like Behaviors in Rat Pups.","authors":"Karema Abu-Elfotuh, Gellan Alaa Mohamed Kamel, Mazin A A Najm, Ahmed M E Hamdan, Mona T Koullah, Rasha K E Fahmy, Heba Abdelnaser Aboelsoud, Manar A Alghusn, Budor R Albalawi, Ahmed M Atwa, Khaled R Abdelhakim, Abdou M A Elsharkawy, Ehsan K Mohamed, Nada S Abdou, Reema Almotairi, Hoda A Salem, Ayah M H Gowifel","doi":"10.1007/s11481-025-10188-4","DOIUrl":"10.1007/s11481-025-10188-4","url":null,"abstract":"<p><p>Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition affecting cognitive and social functions all over childhood. Monosodium glutamate (MSG) is a common food additive associated with ADHD-like symptoms in children. Nutraceuticals, like sesamol (SE) and astaxanthin (AST), or physical activity (PHA) were reported to possess beneficial effects on human health. Meanwhile, still their neuroprotective effect against ADHD has been poorly investigated. This study aimed to investigate the impact of SE, AST and PHA either separately or combined on ADHD-like behaviors induced by MSG in rat pups. Eighty-four male Sprague Dawley rat pups were randomly allocated into seven groups; control, MSG, (PHA + MSG), (SE + MSG), (AST + MSG), (SE + AST + MSG), and (COMB [PHA + SE + AST] + MSG) and treated for eight weeks. MSG-induced ADHD-like behavior was evaluated, via assessing behavioral outcomes; neurotransmitters' levels; five pathway biomarkers, coupled with histopathological and immunohistochemical studies. Rats exposed to PHA or treated with SE or AST either separately or combined exhibited enhanced attention, locomotor, and cognitive abilities, compared to MSG-intoxicated group. All treatments remarkably improved MSG-induced abnormalities in neurotransmitters' levels; biochemical markers; along with histological findings, via modulating HMGB1/RAGE/JAK-2/STAT-3, PI3K/AKT/CREB/BDNF, AMPK/SIRT-1 and PERK/CHOP pathways. Nevertheless, the combination of PHA with nutraceuticals (SE and AST) elicited more favorable effects in all measured parameters and histological findings, compared to other treated groups. In conclusion, this study revealed the superiority of the combination of nutraceuticals with PHA, over other standalone treatments, in amelioration of MSG-induced ADHD-like behaviors in rat pups, via fine-tuning of HMGB1/RAGE, PI3K/AKT/CREB/BDNF, AMPK/SIRT-1 and PERK/CHOP pathways.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"27"},"PeriodicalIF":6.2,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11920304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal Delivery of Lithium Salt Suppresses Inflammatory Pyroptosis in the Brain and Ameliorates Memory Loss and Depression-like Behavior in 5XFAD Mice.","authors":"Piplu Bhuiyan, Wenjia Zhang, Ge Liang, Bailin Jiang, Robert Vera, Rebecca Chae, Kyulee Kim, Lauren St Louis, Ying Wang, Jia Liu, De-Maw Chuang, Huafeng Wei","doi":"10.1007/s11481-025-10185-7","DOIUrl":"10.1007/s11481-025-10185-7","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Alzheimer's disease (AD) is a devastating neurodegenerative disease (AD) and has no treatment that can cure or halt the disease progression. This study explored the therapeutic potential of lithium salt dissolved in Ryanodex formulation vehicle (RFV) and delivered to the brain by intranasal application. We first compared lithium concentrations in the brain and blood of wild-type mice following intranasal or oral administration of lithium chloride (LiCl) dissolved in either RFV or water. The beneficial and side effects of intranasal versus oral LiCl in RFV in these mice were assessed and potential mechanisms underlying the efficacy of anti-inflammation and anti-pyroptosis in the brains were also investigated in both wild-type and 5XFAD Alzheimer's Disease (AD) mice brains.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;For the study of brain versus blood lithium concentrations, wild-type (WT) B6SJLF1/J mice at 2 months of age were treated with intranasal or oral LiCl (3 mmol/kg) dissolved in RFV or in water. Brain and blood lithium concentrations were measured at various times after drugs administration. Brain/blood lithium concentration ratios were then determined. For studying therapeutic efficacy versus side effects and their underlying mechanisms, 5XFAD and WT B6SJLF1/J mice were treated with intranasal LiCl (3 mmol/kg) daily, Monday to Friday each week, in RFV beginning at 2 or 9 months of age with a 12-week treatment duration. Animal behaviors were assessed for depression (tail suspension), cognition (fear conditioning and Y maze), olfaction (buried food test), and motor functions (rotarod) at the age of 5 and 12 months. Blood and brain tissue were harvested from these mice at 13 months. Blood biomarkers for the functions of thyroid (thyroid stimulating hormone, TSH) and kidney (creatinine) were measured using ELISA. Changes in protein expression levels of the endoplasmic reticulum Ca&lt;sup&gt;2+&lt;/sup&gt; release channels type 1 InsP&lt;sub&gt;3&lt;/sub&gt; receptors (InsP&lt;sub&gt;3&lt;/sub&gt;R-1), malondialdehyde (MDA)-modified proteins and 4-hydroxy-2-nonenal (4-HNE), pyroptosis regulatory proteins (NLR family pyrin domain containing 3 (NLRP3), cleaved caspase-1, N-terminal of Gasdermin D (GSDMD)), cytotoxic (IL-1β, IL-18, IL-6, TNF-α) and cytoprotective (IL-10) cytokines and synapse proteins (PSD-95, synapsin-1) were determined using immunoblotting. Mouse body weights were monitored regularly.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Compared to oral LiCl in RFV nanoparticles, intranasal treatment of WT mice with LiCl in RFV markedly decreased blood concentrations at the time range of 30-120 min. The ratio of brain/blood lithium concentration after intranasal lithium chloride in RFV significantly increased, in comparison to those after oral administration lithium chloride in RFV or intranasal administration of lithium chloride in water. Intranasal lithium chloride in RFV inhibited both memory loss and depressive behavior in adult and aged 5XFAD mice. Addition","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"26"},"PeriodicalIF":6.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143652434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Reduction of Lewy Body Pathology by Oral Cinnamon.","authors":"Sumita Raha, Debashis Dutta, Avik Roy, Kalipada Pahan","doi":"10.1007/s11481-025-10187-5","DOIUrl":"https://doi.org/10.1007/s11481-025-10187-5","url":null,"abstract":"","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"25"},"PeriodicalIF":6.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitigating Remote Organ-Induced Brain Injury in Renal Ischemia-Reperfusion: The Role of Oleuropein in Inhibiting Oxidative Stress, Inflammation, Ferroptosis, and Apoptosis in Male Rats.","authors":"Mohammad Ghaffarinasab, Ayat Kaeidi, Jalal Hassanshahi","doi":"10.1007/s11481-025-10184-8","DOIUrl":"10.1007/s11481-025-10184-8","url":null,"abstract":"<p><p>Renal ischemia-reperfusion (RIR) induces brain damage as a distant organ. Oleuropein has antioxidant properties. This study aimed to explore oleuropein's protective effects against brain injury following RIR in rats. Thirty-six male Wistar rats were divided into six groups (n = 6) including sham, oleuropein (200 mg/kg), RIR, and RIR groups treated with oleuropein (50, 100, and 200 mg/kg). 48 h after injury, blood urea nitrogen (BUN) and creatinine levels were surveyed. The western blotting analysis was performed to assay the interleukin-1 beta (IL-1β), IL-10, tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa-light-chain-enhancer of activated B cells p65 (NF-κB p65), Bcl-2 associated X protein (Bax), B-cell lymphoma-2 (Bcl-2), cleaved caspase-3, glutathione peroxidase-4 (GPX4), nuclear factor erythroid-related factor-2 (NRF2), solute carrier family 7, member 11 (SLC7A11), and anti-acyl-CoA synthetase long-chain family 4 (ACSL4) proteins in kidney and/or brain tissues. Also, malondialdehyde (MDA) and total antioxidant capacity (TAC) levels, the activity of GPx, catalase, and superoxide dismutase (SOD) were evaluated. Kidney and brain tissues damage scores (KTDS and BTDS) were determined by H&E staining method. Prussian blue staining was conducted to identify iron accumulation. RIR significantly increased BUN, serum creatinine levels, KTDS, BTDS, iron deposition, MDA concentration, Bax, cleaved caspase-3, IL-1β, TNF-α, NF-κB p65, ACSL4 proteins expression levels, while decreasing TAC content, SOD, GPx, and catalase activity, Bcl-2, GPX4, SLC7A11 and NRF2 proteins expression in kidney and/or brain tissue of RIR group versus the sham (P < 0.05). Moreover, oleuropein attenuated these indicators in the RIR + oleuropein (200 mg/kg) group versus the RIR group (P < 0.05). Our study showed that RIR induced brain damage, and oleuropein exhibited protective effects against brain injury induced by RIR, through inhibiting oxidative stress, inflammation, ferroptosis, and apoptosis mechanisms.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"24"},"PeriodicalIF":6.2,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Comprehensive Review on Utilizing Human Brain Organoids to Study Neuroinflammation in Neurological Disorders.","authors":"Adrian Domene Rubio, Luke Hamilton, Mark Bausch, Mengmeng Jin, Ava Papetti, Peng Jiang, Sowmya V Yelamanchili","doi":"10.1007/s11481-025-10181-x","DOIUrl":"10.1007/s11481-025-10181-x","url":null,"abstract":"<p><p>Most current information about neurological disorders and diseases is derived from direct patient and animal studies. However, patient studies in many cases do not allow replication of the early stages of the disease and, therefore, offer limited opportunities to understand disease progression. On the other hand, although the use of animal models allows us to study the mechanisms of the disease, they present significant limitations in developing drugs for humans. Recently, 3D-cultured in vitro models derived from human pluripotent stem cells have surfaced as a promising system. They offer the potential to connect findings from patient studies with those from animal models. In this comprehensive review, we discuss their application in modeling neurodevelopmental conditions such as Down Syndrome or Autism, neurodegenerative diseases such as Alzheimer's or Parkinson's, and viral diseases like Zika virus or HIV. Furthermore, we will discuss the different models used to study prenatal exposure to drugs of abuse, as well as the limitations and challenges that must be met to transform the landscape of research on human brain disorders.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"23"},"PeriodicalIF":6.2,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11846768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vinpocetine and Lactobacillus Attenuated Rotenone-Induced Parkinson's Disease and Restored Dopamine Synthesis in Rats through Modulation of Oxidative Stress, Neuroinflammation, and Lewy Bodies Inclusion.","authors":"Hanan M Hassan, Hadeer O Abou-Hany, Ahmed Shata, Doaa Hellal, Ahmed M El-Baz, Zeinab H ElSaid, Amira A Haleem, Nesreen Elsayed Morsy, Rawan M Abozied, Bassant M Elbrolosy, Sally Negm, Attalla F El-Kott, Mohammed A AlShehri, Mohamad A Khasawneh, Eman R Saifeldeen, Marwa M Mahfouz","doi":"10.1007/s11481-025-10176-8","DOIUrl":"10.1007/s11481-025-10176-8","url":null,"abstract":"<p><p>Parkinson's disease (PD) is the main neurodegenerative disorder affecting motor activity, there are different pathophysiological pathways contributing to its development including oxidative stress, neuroinflammation, Lewy's bodies accumulation, and impaired autophagy. Vinpocetine is an herbal extract with antioxidant and anti-inflammatory activities that may counteract pathophysiologic neurodegeneration pathways. Moreover, Lactobacillus is a probiotic that can modulate the gut-brain axis and provide the body with the needed precursors of antioxidants and anti-inflammatory mediators. In the current study PD was induced experimentally in Sprague Dawley rats with rotenone (2.5 mg/kg, i.p, daily) for 60 days, vinpocetine; Vinpo (20 mg/kg, orally, daily) and Lactobacillus; Lacto (2.7 × 10⁸ CFU/ml, orally, daily) were applied as protective treatment. Vinpocetine and Lactobacillus treatment significantly ameliorated motor function by increasing distance traveled and rearing frequency in the open field test with a concomitant increase in falling time from both the accelerating rotarod and the wire screen test. Moreover, vinpocetine and Lactobacillus treatment upregulates tyrosine hydroxylase expression (the rate-limiting enzyme in dopamine synthesis), leading to enhanced dopamine synthesis and improved dopaminergic function with regression of histopathological hallmarks. Antioxidant GSH levels were significantly increased after vinpocetine and Lactobacillus treatment with a significant decrease in MDA content in brain homogenates. Furthermore, vinpocetine and Lactobacillus treatment significantly decreased striatal inflammatory markers; nitrite, IL-1β and TNF-α. Proteinopathies were regressed with a substantial decrease in striatal α-synuclein and tau content. In conclusion, vinpocetine and Lactobacillus treatment reduced rotenone neurotoxicity with improved dopamine release and motor activity with correction of oxidative burden, neuro-inflammation, and proteinopathy.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"22"},"PeriodicalIF":6.2,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological Depletion of Microglia Protects Against Alcohol-Induced Corticolimbic Neurodegeneration During Intoxication in Male Rats.","authors":"Erika R Carlson, Jennifer K Melbourne, Kimberly Nixon","doi":"10.1007/s11481-025-10173-x","DOIUrl":"10.1007/s11481-025-10173-x","url":null,"abstract":"<p><p>Excessive alcohol use damages the brain, especially corticolimbic regions such as the hippocampus and rhinal cortices, leading to learning and memory problems. While neuroimmune reactivity is hypothesized to underly alcohol-induced damage, direct evidence of the causal role of microglia, brain-resident immune cells, in this process is lacking. Here, we depleted microglia using PLX5622 (PLX), a CSF1R inhibitor commonly used in mice, but rarely in rats, and assessed cell death following binge-like alcohol exposure in male rats. Eleven days of PLX treatment depleted microglia > 90%. Further, PLX treatment prevented alcohol-induced neuronal death in the hippocampus and rhinal cortices, as the number of FluoroJade-B-positive cells (dying neurons) was reduced to control diet levels. This study provides direct evidence that alcohol-induced microglial reactivity is neurotoxic in male rats. Improved understanding of alcohol-microglia interactions is essential for developing therapeutics that suppress pro-cytotoxic and/or amplify protective microglia activity to relieve alcohol-related damage.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"21"},"PeriodicalIF":6.2,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loganic Acid Alleviates the Olfactory-Brain NLRP3 Inflammasome Activation and Rescues Dopaminergic Neurons in Experimental Models of Parkinson's Disease.","authors":"Samir Ranjan Panda, Pallabi Panja, Meenakshi Singh, Ujjawal Soni, Bishal Rajdev, Pankaj Garg, Sharad D Pawar, Rabinarayan Acharya, Anagha Ranade, V G M Naidu","doi":"10.1007/s11481-025-10183-9","DOIUrl":"10.1007/s11481-025-10183-9","url":null,"abstract":"<p><p>The NLRP3 inflammasome signaling cascade activation is a significant contributor to the initiation and progression of Parkinson's disease (PD). Recent evidence supports that targeting NLRP3 inflammasome assembly could be a potential strategy to halt PD progression. The molecular mechanism of the olfactory-brain axis in mediating PD remains elusive. The current study explores that MPTP exposure to C57BL/6 mice leads to glial cell activation and impairs the olfactory function. The role of NLRP3 inflammasome activation in the olfactory bulb and the brain mediating neuroinflammation and neurodegeneration by activating multiple inflammatory pathways is explored. Loganic acid (LA), an iridoid glycoside, has been shown to provide antioxidant, anti-inflammatory, and inhibit microglial activation. Our results in-vitro studies demonstrated that LA treatment in MPP⁺-induced microglial cells inhibits NLRP3 inflammasome assembly, halts phagocytosis, and downregulates the release of pro-inflammatory cytokines such as IL-1β and IL-18. Further, results confirm that LA increases the neuronal differentiation markers and assists neurite growth. To correlate the in-vitro experiments with the in-vivo study, LA treatment prevented the loss of olfactory and motor function. In immunoblotting, LA treatment significantly inhibits the expression of NLRP3 inflammasome signaling cascade when compared to the MPTP group of the olfactory bulb and substantia nigra. Computational studies on LA on IL-β, NLRP3, caspase-1, and ASC also support strong evidence in the downregulation of inflammasome and cytokines through potential non-covalent interactions. The results confirm the neuroprotective effect of LA in PD by halting the NLRP3 inflammasome activation in the olfactory bulb and nigra region of the mice.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"19"},"PeriodicalIF":6.2,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GDF11 Mitigates Neuropathic Pain via Regulation of Microglial Polarization and Neuroinflammation through TGF-βR1/SMAD2/NF-κB Pathway in Male Mice.","authors":"Tianzhu Liu, Longqing Zhang","doi":"10.1007/s11481-025-10172-y","DOIUrl":"10.1007/s11481-025-10172-y","url":null,"abstract":"<p><p>Spinal microglial activation and the polarization towards the M1 phenotype are implicated in the pathological process of neuropathic pain. Extensive research has elucidated that growth and differentiation factor 11 (GDF11), a constituent of the transforming growth factor-β (TGF-β) superfamily, exerts inhibitory effects on macrophage activation and mitigates inflammatory responses via the activation of TGF-β receptor type I (TGF-βR1). Nonetheless, the influence of GDF11 on spinal microglial polarization and its role in neuropathic pain remains to be ascertained. In the present investigation, a neuropathic pain model was induced via a spared nerve injury (SNI) procedure on the sciatic nerve in male mice. The impact of GDF11 on microglial polarization and neuropathic pain in SNI-subjected mice was evaluated through pain behavior assessments, WB, IF, qRT-PCR, and ELISA. Our findings revealed a significant downregulation of spinal GDF11 and TGF-βR1 expression levels in microglia of mice subjected to SNI. Furthermore, GDF11 treatment notably reversed the mechanical allodynia and thermal hyperalgesia, inhibited M1 microglial polarization, and attenuated neuroinflammatory processes by modulating the SMAD2/NF-κB in SNI mice. However, the analgesic effects of GDF11 on pain hypersensitivity and its modulatory influence on spinal microglial polarization were abrogated by the application of a specific antagonist of TGF-βR1, or the TGF-βR1 siRNA. In summary, GDF11 effectively ameliorated mechanical allodynia and thermal hyperalgesia, suppressed M1 microglial polarization, and alleviated neuroinflammation via the regulation of the TGF-βR1/SMAD2/NF-κB pathway in mice with SNI. These findings suggest that GDF11 holds promise as a therapeutic modality for the management of neuropathic pain.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"20"},"PeriodicalIF":6.2,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}