J Neuroimmune Pharmacol [JOURNAL]
Sun
200 papers
Melatonin Mitigates Central Sensitization and Nociplastic Pain in Spinal Cord and Dorsal Root Ganglia of FM Rat Model: Modulation of SIRT1/PGC-1α/MAPK/NF-κB Signaling.
Osama J, El-Gazar AA, Ragab GM … +2 more , El-Sayed NS, Kamel AS
J Neuroimmune Pharmacol · 2026 Feb · PMID 41686296 · Full text
Fibromyalgia (FM) is a central sensitization syndrome characterized by neuroinflammation and synaptic hyperexcitability, which amplifies pain signals in the spinal cord (SC) and dorsal root ganglia (DRG). Melatonin (MEL)...
Fibromyalgia (FM) is a central sensitization syndrome characterized by neuroinflammation and synaptic hyperexcitability, which amplifies pain signals in the spinal cord (SC) and dorsal root ganglia (DRG). Melatonin (MEL) has demonstrated analgesic and antinociceptive properties in experimental models, supporting its clinical application in various pathological conditions. This study aimed to elucidate the impact of Melatonin on neuroinflammation and glutamatergic dysregulation in the spinal cord and DRG using a Reserpine-induced fibromyalgia model (RIFM). RIFM was induced in female rats by administering Reserpine (1 mg/kg/day, s.c.) for three consecutive days. Melatonin (10 mg/kg, orally) was administered for three days following the peak of pain on day 7. Melatonin significantly ameliorated stimulus-evoked pain in thermal and mechanical tests, with a resolution of spontaneous pain noted by the rat grimace scale. Moreover, motor activity in the open field task and depressive behavior in the tail suspension test (TST) were alleviated following Melatonin administration. Fibromyalgia pain was associated with enhanced glutamatergic transmission, as shown by immunohistochemical assessment of synaptophysin and PSD95 in the DRG along with VGLUT, PSD95, NMDA, NMDA receptor 2B, and AMPA in the spinal cord. Reserpine-induced disturbances in mitochondrial biogenesis markers, SIRT1 and PGC-1α, were followed by an upsurge of TNF-α, NFkB, and P38-MAPK. This neuroinflammatory milieu was marked by elevated ionized calcium-binding adaptor molecule-1 (Iba-1) in activated microglia within the spinal cord. These pathological findings were notably mitigated by Melatonin, as reflected by increased expressions of spinal MT1 and MT2 receptors. In conclusion, Melatonin exhibited antinociceptive and anti-inflammatory effects by modulating glutamate neurotransmission, mitochondrial dysfunction, and microglial activation, thereby alleviating nociplastic pain in the experimental RIFM.
EcoHIV Infection Disrupts Dopamine and Serotonin Transporter Function, Altering Release Dynamics in C57BL/6J Mice.
Zhu J, Moreno C, Torres ACJ … +3 more , Davis SE, Cirincione AB, Maggirwar SB
J Neuroimmune Pharmacol · 2026 Feb · PMID 41670775 · Full text
The long-term expression of neurotoxic viral proteins within the central nervous system plays a critical role in the neuropathology associated with HIV-1, particularly in the development of HIV-1 associated neurocognitiv...
The long-term expression of neurotoxic viral proteins within the central nervous system plays a critical role in the neuropathology associated with HIV-1, particularly in the development of HIV-1 associated neurocognitive disorders. This hypothesis is predominantly supported by findings from rodent models exposed to the HIV-1 transactivator of transcription (Tat) protein, which exhibit disruptions in monoamine transmission that correlate with cognitive deficits. However, previous studies have often overlooked the complex interactions among other viral proteins. To address this gap, we utilized a novel EcoHIV-infected mouse model designed to elucidate the nuances of monoamine transmission and function. EcoHIV, a chimeric virus with the HIV-1/NL4-3 gp120 coding region replaced by gp80 from ecotropic MuLV-1, facilitates infection in mice and serves as an innovative platform for NeuroHIV research. Results reveal that EcoHIV infection in C57BL/6J mice leads to increased dopamine transporter-mediated dopamine uptake in the prefrontal cortex, while simultaneously reducing serotonin transporter-mediated serotonin uptake in the hippocampus. Fast-scan cyclic voltammetry demonstrated augmented dopamine release in the nucleus accumbens paired with normal release levels in the caudate putamen, contrasted by a significant reduction in serotonin release from the substantia nigra. These alterations were accompanied by heightened horizontal activity in EcoHIV-infected mice. Immunohistochemistry and immunofluorescence analyses further revealed reductions in synaptic density and integrity, alongside microglial activation in the affected brain regions. This research offers crucial insights into the neuropathological progression of HIV-associated neurocognitive and depressive disorders, aligning with clinical evidence observed in people living with HIV and paving the way for potential therapeutic interventions.
Beta-lactam Antibiotic Cefepime Attenuates Lipopolysaccharide-induced Pain and Depression By Modulating Inflammatory Response and Astroglial Glutamate Transporter in Mice.
Khan A, Ronan PJ, Rahman S
J Neuroimmune Pharmacol · 2026 Feb · PMID 41627635 · Publisher ↗
Emerging evidence suggests that the brain glutamatergic system has a critical role in the pathophysiology of comorbid pain and depression. Cefepime is a widely used fourth-generation beta-lactam cephalosporin antibiotic...
Emerging evidence suggests that the brain glutamatergic system has a critical role in the pathophysiology of comorbid pain and depression. Cefepime is a widely used fourth-generation beta-lactam cephalosporin antibiotic and it has been shown to have neuroprotective properties in various animal models. In this study, cefepime is hypothesized to exert anti-nociceptive, anti-depressant, anxiolytic, and procognitive-like effects by modulating microglial activation and excessive glutamatergic neurotransmission in mice. Therefore, we have investigated the effects of cefepime on tactile allodynia, thermal hyperalgesia, depression, anxiety, and cognitive deficit-like behaviors in a mouse model of comorbid pain-depression induced by LPS. In addition, we have determined the effects of cefepime on astroglial expression of GLT-1 and microglial expression of Iba-1 in the hippocampus and prefrontal cortex using the Western blot analysis. We also evaluated the effects of cefepime on TNF-α and IL-1β levels in the hippocampus and prefrontal cortex using ELISA. Our results demonstrated that cefepime (50 mg/kg and 200 mg/kg i.p.) significantly attenuated LPS-induced nociceptive pain, depression, anxiety, and cognitive deficit-like behaviors in mice. In contrast, selective blockade of astroglial GLT-1 with dihydrokainic acid (10 mg/kg i.p.) significantly abolished the anti-nociceptive, anti-depressant, anxiolytic, and procognitive-like effects of cefepime (200 mg/kg i.p.), suggesting that these effects are mediated by the astroglial GLT-1 transporter. Western blot analysis indicated that cefepime (200 mg/kg) significantly reversed the LPS-reduced GLT-1 expression in the hippocampus and prefrontal cortex. Moreover, cefepime (200 mg/kg) effectively modulated the LPS-induced microglial activation as evidenced by decreased expression of Iba-1 in the hippocampus and prefrontal cortex. Notably, cefepime (200 mg/kg) significantly prevented the LPS-induced increased TNF-α and IL-1β levels in the hippocampus and prefrontal cortex by targeting glial mechanisms. Overall, these results suggest that novel glutamate transporter modulator cefepime could be developed as potential therapeutic utility for comorbid pain and depression.
Low-dose IL-2 Ameliorates Experimental Autoimmune Myasthenia Gravis in Rats by Restoring the CD4-positive Helper T-cell Balance Via the JAK/STAT5 Pathway.
Peng S, Kong X, Tian W … +11 more , Xu F, Cai H, Wu F, Li Y, Xin G, Niu J, Ren Y, Li L, Wang J, Zhang H, Wang L
J Neuroimmune Pharmacol · 2026 Jan · PMID 41619069 · Publisher ↗
Myasthenia gravis (MG) represents a prototypical autoimmune disorder that targets neuromuscular junctions. Emerging insights into the pathogenic role of cellular immunity in MG have intensified investigations of potentia...
Myasthenia gravis (MG) represents a prototypical autoimmune disorder that targets neuromuscular junctions. Emerging insights into the pathogenic role of cellular immunity in MG have intensified investigations of potential immunomodulatory therapies, and low-dose interleukin-2 (LD-IL-2) has garnered particular attention because of its ability to restore immune balance, maintain immune homeostasis, and ensure immune tolerance. To systematically investigate the therapeutic potential of LD-IL-2 in MG and elucidate its underlying mechanisms, we established an experimental autoimmune myasthenia gravis (EAMG) rat model to assess its therapeutic effects on clinical manifestations and CD4-positive helper T (CD4+ T) cell subset differentiation. Through integrated in vivo and in vitro experiments, we conducted a comprehensive evaluation of the immunoregulatory properties of LD-IL-2 in the context of EAMG pathogenesis. Our results revealed a pronounced imbalance in CD4+ T cells in EAMG model rats. Our research confirmed that LD-IL-2 might restore the Th17/regulatory T (Treg) cell and T follicular helper (Tfh)/T follicular regulatory (Tfr) cell ratios, thereby reestablishing the balance of CD4+ T cells in the EAMG model and improving the clinical severity of EAMG in rats. Moreover, we demonstrated that LD-IL-2 might exert its effects by activating the JAK1/JAK3/STAT5 signaling pathway and modulating CD4+ T cell differentiation. Collectively, our research provides compelling evidence supporting LD-IL-2 as a viable immunotherapeutic candidate for MG, laying a robust experimental foundation for future clinical applications in MG patients.
Exploratory Cohort Study of Depressive Symptoms in South Africans with HIV-1 Subtype C: Associations with Kynurenine Pathway Metabolites and Inflammatory Markers.
Williams ME, Schutte L, Asia LK … +2 more , Wissing MP, Jansen van Vuren E
J Neuroimmune Pharmacol · 2026 Jan · PMID 41575658 · Full text
Background: Depression is common in people living with HIV and may involve immune–metabolic dysregulation. Altered tryptophan (Trp) metabolism via the kynurenine (Kyn) pathway, particularly quinolinic acid (QUIN), has be...
Background: Depression is common in people living with HIV and may involve immune–metabolic dysregulation. Altered tryptophan (Trp) metabolism via the kynurenine (Kyn) pathway, particularly quinolinic acid (QUIN), has been linked to neuroinflammation and depression, yet data from South Africans with HIV-1 subtype C are limited. Methods: In this exploratory cohort, treatment-naïve adults with HIV were assessed at baseline in 2010 (n = 69) and followed up in 2015 (n = 40). Targeted LC-MS/MS quantified Trp–Kyn metabolites (Trp, Kyn, KA, QUIN) and ELISAs measured immune markers (suPAR, IL-6, hsCRP, sCD163, NGAL). Depressive symptoms were evaluated using the PHQ-9 at baseline and follow-up. Results: Baseline QUIN was associated with the PHQ-9 total score (adjusted R²=0.245; β=0.417; p = 0.004, p(Hochberg) = 0.044) and also increased odds of depression risk (OR=61.1; 95%CI 2.24–1664.76; p = 0.015, p(Hochberg) = 0.030) at baseline. Baseline NGAL was significantly lower in the follow-up group with self-harm thoughts compared to the group with no–self-harm thoughts (p = 0.008) and lower NGAL predicted greater odds of follow-up self-harm thoughts (OR = 0.007, 95% CI: <0.001–0.572, p = 0.027, p(Hochberg) = 0.027). When PHQ-9 subscales were examined, baseline QUIN, Kyn, hsCRP, and suPAR showed positive associations with the baseline somatic subscale (β range= 0.34–0.57, all p < 0.01), whereas the baseline cognitive–affective subscale was not associated with any marker. No baseline markers were associated with follow-up depression risk or scores. Over five years, suPAR decreased whereas hsCRP did not change significantly, however changes in these markers over time did not reveal any associations with the PHQ-9 total or subscale scores. Conclusions: In this exploratory cohort, higher peripheral QUIN may be linked to depression risk, particularly with somatic rather than cognitive–affective symptom dimensions. Lower baseline NGAL was the only marker associated with later self-harm thoughts, suggesting a potential neuroimmune signal that warrants further investigation. Larger, adequately powered longitudinal studies with repeated metabolomic assessments are warranted to confirm this finding and clarify temporal and causal relationships between immune–metabolic dysregulation and specific depressive symptom profiles.
Correction: PKR Inhibition Prevents Neuroinflammation and Rescues Depressive‑Like Behaviors Via BDNF/TrkB Signaling.
Hu Y, Ali T, Mou S … +6 more , Gong Q, Gao R, Luo Y, Li S, Ling L, Hao L
J Neuroimmune Pharmacol · 2026 Jan · PMID 41538106 · Publisher ↗
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Repositioning of Alogliptin to Mitigate Secondary Injury Induced by Repetitive TBI: Potential Role of its Antioxidant and Anti- Inflammatory Effects.
Raslan HA, Michel HE, Menze ET … +1 more , El-Gazar AA
J Neuroimmune Pharmacol · 2026 Jan · PMID 41528544 · Full text
Repetitive traumatic brain injury (RTBI) refers to brain injuries resulting from an external mechanical force causing cumulative and frequently severe neurological consequences. This study aimed to explore the neuroprote...
Repetitive traumatic brain injury (RTBI) refers to brain injuries resulting from an external mechanical force causing cumulative and frequently severe neurological consequences. This study aimed to explore the neuroprotective effect of alogliptin (ALO) on RTBI-provoked endoplasmic reticulum (ER) stress and investigate the potential underlying mechanisms. For RTBI induction, rats were exposed to a sharp-edged weight at the right interior frontal area of the right cortex, one drop per day for five successive days. ALO (20 mg/kg/day, p.o.) was administered for one week. Results depicted that ALO recovered motor abnormalities and enhanced motor coordination in the open field test, decreased immobility and increased climbing time in the forced swimming test, and corrected histological aberrations. Moreover, ALO counteracted RTBI-triggered ER stress via suppression of activating transcription factor 6 (ATF6), glucose-regulated protein 78 (GRP78), aggregation of β-amyloid and Tau proteins, as well as elevation of the cortical content of brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrKB). ALO also exhibited an antioxidant and anti-inflammatory potential in addition to its effect on the gene expression of miRNAs (miRNA-322 and miRNA-125b). In conclusion, ALO exhibited a neuroprotective effect by mitigating ER stress induced in an RTBI rat model.
Dexmedetomidine Mitigates Sevoflurane-Induced Neurodevelopmental Effects in Paediatric Anaesthesia: A Meta-Analysis and Preclinical Study.
Lao HC, Huang CW, Wang SH … +6 more , Su YL, Chang CH, Liao CY, Wu JC, Lin YC, Tsai JW
J Neuroimmune Pharmacol · 2026 Jan · PMID 41499049 · Full text
Sevoflurane (Sevo) anaesthesia in children is linked to an increased incidence of postoperative emergence agitation (EA) and potential neurotoxicity in developing brains. However, the specific risks of subanaesthetic foe...
Sevoflurane (Sevo) anaesthesia in children is linked to an increased incidence of postoperative emergence agitation (EA) and potential neurotoxicity in developing brains. However, the specific risks of subanaesthetic foetal or neonatal exposure to Sevo remain unclear. This study evaluates the safety and efficacy of combining dexmedetomidine (Dex) with Sevo to manage EA in paediatric anaesthesia. A systematic review and meta-analysis of randomized controlled clinical trials involving children under 8 years old revealed that Dex significantly reduces EA incidence when administered via intravenous, perineural, and intranasal routes. Using in utero electroporation, we found that pregnant mice exposed to 2.5% Sevo at embryonic days 14.5 and 15.5 exhibited transient neuronal migration deficits, with 25% of neurons delayed in deeper cortical layers. However, these neurons migrated to the cortex by postnatal day 8. Neonatal mice exposed to 2.5% Sevo experienced a 10% reduction in dendritic spine density in adolescence, associated with impaired somatosensory function, as assessed by the Von Frey test. Remarkably, Dex pretreatment ameliorated these pathological and functional changes. Thus, foetal or neonatal Sevo exposure can delay neuronal migration and reduce dendritic spine density. Dex co-administration effectively mitigates these adverse outcomes, supporting its potential use in paediatric anaesthesia to protect developing brains.
Gut Microbiome-Sphingolipid Metabolism-Brain Axis Interactions: Neuroprotective Effects of Amitriptyline as Functional Inhibitor of Acid Sphingomyelinase in a Mouse Model of Tauopathy.
Ibrahim M, Khalil AM, Attia H … +3 more , Alseekh S, Mohamed AF, El-Yamany MF
J Neuroimmune Pharmacol · 2026 Jan · PMID 41484454 · Full text
Tauopathies are neurodegenerative diseases characterized by accumulation of hyperphosphorylated tau protein (P-tau). The gut microbiota (GM) is symbiotic with the host and altered in neurodegenerative diseases. Amitripty...
Tauopathies are neurodegenerative diseases characterized by accumulation of hyperphosphorylated tau protein (P-tau). The gut microbiota (GM) is symbiotic with the host and altered in neurodegenerative diseases. Amitriptyline (AMI) is a functional inhibitor of acid sphingomyelinase (ASM) which is abnormally highly expressed in brains of Alzheimer patients. Little data is known about the role of colonic ASM in management of tauopathy. Therefore, the aim of this study was to investigate the role of AMI on reversing gut dysbiosis, ceramide levels, colonic inflammation and intestinal barrier disruption in tauopathy through the bidirectional gut-brain axis. P301S transgenic mice were administered AMI for 35 days. Colonic ASM, ceramides, inflammation and membrane integrity were assessed besides fecal microbiome analysis and serum lipopolysaccharides to assess intestinal membrane disruption. Levels of hippocampal P-tau, protein phosphatase 2 A and neurogenesis were assessed along with cognitive behavior. AMI treatment significantly reduced colonic ASM, ceramide levels, increased abundance of Harryflintia, Dubosiella, and Parasutterella and decreased abundance of Lactobacillus, Lachnoclostridium, Oscillibacter, Oscillospiracea UCG-003, Colidextribacter, Roseburia, Butyricicoccus, and Sphingomondales. In contrast, P301S mice displayed an altered GM profile with enriched Firmicutes and Clostridia, and low proportions of Bacteroidota- a phylum associated with intestinal barrier protection-, and Ruminococcaceae. Also, AMI treatment decreased inflammation and restored colonic membrane integrity with subsequent decrease in serum lipopolysaccharides, P-tau in hippocampus and improvement in cognitive behaviour and neurogenesis. The current results indicate that AMI has neuroprotective effects against tauopathy through modulation of ASM activity, associated ceramide levels, GM composition, colonic inflammation and membrane integrity through bidirectional gut-brain axis.
Prenatal Interferon-Alpha Exposure Induces Autism-Like Neurobehavioral and Neurochemical Alterations in Male Offspring.
Otkıran G, Erdoğan MA, Uyanıkgil Y … +1 more , Erbaş O
J Neuroimmune Pharmacol · 2026 Jan · PMID 41484215 · Publisher ↗
Maternal immune activation (MIA) during pregnancy has been implicated as a key environmental risk factor in autism spectrum disorder (ASD). Interferon-alpha (IFN-α), a type I interferon, may disrupt fetal neurodevelopmen...
Maternal immune activation (MIA) during pregnancy has been implicated as a key environmental risk factor in autism spectrum disorder (ASD). Interferon-alpha (IFN-α), a type I interferon, may disrupt fetal neurodevelopment, yet its mechanistic impact remains insufficiently understood. This study explores the effects of maternal IFN-α exposure on neurobehavioral and neurobiological outcomes in a Wistar rat model. Pregnant rats received IFN-α on gestational day 10, and offspring were evaluated through behavioral assays, neurochemical analyses, and histopathological assessments. IFN-α exposure resulted in significant reductions in GABA, 5-HIAA, and GAD-67 levels, particularly in male offspring, indicating neurotransmitter dysregulation. Histologically, neuronal loss was observed in the hippocampal CA1 and CA3 regions and cerebellar Purkinje cells. Astrocyte activation, reflected by increased GFAP immunoreactivity, was prominent, suggesting a neuroinflammatory response. Additionally, reduced brain-derived neurotrophic factor (BDNF) and elevated tumor necrosis factor-alpha (TNF-α) levels support the presence of inflammation-induced synaptic dysfunction and impaired neuroplasticity. Behaviorally, male offspring exhibited reduced sociability and impaired social novelty recognition. Both sexes demonstrated deficits in motor coordination and exploratory activity. These findings align with core ASD phenotypes and underscore a heightened male vulnerability. Overall, the study provides compelling evidence that prenatal IFN-α exposure leads to persistent neuroimmune, neurochemical, and structural alterations resembling ASD. The results highlight the need for further research into immune-mediated neurodevelopmental disruptions and sex-specific vulnerabilities, offering potential pathways for preventive and therapeutic interventions targeting MIA-related risk mechanisms.
Modulation of Cognitive Function by TRPM3 Channels in the Dentate Gyrus of a Menopausal Rat Model: Effects of Naringenin Treatment and Ciliary Neurotrophic Factor.
Shirasath KR, Nakhate KT, Goyal SN … +1 more , Awathale SN
J Neuroimmune Pharmacol · 2026 Jan · PMID 41483359 · Publisher ↗
Although transient receptor potential melastatin 3 (TRPM3) channels are primarily known for their role in spinal nociception, emerging evidence suggests their involvement in psychiatric conditions and central reward proc...
Although transient receptor potential melastatin 3 (TRPM3) channels are primarily known for their role in spinal nociception, emerging evidence suggests their involvement in psychiatric conditions and central reward processing. Menopause, characterized by estrogen decline, induces neuroimmune activation and increases pro-inflammatory factors such as ciliary neurotrophic factor (CNTF). While a direct regulatory effect of CNTF on TRPM3 is not well established, both are involved in inflammation-related signaling, suggesting potential crosstalk. TRPM3 responds to neuroinflammatory and neurotrophic signals and may contribute to postmenopausal cognitive decline. However, this link remains unexplored. Naringenin, a natural flavonoid with estrogen-like properties, has been reported to inhibit TRPM3 channels and may help to alleviate postmenopausal memory impairment. This study aimed to investigate the role of elevated CNTF levels in increasing TRPM3 expression in the dentate gyrus (DG), contributing to cognitive deficits, and to assess the potential of naringenin in reversing these effects. Bilateral ovariectomy (OVX) was performed on female Sprague-Dawley rats, followed by treatment with naringenin (2.5, 5 and 10 mg/kg, intraperitoneal) for 14 days. Cognitive functions were assessed using the novel object recognition and passive avoidance tests. CNTF levels in the plasma and the DG, along with TRPM3 expression in the DG, were measured using ELISA and immunohistochemistry, respectively. Dendritic arborization in DG neurons was analyzed using Golgi-Cox staining. OVX rats showed impaired cognition, elevated CNTF and TRPM3 expression, and reduced dendritic complexity. Naringenin treatment reversed these changes, suggesting its potential to improve postmenopausal cognitive decline by modulating CNTF levels and TRPM3 activity in the DG.
Telitacicept as a New Therapeutic Avenue for Generalized Myasthenia Gravis and Thymoma-Associated Myasthenia Gravis.
Zhu Y, Wang B, Hu C … +1 more , Zhu R
J Neuroimmune Pharmacol · 2026 Jan · PMID 41483096 · Publisher ↗
Generalized myasthenia gravis (gMG) is an antibody mediated autoimmune neuromuscular junction disorder characterized by muscle weakness and fatigue as well as acetylcholine receptor antibody (AChR-Ab) as the main presenc...
Generalized myasthenia gravis (gMG) is an antibody mediated autoimmune neuromuscular junction disorder characterized by muscle weakness and fatigue as well as acetylcholine receptor antibody (AChR-Ab) as the main presence. A proportion of patients fail to achieve minimal symptom expression (MSE), furthermore 10-20% of them develop into refractory under conventional immunotherapy. We conducted a retrospective study to explore the effectiveness and safety of telitacicept in gMG and thymoma-associated MG (TAMG) patients. The treatment response was assessed by the variation of QMG, MG-ADL and MG-QOL-15 scores. Time to MSE as well as usage of corticosteroid were also evaluated. In this retrospective study, we included 22 AChR-gMG patients (15 women, 7 men), including 7 refractory and 12 TAMG, who were treated with telitacicept by following-up at least 6 months. Compared to the baseline, a significant decrease in QMG, ADL and MG-QOL-15 scores was observed at every visit, especially for the QMG score with at least 3 points decline in all the patients in week 4. Twenty patients attained MSE and the time to MSE was 4 months during the observed period. At the last follow-up, the dose of prednisone of all the patients treated with telitacicept was ≤ 5 mg/d. The AChR-Ab titers and CD19 B cells significantly decreased from baseline to week 24. Telitacicept is generally well tolerated, the most common (18%) adverse effect was mild and transient injected site swelling. Our study provides evidence to support that telitacicept is beneficial and well tolerated in the management of gMG especially in refractory MG and TAMG. Clinical outcomes showed increased efficacy of telitacicept when used earlier in the disease course, which leads to a sparing of prednisone.
Histamine H3 Receptor Antagonist, Thioperamide, Improves Behavioral and Neuropathological Changes Associated with Subclinical Hypersensitivity to a Cow's Milk Allergen.
Germundson-Hermanson D, Klug MG, Nagamoto-Combs K
J Neuroimmune Pharmacol · 2025 Dec · PMID 41417415 · Full text
Mood and behavior-related comorbidities are often reported with food allergies, an atopic condition that elevates histamine (HA) levels in tissues and circulation. However, whether allergy-induced HA directly affects the...
Mood and behavior-related comorbidities are often reported with food allergies, an atopic condition that elevates histamine (HA) levels in tissues and circulation. However, whether allergy-induced HA directly affects the central nervous system is unclear. Previously, we demonstrated that the levels of HA and its receptor subtype, H3 receptor (H3R), were elevated in the brains of mice with subclinical cow's milk allergy (CMA) generated by sensitizing C57BL/6J mice to a bovine whey allergen, β-lactoglobulin (BLG, Bos d 5). Furthermore, these BLG-sensitized CMA mice showed depression-like behavior associated with mast cell activation, neuroinflammation, and cortical demyelination, leading us to postulate that peripheral immune responses raised brain HA and dysregulated the neuronal histaminergic system. Hypothesizing that the autoregulatory function of H3R signaling is pivotal in eliciting altered behavior and neuropathologies, we investigated whether thioperamide, a brain-permeable H3R-selective antagonist, would attenuate the changes observed in CMA mice. Male and female CMA mice were fed a whey-containing diet for 2 weeks without or with thioperamide. While sensorimotor functions were not impaired in CMA mice of either sex, some aspects of affective and cognitive behaviors were significantly altered in males. Male CMA mice also showed more IgE-immunopositive, degranulated mast cells in the dura mater than females, regardless of thioperamide treatment. Importantly, thioperamide reduced CMA-associated behavioral and neuropathological changes in male mice, although it also uniquely affected female mice. Our results suggest that thioperamide ameliorates CMA-associated behavioral changes and neuropathologies via H3R inhibition in a sex-dependent manner.
Ameliorative Effect of Vitamin C Against Tramadol-Induced Learning and Memory Impairment in Juvenile Rat Via Attenuation of Oxidative Stress and Dysfunctional Synaptic Plasticity.
Mohammadipoor-Ghasemabad L, Esmaeilpour K, Meymandi MS … +4 more , Iranmanesh F, Amiri Khorasani S, Sheibani V, Taheri F
J Neuroimmune Pharmacol · 2025 Dec · PMID 41385158 · Publisher ↗
Tramadol (TM) abuse negatively affects the central nervous system, especially brain regions like the hippocampus involved in cognition. Recent studies have demonstrated neuroprotective effects of Vitamin C (Vit C) in var...
Tramadol (TM) abuse negatively affects the central nervous system, especially brain regions like the hippocampus involved in cognition. Recent studies have demonstrated neuroprotective effects of Vitamin C (Vit C) in various neurological diseases. No study has yet examined the effects of Vit C on tramadol-induced synaptic plasticity impairment. Therefore, we aimed to investigate the neuroprotective effects of Vit C on cognitive performance and synaptic plasticity in tramadol-exposed rats. Fifty-two juvenile male rats (30 days old) were divided into four groups: TM (30 mg/kg/day, intraperitoneally in the first week, 40 mg/kg/day in the second week and 50 mg/kg/day in third and fourth weeks), Vit.C (200 mg/kg/day, orally for 4 weeks), TM + Vit.C (as in the TM and Vit C groups, Vit C administered half an hour prior to TM), and Ctrl (0.25 mL saline/day for 4 weeks). Behavioral tests (open field, Morris water maze, novel object recognition) assessed locomotor activity and memory. In vivo recordings evaluated synaptic plasticity, and hippocampal oxidative stress markers [malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (TAC)] were measured according to the manufacturers' protocols with ELISA. TM caused learning and memory deficits, reduced long-term potentiation (LTP) induction, and disrupted the oxidative stress balance in the hippocampus. In contrast, Vit C inhibited these changes. These findings suggest that Vit C can attenuate cognitive impairments associated with chronic TM consumption, likely through modulation of hippocampal oxidative stress and enhancement of LTP induction. Therefore, Vit C could be a promising candidate for further investigation as a potential therapeutic agent to mitigate cognitive dysfunction associated with TM use.
Fisetin Mitigates Ferroptosis and Promotes Remyelination in a Cuprizone Model of Multiple Sclerosis.
El-Ashmawy NE, Khedr NF, Helmy NN … +1 more , Ibrahim AO
J Neuroimmune Pharmacol · 2025 Dec · PMID 41361067 · Full text
Multiple sclerosis (MS) is a long-lasting autoimmune condition characterized by myelin destruction and neurodegeneration. Research indicates that ferroptosis significantly influences MS pathogenesis, exacerbating neurona...
Multiple sclerosis (MS) is a long-lasting autoimmune condition characterized by myelin destruction and neurodegeneration. Research indicates that ferroptosis significantly influences MS pathogenesis, exacerbating neuronal tissue damage. Our study intended to explore the possible neuroprotective role of fisetin (FIS) in cuprizone (CPZ) model of MS and the associated molecular mechanisms. The 9-week experiment comprised a 5-week demyelination period in which C57BL/6 mice were provided with 0.2% w/w CPZ added to rodent chow, followed by a 4-week remyelination period in which mice were fed CPZ-free chow. FIS (80 mg/kg/day) was given by oral gavage to mice daily for 4 weeks starting in the 2nd week of demyelination. For remyelination, FIS was administered daily during the 4 weeks recovery. During demyelination, FIS significantly improved CPZ-induced behavioral and locomotor deficits, as demonstrated by tail suspension test and inverted screen grip strength test. LFB and H & E staining, MBP, GFAP and vimentin immunostaining revealed that FIS treatment significantly improved myelination, alleviated astrogliosis and neuronal injury in CPZ-fed mice throughout both phases. FIS attenuated ferroptosis and neuroinflammation during de- and remyelination as supported by reduced brain iron deposits, IL-1 β, MDA concentrations and restored GPX4. Moreover, FIS significantly downregulated NCOA4 and TfR1 gene expression and TfR1 protein level but upregulated FTH1 gene expression and ferritin protein level. Additionally, FIS upregulated Olig-1 during demyelination, but not remyelination. Fisetin has a potential neuroprotective effect in CPZ model of MS and can be studied as a promising adjuvant therapy to enhance remyelination and mitigate disability in MS patients possibly by modulating ferroptosis pathway.
Bradykinin Type 2 Receptor Deficiency Reshapes Acute Neuroinflammation and Improves Cell Survival after Ischemic Stroke in Diabetic Mice.
Barić A, Smilović D, Justić H … +3 more , Šimunić I, Škokić S, Dobrivojević Radmilović M
J Neuroimmune Pharmacol · 2025 Dec · PMID 41324819 · Publisher ↗
Diabetes mellitus exacerbates cerebral ischemic damage by potentiating neuroinflammation. We hypothesized that activation of the bradykinin type 2 receptor, a mediator of inflammation and vascular dynamics, might be detr...
Diabetes mellitus exacerbates cerebral ischemic damage by potentiating neuroinflammation. We hypothesized that activation of the bradykinin type 2 receptor, a mediator of inflammation and vascular dynamics, might be detrimental to ischemic injury development in diabetic animals. We monitored the acute phase of cerebral ischemia in type 1 diabetic mice, diabetic bradykinin type 2 receptor knock-out mice, and their non-diabetic controls using neurological assessment, magnetic resonance imaging, and a comprehensive immuno-histochemical and morphological analysis to quantify changes in microglial, neutrophil, and neuronal populations. Our findings reveal that bradykinin type 2 receptor deficiency ameliorates neurological deficit in non-diabetic mice, despite similar ischemic lesion volumes across all investigated groups. Furthermore, in non-diabetic animals, the bradykinin type 2 receptor plays a discernible role in edema resolution, neuroprotection, and regulation of microglial response to ischemia. However, diabetes, as a stroke comorbidity, alters the involvement of the bradykinin type 2 receptor in ischemic injury development. Bradykinin type 2 receptor-deficient diabetic animals demonstrate delayed microglial cell loss and reduced microglial reactivity following ischemia compared to diabetic animals with functional bradykinin type 2 receptors. The attenuated immune response is accompanied by a marked absence of infiltrating neutrophils within the ischemic territory and improved neuronal survival. This study demonstrates that diabetes profoundly modifies the role of bradykinin type 2 receptor in cerebral ischemic injury, influencing both acute neuroinflammation and cell survival. These findings support the potential of the bradykinin type 2 receptor as a therapeutic target for stroke in diabetic population, warranting further investigation.
The Small Molecule Compound Eupalinolide B Alleviates Neuropathic Pain by Regulating the USP7/Keap1/Nrf2 Pathway.
Yang X, Jiang F, Li J … +2 more , Wu Y, Xiang H
J Neuroimmune Pharmacol · 2025 Nov · PMID 41288853 · Publisher ↗
Neuropathic pain is a chronic pain condition characterized by complex pathogenesis and poor prognosis. EB (Eupalinolide B), a highly bioactive sesquiterpene lactone derived from Eupatorium lindleyanum DC, has been demons...
Neuropathic pain is a chronic pain condition characterized by complex pathogenesis and poor prognosis. EB (Eupalinolide B), a highly bioactive sesquiterpene lactone derived from Eupatorium lindleyanum DC, has been demonstrated to possess multiple pharmacological activities, including antihistamine, antibacterial, and antioxidant effects. USP7 (ubiquitin-specific protease 7) is a crucial deubiquitinating enzyme in eukaryotes, while the Keap1, Nrf2, and HO-1 signaling pathways play pivotal roles in the development of neuropathic pain. Our study established a spared nerve injury model in mice and employed multiple molecular biology experiments to investigate the regulatory role of EB in the USP7/Keap1/Nrf2 pathway and its mechanisms in neuropathic pain. Results showed significantly elevated USP7 and Keap1 protein expression in the spinal cord of SNI mice, while Nrf2 and HO-1 levels were markedly reduced. EB treatment downregulated USP7 expression, promoted Keap1 ubiquitination and degradation, thereby elevating Nrf2/HO-1 protein levels. This inhibited microglial proliferation and M1 polarization, reduced the production of proinflammatory factors (TNF-α, IL-1β, IL-6), and significantly ameliorated mechanical and thermal hyperalgesia in SNI mice. Long-term intraperitoneal injection of EB did not cause any significant side effects in the heart, liver, or kidneys of SNI mice. In summary, EB exerts anti-inflammatory and analgesic effects by modulating the USP7/Keap1/Nrf2 signaling pathway, offering a potential novel therapeutic strategy for neuropathic pain.
The Ubiquitin-Proteasome System in Brain Disorders: Pathogenic Pathways, Post-Translational Tweaks, and Therapeutic Frontiers.
Gupta R, Begum MY, Kumar R … +8 more , Gupta J, Nagraik R, Panda SP, Abomughaid MM, Lakhanpal S, D A, Osmani RAM, Jha NK
J Neuroimmune Pharmacol · 2025 Nov · PMID 41264052 · Publisher ↗
Ubiquitination is a key enzymatic process where ubiquitin molecules covalently attach to substrate proteins, regulating their degradation, trafficking, and signaling. This process ensures cellular homeostasis by controll...
Ubiquitination is a key enzymatic process where ubiquitin molecules covalently attach to substrate proteins, regulating their degradation, trafficking, and signaling. This process ensures cellular homeostasis by controlling protein quality and abundance, and it plays a vital role in immunity, DNA repair, and the cell cycle. Further, ubiquitination involves a sophisticated network of enzymes, domains, and receptors, providing pathway flexibility. However, dysregulation of ubiquitination due to aberrant enzyme function is implicated in various disorders, including cancer, diabetes, stroke, and neurodegenerative diseases (NDDs). Additionally, the ubiquitin-proteasome system (UPS) not only mediates protein degradation but also influences inflammation and subcellular localization. This review explores the pivotal role of ubiquitination and deubiquitination enzymes in the onset and progression of NDDs. It highlights their involvement in protein aggregation, mitochondrial impairment, neuroinflammation, and altered synaptic function. Special focus is placed on mutations in E3 ligases (e.g., E3 ubiquitin ligase encoded by PARK2 (Parkin), C-terminus of Hsp70-interacting protein (CHIP)) and deubiquitinases (e.g., USP14, ubiquitin C-terminal hydrolases (UCHL1)), which disrupt proteostasis and lead to the accumulation of neurotoxic proteins, such as Aβ, tau, α-synuclein, and mHtt. Moreover, post-translational modifications (PTMs), including phosphorylation, acetylation, and oxidative stress, further modulate UPS activity and disease progression. Lastly, the review also evaluates emerging therapeutic strategies aimed at restoring proteostasis, including proteasome-targeting small molecules (e.g., bortezomib, IU1-47), natural compounds (e.g., curcumin, resveratrol), RNA-based therapies (e.g., miR-101, circHIPK3), and dietary approaches (e.g., Mediterranean and ketogenic diets), offering a foundation for future neurodegenerative disease treatment.
Activation of µ-δ Opioid Receptor Heteromer Attenuates Chemotherapy-Induced Neuropathic Pain in Mice.
Agrawal S, Tiwari V
J Neuroimmune Pharmacol · 2025 Nov · PMID 41240261 · Publisher ↗
Chemotherapy-induced neuropathic pain (CINP) affects up to 80% of cancer patients treated with cytostatic drugs like paclitaxel (PTX), leading to significant chronic sensorimotor dysfunction. Current pharmacological trea...
Chemotherapy-induced neuropathic pain (CINP) affects up to 80% of cancer patients treated with cytostatic drugs like paclitaxel (PTX), leading to significant chronic sensorimotor dysfunction. Current pharmacological treatments often cause CNS side effects such as sedation and addiction. Increasing evidence indicates that native µ- and δ-opioid receptors (ORs) can associate to form heteromers in discrete brain regions. However, the role of µ-δ heteromer in CINP remains unclear. Therefore, we investigated the analgesic activity of CYM51010, a µ-δ heteromer agonist in CINP and how µ-δ heteromer activation regulates neuropathic pain. Systemic CYM51010 administration significantly alleviated evoked and ongoing pain in CINP mice, without inducing drug-seeking behavior, unlike morphine, which was consistent with earlier findings observed in SNL rats. Molecular analysis revealed that CYM51010 significantly decreased the increased TRPV1 and p38α expression in the dorsal root ganglion as well as spinal tissues of CINP mice. CYM51010 also reduced the expression of NF-κB, microglial markers (ICAM-1 & IBA1), and pro-inflammatory cytokines (TNF-α, IL-1β). Findings from the current study indicate that µ-δ heteromer activation represents a promising therapeutic target for chemotherapy-induced neuropathic pain (CINP), potentially enabling effective pain relief with reduced central side effects.
Neuroprotective Effects of Glucosamine in Huntington's Disease Through NLRP3 Inflammasome Inhibition.
Chu LJ, Hsu YT, Aoh Y … +8 more , Cheng CY, Wang HH, Wu MT, Li HH, Lai XY, Hua KF, Chen CM, Ju TC
J Neuroimmune Pharmacol · 2025 Nov · PMID 41240184 · Publisher ↗
Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. It typically manifests as a triad of progressive psychiatric, cognitive, and motor sympt...
Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. It typically manifests as a triad of progressive psychiatric, cognitive, and motor symptoms. The resulting mutant HTT (mHTT) protein disrupts cellular homeostasis and promotes neuroinflammation. The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome is a key mediator of neuroinflammatory responses, activating caspase-1 and promoting the release of interleukin (IL)-1β and IL-18. In this study, we investigated the neuroprotective potential of glucosamine (GlcN) in HD. Our results demonstrate that GlcN effectively attenuates lipopolysaccharide (LPS)/ATP-induced NLRP3 inflammasome activation in BV2 microglia, leading to a significant reduction in IL-1β and IL-18 secretion. Mechanistically, GlcN suppresses microglial activation by inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway, thereby reducing nuclear factor-κB (NF-κB) activation. In the R6/2 transgenic mouse model of HD, oral administration of GlcN significantly enhanced neuronal survival, reduced mHTT aggregation, suppressed NLRP3 inflammasome activation, and attenuated astrocytic and microglial activation. Furthermore, GlcN improved motor performance and extended the lifespan of R6/2 mice. These findings suggest that GlcN confers neuroprotection in HD by attenuating neuroinflammation through inhibition of the NLRP3 inflammasome. Our study shows that GlcN is an effective treatment candidate for HD by targeting neuroinflammatory pathways, particularly through inhibition of the NLRP3 inflammasome, thereby presenting a promising strategy to slow disease progression.
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