J Neuroimmune Pharmacol [JOURNAL]
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200 papers
Δ-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) Diminish CD16 Monocyte-Induced Astrocyte Inflammation, while THC Uniquely Inhibits Monocyte Chemotaxis Independent of HIV Status.
Sermet S, Crawford RB, Gulick P … +1 more , Kaminski NE
J Neuroimmune Pharmacol · 2026 Jul · PMID 42400870 · Publisher ↗
CD16 monocytes are a minor subset of the total monocyte population that play a disproportionate role in contributing to neuroinflammation in human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND)....
CD16 monocytes are a minor subset of the total monocyte population that play a disproportionate role in contributing to neuroinflammation in human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND). This has been evidenced by the enhanced transmigration of CD16 monocytes into the brain compared to their CD16 counterpart. CD16 monocytes can be activated by HIV ssRNAs through toll-like receptors (TLR) 7 and TLR8, and subsequently interact with brain-resident cells, including astrocytes. Previous studies from our laboratory identified monocyte-derived IL-1ß as an inducing cytokine for astrocyte-derived neuroinflammatory factors. Despite cannabis use among the HIV community, the mechanisms by which immune-modulating cannabinoids, Δ-tetrahydrocannabinol (THC) and cannabidiol (CBD), alter human immune responses in the context of HAND-associated neuroinflammation remain elusive. We hypothesized that THC and CBD suppress CD16 monocyte-induced astrocyte secretion of inflammatory mediators and monocyte recruitment via chemotaxis in the context of HIV. Results from this study show that THC and CBD impair CD16 monocyte IL-1ß-mediated astrocyte production of IL-6, IL-8, and MCP-1 when these two cell types are cocultured in the presence of TLR7 or TLR8 stimulation. Additionally, monocytes from HIV+ subjects exhibited enhanced migration compared to monocytes from HIV- subjects, which was suppressed by THC treatment but not by CBD. The effects on migration were associated with reduced cellular expression of polymerized actin and high-affinity conformation integrin receptors. Collectively, these findings suggest that THC, and to a lesser extent CBD, may have therapeutic potential for mitigating CD16 monocyte-mediated neuroinflammation associated with HAND.
Neuroimmune Correlates of HIV and Marijuana Use: Peripheral Biomarkers and Cognitive Function.
Larson ME, Romero-Sandoval EA, Towe SL … +2 more , Carrico AW, Meade CS
J Neuroimmune Pharmacol · 2026 Jun · PMID 42332257 · Full text
People with HIV (PWH) exhibit persistent immune activation despite suppressive antiretroviral therapy, contributing to neurocognitive vulnerability. Marijuana use is common among PWH and may influence inflammatory pathwa...
People with HIV (PWH) exhibit persistent immune activation despite suppressive antiretroviral therapy, contributing to neurocognitive vulnerability. Marijuana use is common among PWH and may influence inflammatory pathways, but its in vivo immunologic effects in treated HIV remain unclear. In this cross-sectional study (Durham, NC; 2021-2023), 238 adults with and without HIV were grouped by chronic marijuana use. Soluble immune biomarkers were measured in plasma/serum, and log-transformed outcomes were analyzed using hierarchical multivariable regression. Seven biomarkers showed significant model fit: sCD163, IFN-γ, TNF-α, TNF-RII, CXCL10, CCL4, and VCAM-1. Among HIV-negative participants, marijuana use was linked to reduced CXCL10, suggesting disruption of IFN-γ-dependent chemotactic signaling. In contrast, HIV infection in the absence of marijuana use was associated with a broad, multi-pathway inflammatory profile, including TNF signaling, interferon activation, monocyte/macrophage activation, and endothelial recruitment. Among PWH, marijuana use did not modulate these effects, although CCL4 and VCAM-1 were not significantly elevated in this group compared to controls. However, these markers did not differ between marijuana-using and non-using PWH, suggesting a potential divergence from the broader inflammatory profile rather than a clear marijuana-associated attenuation. Cognitive analyses demonstrated a modest inverse association between memory performance and TNF-related markers, indicating that HIV-associated inflammatory signaling may relate to memory function, whereas marijuana-related cognitive effects require further study.
Therapeutic Effects of Zhilong Huoxue Tongyu Capsule on Oxidative Stress and Neuroprotection in a Rat Model of Intracerebral Hemorrhage.
Wang L, Zhu G, Luo G … +4 more , Yang L, Ren W, Wang R, Xu H
J Neuroimmune Pharmacol · 2026 Jun · PMID 42307855 · Publisher ↗
The purpose of this study is to investigate the mechanism of Zhilong Huoxue Tongyu (ZL) capsule on the treatment of intracerebral hemorrhage (ICH). In this study, ICH model was established to assess the neuroprotective e...
The purpose of this study is to investigate the mechanism of Zhilong Huoxue Tongyu (ZL) capsule on the treatment of intracerebral hemorrhage (ICH). In this study, ICH model was established to assess the neuroprotective efficacy of ZL capsule. The ICH-induced neurological deficits were analyzed by behavioral studies including Zea-Longa score, Neurological Severity Score, Open filed test, Y-maze test, Morris water maze, Rotarod test and pathological staining such as HE staining and Nissl staining. Perls staining was used to measure iron deposition after ICH. Malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) assay kits were performed to measure the level of lipid peroxide after ICH. The levels of oxidative stress-related targets were verified by quantitative real-time PCR and western blot. This study demonstrated that ZL capsule treatment significantly reduced ICH-induced neurological deficits after ICH, improved the memory learning functions of rats and attenuated ICH‑Induced neuron damage in rats. After ICH, oxidative stress in brain tissue increased and ZL capsule could alleviate the pathological state of oxidative stress. The SOD and GSH activities were dramatically increased after the treatment of ZL capsule compared with the Ns group, while the content of MDA was markedly decreased after treatment with ZL capsule compared with Ns group. After ICH, the SLC40A1, SLC7A11, SESN2 and GPX4 mRNA in brain tissue increased, and the NOX4 and TFR1 mRNA in brain tissue decreased after the treatment of ZL capsule. Proteomics analysis also confirmed these results. Our data suggested that ZL capsule showed a neuroprotective function after ICH and alleviated ICH induced neurological deficits in rats. The possible mechanism may be that ZL capsule inhibits iron deposition and lipid peroxidation, lessening oxidative stress in brain tissue. This study offers new insights into how the ZL capsule affects ICH at the molecular level and could be conducive to developing therapeutic drugs for ICH and traditional Chinese medicine.
Neuropeptide Y as a Neuro-Immune Checkpoint in Cancer.
Eftekhari Z, Sadeghi SA, Kazemi-Lomedasht F
J Neuroimmune Pharmacol · 2026 Jun · PMID 42287338 · Publisher ↗
Neuropeptide Y (NPY) is a highly conserved 36-amino acid neuropeptide broadly distributed throughout the central and peripheral nervous systems, where it classically regulates appetite, stress responses, and circadian rh...
Neuropeptide Y (NPY) is a highly conserved 36-amino acid neuropeptide broadly distributed throughout the central and peripheral nervous systems, where it classically regulates appetite, stress responses, and circadian rhythms. Increasing evidence now positions NPY as a critical mediator at the interface of neural and immune signaling within the tumor microenvironment (TME). In cancer, NPY is released not only from tumor-innervating sympathetic fibers but also, in some contexts, directly from tumor cells, thereby establishing autocrine and paracrine signaling circuits that support tumor progression. Acting through its G protein-coupled receptors (Y1, Y2, Y4, Y5, and Y6), NPY exerts pleiotropic effects on both malignant and immune cell populations. Activation of Y1R and Y2R has been associated with enhanced tumor cell proliferation, angiogenesis, and vascular remodeling, whereas Y5R links stress-associated neuroendocrine signaling to accelerated tumor growth. Importantly, within the immune compartment, NPY promotes macrophage polarization toward an M2-like immunosuppressive phenotype, suppresses natural killer cell cytotoxicity, and dampens T cell activation, collectively fostering a tolerogenic and immune-evasive TME. These convergent neural and immunological effects highlight NPY as a dual-function neuromodulator and immunoregulator in cancer. In this review, we propose that NPY signaling represents a previously underappreciated neuro-immune checkpoint that integrates stress signals with tumor immune suppression. Targeting the NPY-receptor axis may therefore offer novel opportunities to reprogram the neuro-immune landscape of tumors and enhance the efficacy of cancer immunotherapy, particularly in stress-responsive malignancies.
Natural Killer Cells: Dual Regulators and Therapeutic Targets in Multiple Sclerosis Immunopathogenesis.
Lasemi MV, Mehravar M, Izadpanah A … +5 more , Halvachi D, Parkhideh S, Hasheminasab H, Hajifathali A, Roshandel E
J Neuroimmune Pharmacol · 2026 Jun · PMID 42268364 · Publisher ↗
Multiple sclerosis is a chronic immune-mediated disorder of the central nervous system characterized by demyelination, axonal injury, and neurodegeneration. Natural killer cells participate in MS through context-dependen...
Multiple sclerosis is a chronic immune-mediated disorder of the central nervous system characterized by demyelination, axonal injury, and neurodegeneration. Natural killer cells participate in MS through context-dependent regulatory and cytotoxic functions, yet their precise contribution to disease remains incompletely defined. This review summarizes current knowledge on NK cell development, receptor-mediated activation and inhibition, and mechanisms shaping NK cell responses in the inflamed central nervous system. We examine evidence from experimental autoimmune encephalomyelitis and clinical studies describing how distinct NK subsets may exert protective or pathogenic effects depending on disease stage and microenvironment. Emerging strategies to modulate NK cell function, including cytokine-based stimulation, metabolic and epigenetic regulation, and engineered NK platforms, are also discussed. These approaches have been primarily developed in oncology, and their relevance to MS currently remains preclinical, with only early exploratory efforts reported in autoimmune contexts. Overall, we aim to provide a clear and updated assessment of NK cell biology in MS and to outline the opportunities and limitations of NK-targeted interventions. Further mechanistic and translational studies are required before NK-focused strategies can be reliably considered for therapeutic development in MS.
Lamotrigine Ameliorates Epilepsy during Pregnancy in Rats by Inhibiting Astrocyte Activation via the NLRP3/TXNIP Pathway.
You C, Dong Y, Zhang D … +4 more , Wang T, Zhang W, Zhao X, Sun J
J Neuroimmune Pharmacol · 2026 Jun · PMID 42234255 · Publisher ↗
This study was designed to investigate the impact of Lamotrigine (LTG) on astrocyte activation in epilepsy during pregnancy and to elucidate its potential underlying mechanisms. A rat model of epilepsy during pregnancy w...
This study was designed to investigate the impact of Lamotrigine (LTG) on astrocyte activation in epilepsy during pregnancy and to elucidate its potential underlying mechanisms. A rat model of epilepsy during pregnancy was established using pentylenetetrazole (PTZ) injection. CTX-TNA2 cells were treated with IL-1β to activate astrocytes. NLRP3 expression was modulated using NLRP3 inhibitor and pcDNA 3.1-NLRP3 overexpression. Neuronal damage, apoptosis, and astrocyte activation were evaluated by HE staining, TUNEL staining, and immunofluorescence, respectively. Levels of inflammatory cytokines were determined by ELISA. Protein and mRNA expression levels associated with inflammation and astrocyte activation were analyzed by Western blot and RT-qPCR. LTG significantly reduced the expression of NLRP3, TXNIP, and suppressed inflammatory responses. In vivo, LTG attenuated neuronal damage and apoptosis in the cerebral cortex and hippocampal CA1 region, accompanied by decreased levels of TNF-α, IL-1β, and IL-6, as well as reduced expression of GFAP, GLAST, and phosphorylated p65. Co-treatment with the NLRP3 inhibitor MCC950 further enhanced these effects. In vitro, LTG inhibited astrocyte proliferation and activation, whereas NLRP3 overexpression partially reversed these effects. LTG alleviates astrocyte activation and neuroinflammation in pregnancy-associated epilepsy, potentially through modulation of the NLRP3/TXNIP axis. These findings provide novel insights into the pathogenesis of epilepsy during pregnancy and suggest potential therapeutic strategies.
Neuroimmunomodulation of AMPA Receptors Through Combination of Medium-Chain Triglycerides and Perampanel to Treat Status Epilepticus in Anti-NMDA Receptor Encephalitis.
Stadler LM, Schappe L, Lochner P … +5 more , Bonifer L, Fousse M, Meuth SG, Groppa S, Winter Y
J Neuroimmune Pharmacol · 2026 May · PMID 42154348 · Full text
Recent studies have shown that a ketogenic diet containing medium-chain triglycerides (MCTs) has a synergistic effect with perampanel in modulating AMPA receptors. Both MCTs and perampanel have immunomodulatory propertie...
Recent studies have shown that a ketogenic diet containing medium-chain triglycerides (MCTs) has a synergistic effect with perampanel in modulating AMPA receptors. Both MCTs and perampanel have immunomodulatory properties. However, the use of the combination of MCTs and perampanel to treat status epilepticus caused by autoimmune encephalitis has never been investigated. After multiple antiseizure (benzodiazepines, levetiracetam, brivaracetam, lacosamide, ketamine, propofol, and isoflurane) and immunomodulatory treatments (glucocorticoid pulse (days 4-8), intravenous immunoglobulin (days 10-12), plasmapheresis (days 13-19), rituximab (days 22 and 34), cyclophosphamide (day 38)), failed to interrupt status epilepticus in a 33-year-old woman caused by paraneoplastic anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, we initiated perampanel treatment (12 mg/day), which significantly reduced ictal activity in the EEG. Status epilepticus was finally terminated when MCTs were added to the perampanel treatment regimen. Our clinical data may support previous in vitro studies demonstrating that combining perampanel with MCTs improves the neuroimmunomodulatory effect on AMPA receptors. MCTs may have a synergistic effect when added to perampanel to treat autoimmune status epilepticus. The possible cumulative effects of combination with other immune therapies in our case cannot be completely excluded.
Chrysin Ameliorated Neurochemical and Behavioural Changes Mediated By Combined Exposure of Interleukin-17 A With Amyloid Beta in Mice.
Gautam AS, Singh RK
J Neuroimmune Pharmacol · 2026 May · PMID 42149389 · Publisher ↗
Neuroinflammation is one of the major hallmarks of neurodegenerative diseases, including Alzheimer's disease (AD). Interleukin-17 (IL-17) cytokine and its downstream signaling have been shown to be implicated in preclini...
Neuroinflammation is one of the major hallmarks of neurodegenerative diseases, including Alzheimer's disease (AD). Interleukin-17 (IL-17) cytokine and its downstream signaling have been shown to be implicated in preclinical and clinical models of AD. Moreover, the combination of recombinant IL-17 A with amyloid beta (Aβ) has been shown to be involved in promoting neuroinflammation during AD pathology. Hence, it is speculated that IL-17 may exacerbate Aβ-induced neuronal damage and inflammatory events in the brain. Although natural flavonoids have been reported to protect against neuroinflammation in AD, their role in IL-17 exacerbated Aβ-induced responses has not been reported previously. The current research explored the ability of Chrysin in regulating the exacerbation of neuronal damage and inflammation during AD pathology induced due to the combination of recombinant mouse IL-17 A (rmIL-17 A) with Aβ in animals. Adult male BALB/c mice were exposed to intranasal Aβ (5 µg/10µL in phosphate-buffered saline (PBS)/animal) and rmIL-17 (4 µg/kg in 10 µL PBS/animal) from day 1 to day 14 on alternate days with therapeutic oral administration of Chrysin suspension (100 mg/kg) during the last 7 days. Oral treatment with Chrysin demonstrated significant protective effects in improving the memory functions of the animals, along with the modulation of neurodegenerative and neuroinflammatory signalling, microglial and astrocytic activation, and redox balance in the hippocampus and cortex areas of the animal brain tissues. These results supported the neuroprotective ability of Chrysin against the exacerbation caused by rmIL-17 A in Aβ-induced AD in a mouse model.
CA Inhibitor 1 Treatment Does Not Affect Estrous Cyclicity in Mice.
Giacometti LL, Dalere DM, Lwamba B … +3 more , Goldberg SL, Feliciano K, Barker JM
J Neuroimmune Pharmacol · 2026 May · PMID 42105019 · Full text
Approximately 45% of new HIV infections worldwide occur in women and girls and adherence to pre-exposure prophylaxis (PrEP) to prevent HIV infection is limited, particularly in women. Long-acting PrEP such as lenacapavir...
Approximately 45% of new HIV infections worldwide occur in women and girls and adherence to pre-exposure prophylaxis (PrEP) to prevent HIV infection is limited, particularly in women. Long-acting PrEP such as lenacapavir may improve adherence. One barrier to PrEP usage in women and girls is impact on the menstrual cycle, though impacts of long-acting PrEP are unclear. To model the effect of lenacapavir administration on cyclicity, adult female C57Bl/6J mice were injected with capsid (CA) inhibitor, an analog of lenacapavir, 1 and assessed for estrous cyclicity. Injection of either CA inhibitor 1 did not impact estrous cycle. CA inhibitor 1 did not impact astrocyte immunoreactivity or chronic cellular activity in the medial preoptic area (mPOA), a major regulator of the estrous cycle. These findings warrant further investigation into the effects of lenacapavir on menstrual cycle as it may promote PrEP adherence for those concerned with PrEP impacts on menstrual cycle.
Protective Effects of Pomiferin on Aluminum Chloride-induced Memory Impairment: Evidence from Behavioral, Biochemical, and Insilico Studies.
Alqasem AA, Binshaya AS, Abalkhail A
J Neuroimmune Pharmacol · 2026 May · PMID 42062632 · Publisher ↗
This investigation aims to assess the neuroprotective effect of pomiferin against aluminum chloride (AlCl₃)-induced memory dysfunction in rats. Wistar rats (180 ± 20 g; 10–12 weeks old) were randomly divided into four gr...
This investigation aims to assess the neuroprotective effect of pomiferin against aluminum chloride (AlCl₃)-induced memory dysfunction in rats. Wistar rats (180 ± 20 g; 10–12 weeks old) were randomly divided into four groups (n = 8) and treated over 47 days. Group I received normal saline (control), and Group II was administered AlCl₃ (100 mg/kg, p.o.) to induce neurotoxicity. In comparison, Groups III and IV received pomiferin (10 and 20 mg/kg, p.o., respectively) once daily for 42 consecutive days, administered orally 1 h prior to AlCl₃ during the morning session to ensure optimal absorption and assess its preventive neuroprotective potential. To assess spatial and working memory performance, behavioral evaluations were conducted using the Morris Water Maze on day 42 and the Y-maze test on day 47 of the experimental period. Subsequently, biochemical analyses were performed to measure acetylcholinesterase (AChE), choline acetyltransferase (ChAT), acetylcholine (ACh), γ-aminobutyric acid (GABA), glutamate, glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), brain-derived neurotrophic factor (BDNF), caspase-3, cAMP response element-binding protein (CREB), peroxisome proliferator-activated receptor gamma (PPAR-γ), and p38 mitogen-activated protein kinase (p38 MAPK) levels. Additionally, histopathological analyses, molecular docking, and molecular dynamics simulations (MDS) were carried out. AlCl₃ induced substantial alterations in biochemical, neuroinflammatory, and neuronal enzymatic parameters, as well as in brain histology. However, these changes were ameliorated by pomiferin, accompanied by the regulation of apoptotic markers. Furthermore, pomiferin significantly improved working and spatial memory in behavioral paradigms. Furthermore, pomiferin demonstrated favorable binding affinities to target proteins, including TNF-α (-8.831 kcal/mol), CREB (-8.101 kcal/mol), caspase-3 (-7.624 kcal/mol), and BDNF (-7.080 kcal/mol). Additionally, MDS demonstrated significant conformational changes induced by pomiferin, resulting in a more favorable binding affinity to TNF-α and CREB. In conclusion, pomiferin exhibits promising neuroprotective potential in experimental models of neurodegeneration induced by AlCl₃.
Targeting Neuroinflammation in the Piriform Cortex-Amygdala: Enhanced Efficacy of Niosome-Based Sodium Butyrate in Ischemic Stroke.
Naseri N, Bigdeli MR, Moghadam FM … +1 more , Kazemi B
J Neuroimmune Pharmacol · 2026 Apr · PMID 42012556 · Publisher ↗
Ischemic stroke induces extensive neuronal damage in multiple brain regions, including the piriform cortex-amygdala (PCA), critical for olfaction and emotional regulation. The present study evaluated the efficacy of sodi...
Ischemic stroke induces extensive neuronal damage in multiple brain regions, including the piriform cortex-amygdala (PCA), critical for olfaction and emotional regulation. The present study evaluated the efficacy of sodium butyrate (SB) as a neuroprotective agent against the stroke-induced damage in the PCA. SB possesses poor pharmacokinetic properties. Therefore, to overcome this obstacle, the niosome nanoparticles, containing SB, were formulated and analyzed for physicochemical features. A particle size of 85.82 nm, polydispersity index (PDI) of 0.277, zeta potential of -39.8 mV, and a controlled release pattern were determined for nio-SB. To evaluate the treatment efficacy of SB and nio-SB on PCA, male Wistar rats were assigned to four groups of sham, MCAO, SB, and nio-SB. Ischemia was induced by middle cerebral artery occlusion (MCAO). Following 24 h reperfusion, neurological deficiencies, infarct volume, blood-brain barrier (BBB) permeability, histopathological status, biochemical parameters, and relative mRNA expression of proinflammatory and the BBB tight junction proteins were assessed. SB and nio-SB improved the neurological deficiency score, stroke volume, BBB leakage, and neuronal death in the PCA. However, the effects of nio-SB were significantly more pronounced. Nio-SB also increased the superoxide dismutase and glutathione peroxidase activity, and decreased malondialdehyde levels. Furthermore, nio-SB declined the mRNA expression of interleukin-1β and tumor necrosis factor-α in the PCA and preserved the BBB integrity by attenuating matrix metalloproteinase-9 and upregulating claudin-5 and zonula occludens-1 mRNA levels. In conclusion, the study underscores the SB efficacy in alleviating the stroke-derived injuries in the PCA, and the niosome nanoparticles probably improve its effectiveness.
Naringin Reverses Chronic Stress-Induced Cognitive Deficits and Enhances Hippocampal Neuroplasticity in Mice.
Ojiakor VO, Ben-Azu B, Ani PN … +5 more , Ozioko MO, Oviosun A, Ozor II, Esom EA, Anyanwu EG
J Neuroimmune Pharmacol · 2026 Apr · PMID 41973325 · Publisher ↗
Chronic stress, such as chronic unpredictable mild stress (CUMS), induces hippocampal oxidative stress, inflammation, and neurochemical imbalances, resulting in cognitive and synaptic deficits. However, the role of narin...
Chronic stress, such as chronic unpredictable mild stress (CUMS), induces hippocampal oxidative stress, inflammation, and neurochemical imbalances, resulting in cognitive and synaptic deficits. However, the role of naringin, a citrus bioflavonoid with antioxidant and neurotrophic properties in reversing hippocampal oxidative–inflammatory effects in CUMS remains largely unexplored. This study uniquely elucidates the neurocognitive and synaptic mechanisms through which naringin restores hippocampal integrity, emphasizing its dual antioxidant and neurogenic actions against CUMS-induced cognitive dysfunction. Adult male mice were divided into six groups (n = 9/group): control, CUMS, naringin (2.5, 5, 10 mg/kg), and fluoxetine (10 mg/kg). All mice except the control group were exposed to CUMS daily for 21 days. After 21 days of treatment post-CUMS exposure, behavioral assessments, biochemical assays, immunohistochemical assay for neuroplasticity-related proteins, and histological analyses were conducted. Naringin significantly improved memory performance in the Y-Maze and NORT, as evidenced by increased % alternation and discrimination index. Naringin significantly reduced nitrite and acetylcholinesterase enzyme activity while attenuating the depletion of reduced glutathione, superoxide dismutase and catalase activities in the brains of CUMS mice. CUMS exposure increased proinflammatory cytokines (TNF-α and IL1-β), which were attenuated by naringin. Likewise, hippocampal neurotransmitters, including serotonin, dopamine and noradrenaline, were restored by naringin relative to CUMS group. Naringin upregulated neurotrophic (BDNF), neuronal (NeuN), and proliferative (Ki-67) markers while suppressing astroglia activation (GFAP), indicating enhanced neuronal survival, synaptic remodeling, and hippocampal neurogenesis that collectively supported behavioral recovery. In conclusion, naringin ameliorates CUMS-induced cognitive impairment through inhibition of oxidative stress, inflammation, neurotransmitter imbalance, and enhancing hippocampal neurogenesis.
Comparative Effectiveness of Rituximab in Treatment-Naïve vs. Switch Patients with Multiple Sclerosis: A Real-World Retrospective Study.
Elshony H, Almuhanna R, Al-Ghamdi A … +6 more , Almatrafi MK, Ashshi MA, Almatani MU, Al-Ghamdi T, Tawakul A, Muddassir R
J Neuroimmune Pharmacol · 2026 Apr · PMID 41973316 · Publisher ↗
BACKGROUND: Rituximab, an anti-CD20 monoclonal antibody, is increasingly used off-label for multiple sclerosis (MS), particularly in regions where access to approved B-cell–depleting therapies is limited. This study eval...
BACKGROUND: Rituximab, an anti-CD20 monoclonal antibody, is increasingly used off-label for multiple sclerosis (MS), particularly in regions where access to approved B-cell–depleting therapies is limited. This study evaluated the real-world effectiveness and safety of rituximab in treatment-naïve and switch patients at a single center in Saudi Arabia. METHODS: In this retrospective cohort study, 102 patients with MS treated with rituximab between January 2018 and October 2025 were analyzed. Patients were categorized as treatment-naïve (n = 48) or switch (n = 54). The primary endpoint was No Evidence of Disease Activity (NEDA-3) at 12 months. Secondary outcomes included annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS), MRI activity, and safety. Multivariable logistic regression was used to identify predictors of NEDA-3, with findings interpreted as exploratory due to the absence of correction for multiple comparisons. RESULTS: Rituximab was associated with substantial reductions in relapse activity and absence of new MRI lesions. NEDA-3 was achieved in 93.8% of treatment-naïve and 83.3% of switch patients (p = 0.60). After adjustment for age, sex, disease duration, baseline ARR, and EDSS, the difference between groups was not statistically significant (adjusted OR = 1.52; 95% CI: 0.54–4.32; p = 0.43). ARR declined significantly in both groups (p < 0.001), with all treatment-naïve patients remaining relapse-free. No new or enlarging T2 or gadolinium-enhancing lesions were observed on 12-month follow-up MRI. EDSS remained stable. Rituximab was generally well tolerated: mild infusion reactions occurred in 3 patients (2.9%), and 3 mild infections were documented (all in the switch group). However, serum immunoglobulins were not routinely monitored, limiting assessment of infection risk related to humoral immunosuppression. Lower baseline ARR independently predicted NEDA-3 achievement (adjusted OR = 0.58 per additional relapse; 95% CI: 0.36–0.91; p = 0.02). CONCLUSION: In this single-center Saudi cohort, rituximab was associated with high short-term NEDA-3 rates and acceptable tolerability in both treatment-naïve and switch patients. A baseline ARR > 2.5 relapses/year may identify individuals at higher risk of treatment non-response. Given the retrospective design, single-center setting, short follow-up (median 14 months), and lack of immunoglobulin monitoring, findings should be interpreted cautiously. Prospective multicenter studies with standardized immune monitoring and longer follow-up are needed to confirm long-term safety and effectiveness. REGISTRATION: The study was approved by the Institutional Review Board of Security Forces Hospital, Makkah (IRB #0749-081024; HAP-02-K-052), with waiver of informed consent.
Ganoderic Acid a Promotes Functional Recovery After Traumatic Brain Injury By Protecting Blood-brain Barrier Integrity and Modulating Microglial Polarization.
Wu J, Tang Y, Wang Y … +8 more , Liu B, Xu M, Tan Y, Cai D, Chen Y, Zeng J, Liu K, Liu Y
J Neuroimmune Pharmacol · 2026 Apr · PMID 41973273 · Publisher ↗
Traumatic brain injury (TBI) induces complex secondary damage, including blood-brain barrier (BBB) disruption, neuroinflammation, and synaptic dysfunction. However, TBI currently lacks effective treatments. This study in...
Traumatic brain injury (TBI) induces complex secondary damage, including blood-brain barrier (BBB) disruption, neuroinflammation, and synaptic dysfunction. However, TBI currently lacks effective treatments. This study investigated the neuroprotective effects and mechanisms of Ganoderic acid A (GAA), a triterpenoid from Ganoderma lucidum, in TBI mice and H₂O₂-induced BV-2 microglial cells. Results demonstrated that GAA treatment significantly preserved BBB integrity by reducing Evans blue extravasation, brain edema, and MMP-9 expression, while up-regulating tight junction proteins (ZO-1, Occludin, Claudin-5). GAA attenuated neuroinflammation by inhibiting microglial/astrocytic activation, promoting a shift from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype, and modulating cytokine levels. Furthermore, GAA enhanced synaptic plasticity, increased dendritic spine density, up-regulated PSD95 and SYN expression, and reduced neuronal loss. In vitro, GAA mitigated oxidative stress and inflammation in BV-2 cells. Consequently, GAA improved functional recovery, alleviating anxiety-like behavior and spatial memory deficits in TBI mice. These findings demonstrate that GAA is a multi-target therapeutic candidate for TBI, acting via mechanisms of BBB protection, anti-inflammation, antioxidant activity, and synaptic restoration.
Rethinking MS Therapeutics: From Disease Pathogenesis Mechanisms to AI-Driven Drug Discovery.
Ziaei M, Sehhati M, Torabi M … +2 more , Esmaeil N, Ghasemi F
J Neuroimmune Pharmacol · 2026 Apr · PMID 41973156 · Publisher ↗
Multiple sclerosis (MS) is a chronic autoimmune disorder of the CNS, characterized by inflammation, demyelination, and progressive neurodegeneration. Disease progression involves four key interconnected stages: the activ...
Multiple sclerosis (MS) is a chronic autoimmune disorder of the CNS, characterized by inflammation, demyelination, and progressive neurodegeneration. Disease progression involves four key interconnected stages: the activation of immune cells in peripheral lymph regions, the migration of autoreactive cells across the blood-brain barrier, demyelination, and an often incomplete remyelination response. Despite such significant therapeutic advances, major challenges remain in early diagnosis, patient stratification, and personalized intervention. Artificial intelligence has emerged as a powerful tool to address these challenges by integrating complex, multimodal data sets and uncovering patterns. This review provided a comprehensive overview of MS pathogenesis and evaluated current and emerging therapeutic strategies. Recent advances in applying AI-driven approaches to MS diagnosis, including MRI-based lesion detection, disease-activity prediction, and support for individualized prognosis, were also investigated. Additionally, generative and predictive computational frameworks that enable rapid drug development, repositioning, therapeutic target identification, and the rational design of new molecules with optimized safety and efficacy profiles in MS were reviewed. Finally, current limitations, ethical considerations, and barriers to clinical translation are discussed, emphasizing the need for high-quality datasets, standardized evaluation, and robust validation strategies. Synthesizing the emerging evidence, the current review highlights how AI-enabled methodologies are reshaping MS research, connecting molecular insights with clinical decision-making and opening new perspectives for more accurate diagnosis, deeper mechanistic understanding, and personalized therapeutic development.
Modulation of the AMPK/TFEB Axis by Ezetimibe Attenuates Neuroinflammatory, Oxidative Stress, and Neurotransmitter Dysregulation in Naloxone-precipitated Tramadol Withdrawal in Mice.
Aditi, Wani SN, Akanksha … +5 more , Kumar A, Singh V, Singh TG, Grewal AK, Silakari P
J Neuroimmune Pharmacol · 2026 Apr · PMID 41944914 · Publisher ↗
Tramadol withdrawal is associated with neuroinflammation, oxidative stress, and neurotransmitter imbalance, yet effective therapeutic strategies remain limited. Activation of the AMPK–TFEB (AMP-activated protein kinase-t...
Tramadol withdrawal is associated with neuroinflammation, oxidative stress, and neurotransmitter imbalance, yet effective therapeutic strategies remain limited. Activation of the AMPK–TFEB (AMP-activated protein kinase-transcription factor EB) signaling axis enhances autophagy and cellular homeostasis and may mitigate withdrawal-associated neurotoxicity. To investigate whether ezetimibe attenuates naloxone-precipitated tramadol withdrawal in mice through modulation of the AMPK/TFEB pathway. Swiss albino mice received chronic tramadol exposure followed by naloxone to induce withdrawal. Ezetimibe (5 and 10 mg/kg, p.o.) was administered with or without the TFEB inhibitor eltrombopag. Behavioral outcomes (withdrawal severity score, jumping frequency, hyperalgesia), oxidative stress and inflammatory markers, neurotransmitter levels, and molecular docking interactions with TFEB were evaluated. Ezetimibe significantly reduced withdrawal severity, jumping frequency, hyperalgesia, lipid peroxidation, glutamate levels, and pro-inflammatory cytokines, while restoring antioxidant status, dopamine, and serotonin. Co-administration of eltrombopag attenuated these effects. Docking analysis revealed a stable interaction between ezetimibe and TFEB. Ezetimibe ameliorates tramadol-withdrawal-induced neurobehavioral and molecular alterations, most likely via AMPK-mediated activation of TFEB and enhancement of autophagy, highlighting its therapeutic potential in opioid withdrawal.
Efficacy and Safety of Adjunctive Minocycline in the Treatment of Autoimmune Encephalitis (MEET): A Proof of Concept Study.
Zhang Y, Zhao J, Fan Z … +7 more , Wang X, Shi X, Wang X, Wan T, Du F, Wu K, Jiang W
J Neuroimmune Pharmacol · 2026 Mar · PMID 41902986 · Publisher ↗
BACKGROUND: This study aims to determine whether 4 weeks of adjunctive minocycline can improve cognitive and neurological symptoms in patients with autoimmune encephalitis (AE). METHODS: In this randomized, open-label, b...
BACKGROUND: This study aims to determine whether 4 weeks of adjunctive minocycline can improve cognitive and neurological symptoms in patients with autoimmune encephalitis (AE). METHODS: In this randomized, open-label, blinded-endpoint trial, participants were randomized (1:1) to receive first-line immunotherapy with or without minocycline (100 mg twice daily for 4 weeks). Clinical outcomes included changes in the Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Hamilton Anxiety Rating Scale (HAMA), Hamilton Depression Rating Scale (HAMD), modified Rankin Scale (mRS), and Clinical Assessment Scale in Autoimmune Encephalitis (CASE). The exploratory outcome was the change in Soluble Triggering Receptor Expressed on Myeloid cells 2 (sTREM2), a biomarker of microglial activation. Follow-up assessments were conducted at weeks 4, 12, 24, and 48. RESULTS: Sixty patients with AE were enrolled. For the primary outcome, the difference in mean change in MoCA scores between the groups was 1.05 (P = 0.46) from baseline to week 12. However, at week 4, the minocycline group demonstrated significantly improvements in MoCA (difference, 3.85; 95% CI, 1.04 to 6.66; P = 0.008) and MMSE (difference, 3.23; 95% CI, 0.20 to 6.26; P = 0.037) compared to the control group. CSF sTREM2 levels decreased in the minocycline group (difference, –93.3; 95% CI, –186.60 to –0.05; P = 0.050). No other secondary outcomes differed between groups. Adverse events were mild, and no allergic reactions were reported. CONCLUSIONS: Adjunctive minocycline for 4 weeks showed a significant improvement in cognitive performance. However, no sustained benefits were observed beyond the treatment period. CLINICAL TRIALS REGISTRATION: NCT06033846.
5,7,4'-Trimethoxyflavone Attenuates Cognitive Impairment in Diabetic Mice via Inhibition of NLRP3 Inflammasome Activation.
ALNasser MN, Rajendran P
J Neuroimmune Pharmacol · 2026 Mar · PMID 41886133 · Publisher ↗
Diabetic encephalopathy is a severe consequence of diabetes mellitus characterised by cognitive deterioration. Neuroinflammation is pivotal in the pathophysiology of this illness. This study examined the efficacy of 5,7,...
Diabetic encephalopathy is a severe consequence of diabetes mellitus characterised by cognitive deterioration. Neuroinflammation is pivotal in the pathophysiology of this illness. This study examined the efficacy of 5,7,4′-trimethoxyflavone (TMF) in modulating neuroinflammation to mitigate cognitive deficits in streptozotocin (STZ)-induced diabetic mice. Diabetes was induced in male mice through STZ administration before treatment with TMF. Cognitive function was evaluated using the Morris water maze and Y-maze tests. Brain tissue was examined for indicators of oxidative stress, including superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA). The expression levels of critical neuroinflammatory components – including the NLR family pyrin domain containing 3 (NLRP3) inflammasome and its apoptosis-associated Speck-like protein containing a CARD (ASC) – together with the downstream cytokines interleukin-1 beta (IL-1β) and interleukin-18 (IL-18), were assessed. In addition, the concentrations of brain-derived neurotrophic factor (BDNF), cleaved caspase-1, glial fibrillary acidic protein (GFAP), and neuron-specific nuclear protein (NeuN) were measured. TMF treatment markedly boosted cognitive function in diabetic mice, as reflected by improved spatial learning and memory in the Morris water maze and superior working memory performance in the Y-maze. Moreover, TMF treatment diminished oxidative stress, as evidenced by elevated SOD and CAT activity and decreased MDA levels. TMF markedly inhibited the activation of the NLRP3 inflammasome by diminishing the expression of NLRP3 and ASC, thereby reducing the levels of IL-1β and IL-18. Furthermore, TMF therapy elevated BDNF levels and decreased cleaved caspase-1 expression, indicating neuroprotective properties. Immunohistochemistry demonstrated that TMF reduced GFAP expression and elevated NeuN expression in the hippocampus. The results collectively indicate that TMF provides neuroprotection and mitigates cognitive deficits in STZ-induced diabetic mice, effectively suppressing neuroinflammation and oxidative stress pathways in a dose-dependent manner. Consequently, TMF holds potential as a treatment for diabetic encephalopathy.
Molecular Mechanisms of Mangiferin on Neuroinflammation for Treating Major Depressive Disorder Based on Network Pharmacology and Bioinformatics Analysis.
Chen CY, Lei L, Yang X … +2 more , Wang YF, Zhang Y
J Neuroimmune Pharmacol · 2026 Mar · PMID 41831105 · Publisher ↗
Major depressive disorder (MDD) is a heterogeneous disease with complex etiology, accompanied by high morbidity and disability. Recently, neuroinflammation has been identified as a crucial mechanism in major depressive d...
Major depressive disorder (MDD) is a heterogeneous disease with complex etiology, accompanied by high morbidity and disability. Recently, neuroinflammation has been identified as a crucial mechanism in major depressive disorder. Mangiferin (MGF) is a natural flavonoid polyphenolic compound primarily extracted from Anemarrhenae Rhizome or mango that exhibits promising anti-inflammatory activity in the preclinical treatment of MDD. The present research used network pharmacology and bioinformatics to identify 3 core targets (ICAM1, MAPK3, and MMP9) associated with MGF for treating neuroinflammation in MDD. We have identified MDD as being closely associated with immunity and neuroinflammation, with core targets primarily related to calcium and the NOD-like receptor signaling pathway, among others. Based on molecular docking studies, MGF has good binding activity with MAPK and MMP9. This research suggests that MGF has the potential to treat neuroinflammation in MDD, providing a basis for further exploration of its clinical application in treating neuroinflammation associated with MDD.
Formyl Peptide Receptor-2-Suppressed Autophagy Promotes the Migration and Invasion of Human Glioblastoma Cells Through PI3K/Akt Signaling.
Luo Z, Kong D, Qi G … +3 more , Zheng C, Zhao W, Lu Z
J Neuroimmune Pharmacol · 2026 Mar · PMID 41801563 · Full text
Formyl peptide receptor-2 (FPR2) belongs to the G protein-coupled receptor (GPCR) family and plays a critical role in the development of various tumors. However, the roles and mechanisms of FPR2 in glioblastoma (GBM) rem...
Formyl peptide receptor-2 (FPR2) belongs to the G protein-coupled receptor (GPCR) family and plays a critical role in the development of various tumors. However, the roles and mechanisms of FPR2 in glioblastoma (GBM) remain poorly understood. In this study, we observed significant upregulation of FPR2 in glioma cell lines and tissues, and elevated FPR2 expression levels are correlated with poor patient survival. Furthermore, we found that FPR2 suppresses the autophagy mediated by BECN1 and ATG5 in GBM cells. Using Western blot analysis, we revealed that FPR2 regulates GBM cell invasion via the PI3K/AKT signaling pathway. Additionally, we demonstrated that knocking down FPR2 expression in GBM cells reduced tumor cell migration and invasion in vitro and tumor growth in vivo. The inhibition of FPR2 led to cell cycle arrest at the G2/M phase and increased apoptosis. Finally, our findings indicate that FPR2 may prevent autophagy-induced epithelial‒mesenchymal transition (EMT)-like changes by preventing autophagy-induced degradation of Snail. Our findings suggest that FPR2 promotes GBM cell migration and invasion through the inhibition of autophagy and the activation of the PI3K/AKT signaling pathway, highlighting the potential of inducing autophagy as a therapeutic approach to inhibit invasion in GBM with high FPR2 expression.
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