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

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.

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_1-42) has been shown to be involved in promoting neuroinflammation during AD pathology. Hence, it is speculated that IL-17 may exacerbate Aβ_1-42-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_1-42-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_1-42 in animals. Adult male BALB/c mice were exposed to intranasal Aβ_1-42 (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_1-42-induced AD in a mouse model.

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.

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.

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.

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.

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.

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.

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.

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.