Maternal separation (MS) correlates with adult cognitive impairment and neuroinflammation. The voltage-gated sodium channel Nav1.6 is critical in neuroinflammatory and neurodegenerative processes, but its role in MS-induced cognitive impairment is unclear. This study investigated whether hippocampal AAV-shRNA-mediated Nav1.6 reduction protects against MS-induced cognitive deficits in mice, exploring mechanisms involving hippocampal neuroinflammation, autophagy-related markers, and apoptosis-related changes. C57BL/6 mice (male/female) were subjected to daily MS (3 h/day, postnatal days 1–21). Nav1.6 was knocked down via stereotactic injection of AAV-GP-2-SCN8A-mus into the hippocampus of MS-sensitive mice (6 weeks). Cognitive function was evaluated using Morris water maze, novel object recognition, Y-maze, and open field tests. Hippocampal synaptic plasticity (LTP), protein expressions (Nav1.6, LC3B, p62, PSD95, Syn, Bax, Bcl-2), and inflammatory cytokines were analyzed via electrophysiology, Western blotting, RT-PCR, and ELISA, respectively. MS-sensitive mice exhibited significant cognitive deficits, reduced hippocampal synaptic plasticity, and increased Nav1.6 immunoreactivity in Iba1-positive cells. Hippocampal Nav1.6 reduction improved cognitive function, altered autophagy-related markers (reduced LC3B-II and elevated p62), altered apoptosis-related markers, and mitigated neuroinflammation (reduced IL-6, TNF-α, IL-1β). Hippocampal Nav1.6 reduction alleviates MS-induced cognitive impairment and is associated with modulation of autophagy- and apoptosis-related changes and neuroinflammatory responses, suggesting Nav1.6 as a potential therapeutic target for stress-related cognitive disorders.
Spinal cord injury (SCI) is a severe neurological disorder with limited therapeutic options. 6-gingerol, a major bioactive component of ginger, possesses anti-inflammatory and neuroprotective activities; however, its role in SCI remains incompletely understood. This study investigated the effects and underlying mechanisms of 6-gingerol in SCI-induced microglial pyroptosis. A rat SCI model was established and treated with 6-gingerol. Neurological function, histopathological changes, microglial activation, and pyroptosis were evaluated. An LPS/ATP-induced BV2 microglial pyroptosis model was used for in vitro mechanistic studies. Cell viability, LDH, pyroptosis-related proteins, and inflammatory cytokines were analyzed. The expression of EZH2, USP7, and FOXO3 was determined by qRT-PCR and Western blot. Chromatin immunoprecipitation was performed to evaluate EZH2 and H3K27me3 mediated regulation of the USP7 promoter, while co-immunoprecipitation and ubiquitination assays were used to examine the interaction between USP7 and FOXO3. 6-gingerol significantly improved locomotor recovery, attenuated spinal cord tissue damage, and reduced microglial pyroptosis and inflammatory response after SCI. Mechanistically, 6-gingerol suppressed EZH2 expression and reduced H3K27me3 enrichment at the USP7 promoter, thereby restoring USP7 expression. Increased USP7 enhanced FOXO3 deubiquitination and stabilization, leading to suppression of pyroptotic signaling. Furthermore, EZH2 overexpression, USP7 inhibition, or FOXO3 knockdown partially abolished the anti-pyroptotic effects of 6-gingerol in vitro, and EZH2 overexpression attenuated the neuroprotective effects of 6-gingerol in SCI rats. In conclusion, 6-gingerol treatment alleviates SCI-induced neuroinflammation and microglial pyroptosis through the EZH2/USP7/FOXO3 axis, highlighting a potential therapeutic strategy for SCI.
Glioblastoma (GB) is the most aggressive primary brain tumor, characterized by rapid progression, therapeutic resistance, and poor prognosis. Increasing evidence suggests that oxidative and nitrosative stress, together with a proinflammatory tumor microenvironment (TME), play a critical role in gliomagenesis. In this study, we analyzed a cohort of 89 Algerian patients with GB glioblastoma, to characterize systemic and intratumoral oxidative/ nitrosative status. Hydrogen peroxide, malondialdehyde, total nitrite levels, and catalase activity were quantified in serum or plasma, cystic fluid, and tumor homogenates to assess redox balance across different histological glioblastoma subtypes. In parallel, tumor expression of proinflammatory cytokines: interleukin-6 (IL-6), interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and key mediators of tumor progression: Nuclear factor kappa B p65 (NF-κB p65), inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF), was evaluated. Additionally, we investigated the interplay between redox balance and inflammatory signaling, and its potential implications for prognosis and theranostic therapeutic decision-making. Our findings demonstrated systemic and intratumoral redox imbalance in serum/ plasma compared with TME tumor microenvironment compartments, without impact from any subtypes. However, we noted pronounced intratumoral proinflammatory cytokines expression, as well as NF-κB p65, iNOS and VEGF in most cases, consistent with ongoing neuroinflammatory signaling, a highly reactive TME and more aggressive histopathological features. Combined assessment of oxidative/ nitrosative stress biomarkers and proinflammatory cytokines provides valuable insight into GB glioblastoma prognostic relevance. Targeting redox imbalance and inflammatory pathways within the GB glioblastoma TME represents a promising strategy to enhance therapeutic efficacy and improve patient outcomes.
HIV-associated neurocognitive impairment (NCI) remains prevalent among virally suppressed people living with HIV (PLWH) and approved treatments target these symptoms. Cannabidiol (CBD), a non-intoxicating cannabinoid with neuroprotective and anti-inflammatory properties, has been proposed as a potential therapeutic candidate for HIV-associated NCI, yet its cognitive effects in the context of HIV have not been experimentally tested. Female and male HIV-1 transgenic (HIV-1Tg; n = 57) and Fischer 344 (F344; n = 57) control rats were assessed using a translational cognitive battery measuring risk-based decision-making (Iowa Gambling Task; IGT), learning and cognitive flexibility (Probabilistic Reversal Learning Task; PRLT), and effortful motivation (Progressive Ratio Breakpoint Task; PRBT). Animals were tested at baseline to establish innate cognitive performance, then retested following acute and chronic (16-day) CBD administration (0, 0.3, and 3 mg/kg). HIV-1Tg rats exhibited subtle IGT deficits and persistent reversal learning deficits in the PRLT, with preserved learning and motivation, modeling key features of HIV-associated NCI. These selective impairments in cognitive flexibility persisted across testing periods, with performance in other domains largely intact. CBD produced modest, dose-specific effects on response latencies and motivation but did not affect cognitive performance. HIV-1Tg rats exhibited selective cognitive deficits similar to those seen in PLWH, supporting their utility as a preclinical model of HIV-associated NCI. Across multiple translatable cognitive domains CBD did not significantly alter cognitive performance in HIV-1Tg rats at the doses tested. Further research using broader dosing, different administration routes, and co-administration with other cannabinoids is needed to fully explore the therapeutic potential of CBD for targeting HIV-associated NCI.
CNS inflammatory demyelinating diseases (CNS-IDDs), including multiple sclerosis and related conditions, have increasingly been associated with Epstein–Barr virus (EBV). However, data on EBV genetic diversity, particularly regarding EBNA-1 gene variants, across different CNS-IDD subtypes in South Asian populations remain limited. This study examined EBV DNA prevalence and EBNA-1 sequence variation in 40 patients with CNS-IDD and 40 healthy controls from Pakistan. EBV DNA was found in 21 of 80 samples (26
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is an essential cytosolic DNA-sensing system that plays an important role in the regulation of innate immune and inflammatory responses in the central nervous system (CNS). It was first discovered as a promising antiviral defense cascade and has since been shown to execute broader functions in neuroinflammation and neurodegeneration. The pathway can become hyperactive with the release of endogenous DNA from damaged nuclei, mitochondria, or genomic instability, leading to chronic production of type I interferon (TI-IFN), various pro-inflammatory cytokines, and eventually contributing to chronic neuroinflammatory diseases. Recent studies have found that dysregulated cGAS-STING signaling is associated with several neurological disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), stroke, and age-related neurodegeneration. In the CNS, chronic activation of this pathway leads to activation of microglia, oxidative stress, breakdown of the blood-brain barrier (BBB), impaired function of the synapses, and neuronal death. Mitochondrial dysfunction and cytosolic release of mitochondrial DNA (mtDNA) further promote inflammatory signaling, thus perpetuating neurodegeneration. This review highlights the molecular and pathological mechanisms of cGAS-STING signaling in a broader aspect of neurological disorders and appraises the novel therapeutics already under development to inhibit this pathway to regulate neuroinflammation and enhance neurological outcomes.
Neuropathic pain is a chronic pain disorder refractory to conventional analgesics. Iron-dependent neuronal ferroptosis has been implicated in its pathogenesis. G protein-coupled receptor 4 (GPR4), a proton-sensing receptor, is involved in inflammation and ferroptosis, but its role in neuropathic pain and spinal neuronal ferroptosis remains unclear. Neuropathic pain was induced in rats using the spared nerve injury (SNI) model, and GPR4 expression and its effects on pain behaviors, neuronal ferroptosis, and spinal inflammation were examined. GPR4 was inhibited by a selective antagonist or small interfering RNA (siRNA), while Ras homolog family member A (RhoA) and Yes-associated protein (YAP) were activated via intrathecal injection of specific agonists. Spinal GPR4 expression was significantly upregulated and neuronal ferroptosis was induced by SNI, as evidenced by increased iron accumulation, lipid peroxidation, and dysregulated ferroptosis-related protein expression. SNI-induced mechanical allodynia, cold hyperalgesia, neuronal ferroptosis, and spinal inflammation were attenuated by GPR4 inhibition or knockdown. Mechanistically, the spinal RhoA/YAP signaling pathway was activated by SNI, and this activation was reversed by GPR4 inhibition. Furthermore, the analgesic and anti-ferroptotic effects of GPR4 inhibition were abolished by RhoA or YAP activation. It is demonstrated that GPR4 regulates neuropathic pain, neuronal ferroptosis, and spinal inflammation via the spinal RhoA/YAP signaling pathway, suggesting that GPR4 inhibition may represent a promising novel therapeutic strategy for neuropathic pain.
Alzheimer’s disease (AD) features Aβ-driven neuroinflammation and synaptic dysfunction that converge on cognitive decline, underscoring the potential value of multi-target interventions. Aurantio-obtusin (AO), a bioactive anthraquinone from Cassia obtusifolia L., exhibits reported anti-inflammatory and antioxidant activities; however, whether AO counteracts Aβ-associated behavioral impairment through coordinated modulation of inflammatory and synaptic alterations remains unclear. Here, we investigated whether AO alleviates Aβ₁₋₄₂-induced cognitive deficits and examined synapse- and inflammation-related molecular correlates. Male C57BL/6 mice received intracerebroventricular Aβ₁₋₄₂ to establish an acute AD-like model and were treated with AO (10 mg/kg/day, oral gavage) for consecutive weeks. The results showed that AO improved spatial learning and memory in the Morris water maze, recognition memory in the novel object recognition test, and working memory in the Y-maze, without affecting spontaneous locomotor activity. Furthermore, AO alleviated synaptic dysfunction by restoring synaptophysin expression and upregulating GAD65, and mitigated neuroinflammation by elevating anti-inflammatory factors (IL-4, IL-10, ARG1) and reducing TNF-α. In vitro experiments confirmed that AO was non-cytotoxic to N2AAPP cells across 0–80 μM, mildly downregulated BACE1 expression, and suppressed the Aβ-induced upregulation of pro-inflammatory mediators (IL-6, iNOS) in BV2 microglial cells. Overall, AO attenuated Aβ1-42-driven behavioral impairment in parallel with improvements in synapse-associated markers and inflammatory readouts. These findings support further evaluation of AO as a natural compound associated with modulation of Aβ-related neuroinflammatory and synapse-associated alterations.
Gradual loss of the homeostatic balance owing to deregulation of endogenous antioxidant defense pathways, such as nuclear factor erythroid 2-related factor 2 (Nrf2), contributes, at least in part, to the characteristic oxidative stress, neuronal loss, and cognitive decline associated with aging. Here, we adopted an integrated approach using behavioral, biochemical, histological, molecular, and in silico methods, exploring the neuroprotective efficacy of vitamin D against D-galactose-induced oxidative stress, neuroinflammation, and neurodegeneration. Chronic D-galactose administration (150 mg/kg, s.c) led to profound deficits in spatial learning, working memory, and recognition memory, besides increased oxidative stress, reduced antioxidant enzyme activity, suppression of Nrf2 and heme oxygenase-1 (HO-1) expression, and frank hippocampal neurodegeneration, as revealed by nissl staining. Vitamin D treatment (5 µg/kg i.p) significantly improved such deficits by restoring cognitive performance, reducing ROS and lipid peroxidation, enhancing endogenous antioxidant activities such as superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and glutathione peroxidase (GPx), and upregulating Nrf2 and HO-1 expression comparable to positive control, dimethyl fumarate (DMF). Co-administration of all-trans retinoic acid (ATRA), an antagonist for Nrf2, abrogated these protective effects, confirming the pathway specificity. Molecular docking studies have shown a strong binding affinity of Vitamin D to the regulatory domain of Nrf2, supporting a direct stabilizing interaction that may facilitate the activation of Nrf2. Nissl quantification has further demonstrated substantial preservation of neuronal integrity in hippocampal CA1, CA3, and DG regions following the treatment with vitamin D. Altogether, findings from this study show that vitamin D confers robust neuroprotection through Nrf2-dependent antioxidant mechanisms and mitigates aging-related neurodegeneration induced by D-galactose. The results highlighted vitamin D as a readily accessible therapeutic candidate for mitigating oxidative stress-driven cognitive decline.
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, Δ9-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.
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.
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 (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.
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. This review highlights the dual and context-dependent roles of NK cell subsets in multiple sclerosis (MS), illustrating how CD56bright immunoregulatory NK cells may alleviate inflammation through anti-inflammatory mediators (e.g., IL-10, TGF-β), whereas CD56dim cytotoxic NK cells can exacerbate CNS inflammation via pro-inflammatory cytokines (e.g., IFN-γ, TNF-α) and cytotoxic mechanisms such as granzyme B release, ultimately influencing CNS inflammation. It summarizes:
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.
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 (Aβ1−42) has been shown to be involved in promoting neuroinflammation during AD pathology. Hence, it is speculated that IL-17 may exacerbate Aβ1−42-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 Aβ1−42-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 Aβ1−42 in animals. Adult male BALB/c mice were exposed to intranasal Aβ1−42 (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 Aβ1−42-induced AD in a mouse model.
Approximately 45% of new HIV infections worldwide occur in women and girls and adherence to pre-exposure pro-phylaxis (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 cel-lular 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.
