Chronic neuroinflammation and impaired proteostasis are increasingly recognized as interconnected drivers of Parkinson's disease (PD). Due to their pleiotropic character, multicomponent herbal remedies combining anti-inflammatory and proteostatic activity may counteract these disease-promoting processes. This study investigated a hydroethanolic extract of Filipendula ulmaria (FE) for its ability to modulate neuroinflammation, proteostasis, and aging-associated mechanisms relevant to PD. The effects of FE on lifespan and health span were assessed in wild-type and on α-syn::YFP fluorescence, survival and thermoresistance in transgenic NL5901 Caenorhabditis elegans. FE was fractionated by flash chromatography, and bioactivity was assigned to individual constituents using LC-MS dereplication and a 1H NMR-based biochemometric approach. Identified constituents were further examined for their capacity to reduce α-syn::YFP fluorescence and enhance thermotolerance in NL5901. To assess their relevance in neuroinflammation, all samples were examined in LPS-stimulated human microglial HMC3 cells for their effects on pro-inflammatory gene expression. FE extended lifespan, improved health span and reduced α-syn::YFP fluorescence in NL5901 by up to 25% at 200μg/mL. In HMC3 cells, FE significantly downregulated IL-1β, IL-6, and MCP-1 expression at 100μg/mL without cytotoxicity. Biochemometric and LC-MS analyses identified the flavonoid glycosides spiraeoside and miquelianin as key constituents, reducing the α-syn::YFP fluorescence by 32% and 35% at 200 μg/mL, respectively, while simultaneously increasing thermotolerance in NL5901 and suppressing pro-inflammatory cytokine expression in microglia. FE represents a promising source of neuroprotective agents targeting both neuroinflammation and proteostasis, supporting spiraeoside and miquelianin as hit candidates for preventive strategies against early neurodegenerative mechanisms.

Chemotherapy is a crucial part of cancer treatment, but it has been linked to a set of cognitive impairments. 5-Fluorouracil, a chemotherapeutic drug causing mitochondrial dysfunction and neurodegeneration. This study primarily aimed to evaluate the effect of Plumbagin on mitochondrial dynamics, neuroinflammation and oxidative stress in adult zebrafish subjected to 5-Fluorouracil-induced cognitive impairment. In this study, initially in-silico studies were conducted for lead compound identification. For the in-vivostudies, adult zebrafish (~ 6-8months old; 470-530mg; 126 animals are used) were randomly assigned to 7 groups and treated with 5-Fluorouracil (25mg/kg; i.p.) for 1day followed by post-treated with Plumbagin (10 and 20mg/kg; i.p.) and Donepezil (5mg/kg; i.p.) for 6days. Behavioral, biochemical, molecular, mitochondrial, and histopathological analyses were performed after completion of the study. In-silico analyses revealed that Plumbagin exhibits stronger binding affinity as compared to 5-Fluorouracil. In vivo findings further demonstrated that post-treatment with Plumbagin significantly mitigates oxidative stress markers, reduces neuroinflammatory cytokines, and enhances mitochondrial functioning (mitochondrial enzyme complexes, caspases-3, and cellular viability) relative to zebrafish treated with 5-Flurouracil alone. Additionally, Plumbagin treatment led to marked reduction in GSK-3β expression, improvements in mitochondrial structure (as observed through Transmission electron microscopy analysis. Further, post-treatment with Plumbagin significantly improved mitochondrial morphology (as observed through TEM analysis) and neuronal morphology (assessed via Hematoxylin and Eosin staining and Nissl staining) as compared to 5-Fluorouracil -treated zebrafish. Our findings provide strong evidence that Plumbagin significantly reduced neuroinflammation, provided neuroprotective support, and alleviates cognitive impairment, as demonstrated through in-silico and in-vivo analyses.

HighlightsWhat are the main findings?Cytokines may be beneficial as biomarkers of pediatric TBI severity and prognosisWhat are the implications of the main findings?Additional studies may be beneficial in delineating the role of cytokines in assessing pediatric TBI.Traumatic brain injury (TBI) is one of the leading causes of death and neurological disability worldwide. The search for biomarkers that indicate TBI severity and prognosis with greater accuracy is ongoing. This study aimed to evaluate the significance of several neuroinflammatory cytokines and chemokines, assessing their potential as biomarkers in pediatric TBI (pTBI). This was an exploratory analysis of inflammatory cytokines and chemokines measured in a subset of 26 children aged 0–18 years with TBI and 21 controls. TBI severity was determined by GCS. The functional outcome was measured via the GOS-E score at 6 weeks and 3, 6, 9, and 12 months post-injury. Serum samples were analyzed for ICAM-1, VCAM-1, SAA, CRP, IFN-g, IL-10, IL-12p70, IL-13, IL-1b, IL-2, IL-4, IL-6, IL-8, TNF-a, TNF-b, eotaxin, eotaxin-3, IP-10, MCP-1, MCP-4, MDC, MIP-1a, MIP-1b and TARC. Levels of IL-6, IL-10, IL-13, IL-16, MDC, and GM-CSF were increased, and IFN-γ, IL-5, IL-8, and eotaxin-3 were decreased at enrollment when compared with controls. Elevated IL-6 and IL-10 at enrollment were associated with severe TBI (AUC of 1, p = 0.0002 and p = <0.0001, respectively). IL-6, IL-10, IL-16, and TNF-β at enrollment and IL-5 at 24 h were elevated in children with unfavorable outcomes, with an AUC > 0.8, suggesting biomarker potential. Our data indicate that several cytokines and chemokines measured after TBI may aid in the assessment of pTBI severity and prognosis. IL-6, IL-10, and IL-16 may show potential as biomarkers for pTBI severity and outcomes.

Tobacco companies reported that electronic cigarette products were developed to reduce the adverse health effects of conventional cigarettes; however, impairments of lung, brain, and kidney are reported in subjects exposed to electronic cigarettes. Both types contain nicotine in varying amounts, raising concerns about nicotine's toxicity in the body. Studies suggest that modulating glutamate transporters with beta-lactam, ceftriaxone, can reduce nicotine intake. We here tested the pharmacological effects of ceftriaxone and MC-100093 as a novel synthetic beta-lactam, which doesn't have antibiotic action, in mouse model of nicotine self-administration. Male C57BL/6 mice were exposed to nicotine-self administration for five weeks, and the effects of ceftriaxone and MC-100,093 on nicotine intake were determined in week 5. Brains were collected for determination of changes in glutamatergic system and neuroinflammatory cytokines levels. Blinded in silico study was conducted to determine the binding properties of ceftriaxone and MC-100093 to glutamate transporter 1 (GLT-1). The results revealed that MC-100093 and ceftriaxone reduced nicotine self-administration. Both compounds attenuated nicotine-induced downregulation of glutamate transporters such as GLT-1 and cystine/glutamate antiporter (xCT), and this effect was associated with attenuation of nicotine-induced increase in glutamate content in the nucleus accumbens. Furthermore, MC-100093 and ceftriaxone attenuated nicotine-increased in TNF-α and IL-6, which indicate that both compounds have a neuroprotective effect. Additionally, the in-silico docking study predicted that both MC-100093 and ceftriaxone exhibited acceptable binding properties into GLT-1. Together, these data report potential therapeutic effects of MC-100093 targeting glutamate transporters for treating substance use disorders, particularly tobacco-use disorder.

BackgroundAlzheimer’s disease (AD) is a chronic and progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and behavioral impairment. A central hallmark of AD pathology is the abnormal accumulation of amyloid‐β (Aβ) plaques and neurofibrillary tangles, accompanied by a sustained neuroinflammatory response. Emerging evidence suggests that inflammatory mediators, both central and peripheral, play a significant role in the pathogenesis and progression of AD, particularly neuroinflammatory cytokines, which influence Aβ production, aggregation, and clearance.MethodsThis study aimed to explore the association between systemic inflammatory cytokines and circulating Aβ levels in the peripheral blood of AD patients. Serum levels of pro‐inflammatory cytokines, including interleukin‐1β (IL‐1β), tumor necrosis factor‐α (TNF‐α), and interleukin‐6 (IL‐6), were measured in AD patients and compared with age‐matched healthy controls. Additionally, plasma Aβ₄₂ levels and the Aβ₄₂/Aβ₄₀ ratio were assessed to investigate amyloid metabolism in the periphery. Correlation analysis was performed to examine the relationship between cytokine levels and Aβ concentrations.ResultsAD patients exhibited significantly elevated serum levels of IL‐1β, TNF‐α, and IL‐6, with IL‐6 showing the most pronounced increase. Plasma Aβ₄₂ levels and the Aβ₄₂/Aβ₄₀ ratio were also significantly higher in AD patients, indicating altered amyloid metabolism in the peripheral circulation. A strong positive correlation was observed between IL‐6 levels and plasma Aβ₄₂ concentrations (r = 0.72, p < 0.01), suggesting that systemic inflammation may contribute to amyloid dysregulation in AD.ConclusionThese findings support the potential use of blood‐based biomarkers for the early detection and monitoring of AD. The study highlights the significance of targeting neuroinflammatory pathways as a potential therapeutic strategy to mitigate Aβ accumulation and slow disease progression. A deeper understanding of the molecular interactions between inflammatory cytokines and Aβ could open new therapeutic avenues for AD intervention.

PURPOSE: Exercise training is widely recognized as a complementary intervention that provides both therapeutic and preventive benefits for neurodegenerative diseases, given its strong association with brain health. Regulating the expression of neurotrophic factors can significantly enhance cognitive function and memory processes, particularly in conditions such as Alzheimer’s disease (AD). However, the effects of high-intensity interval aerobic exercise training (HIE) on brain-derived neurotrophic factors and astrocyte activation in the cortex (CTX) and the hippocampus (HIP) remain unclear. Therefore, this study aimed to investigate whether HIE regulates the expression of neurotrophic factors and neuroinflammatory cytokines in the CTX and HIP.METHODS: Eighteen-week-old female C57BL/6 mice were assigned to control (Cnt) and HIE groups. After 12 weeks of HIE, the brains were harvested for immunoblotting, immunofluorescence, real-time PCR (qRT-PCR), and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays.RESULTS: HIE increased the expression of glial cell line-derived neurotrophic factor (GDNF) protein in the CTX but not in the HIP. Additionally, HIE exerted a protective effect against neuroinflammation by significantly upregulating A2-specific astrocytic transcripts. These findings suggest that HIE promotes neurotrophic and anti-inflammatory responses in both CTX and HIP.CONCLUSIONS: Our study results suggest that HIE exerts protective regulatory effects on neurotrophic factors, neuroinflammation, and A1/A2 type astrocytic reactivity in CTX and HIP of animal models. These findings suggest that HIE has beneficial effects on brain health. However, as these results were derived from animal studies, further clinical research is required to determine whether similar neuroprotective effects can be observed in humans.

Modified Xiaoyao San (MXYS) is a well-established clinical prescription for the treatment of depression in China. While MXYS shows considerable promise for the development of new antidepressants, its pharmacological mechanisms remain poorly understood. This study aims to investigate the antidepressant potential and underlying mechanisms of MXYS in lipopolysaccharide (LPS)-induced depression-like behaviors in mice. Behavioral assessments (sucrose preference test, tail suspension test, open field test) demonstrated that MXYS significantly ameliorated LPS-induced anhedonia and behavioral despair. Histopathological and molecular analyses revealed that MXYS mitigated LPS-induced neuronal damage in the prefrontal cortex (PFC), restored dendritic spine density, and rebalanced neuroinflammatory cytokines by reducing the pro-inflammatory IL-1β and elevating the anti-inflammatory IL-10. Moreover, MXYS promoted microglial polarization toward the anti-inflammatory M2 phenotype (CD206⁺) while suppressing the pro-inflammatory M1 phenotype (CD68⁺). Mechanistically, MXYS inhibited NLRP3 inflammasome activation and pyroptosis through the upregulation of the E3 ubiquitin ligase TRIM31, which facilitated NLRP3 degradation. Transmission electron microscopy confirmed that MXYS inhibited LPS-induced microglial pyroptosis, as evidenced by reduced Gasdermin D (GSDMD) expression and preserved cellular ultrastructure. In vitro validation using LPS-stimulated BV2 microglia further corroborated the MXYS-mediated suppression of NLRP3 inflammasome activity, pyroptosis, and inflammatory cytokine dysregulation, alongside enhanced TRIM31 expression. Collectively, these findings demonstrate that MXYS exerts antidepressant effects by modulating neuroinflammation through TRIM31-dependent NLRP3 ubiquitination, microglial phenotype switching, and the inhibition of pyroptosis, providing novel insights into its therapeutic potential for the treatment of depression.

Generation of a perfusable three-dimensional human neurovascular chip to model brain drug delivery and immune cell extravasation.

Zexieyin formula attenuates Alzheimer's disease via suppressing A1 astrocyte activation: A serum pharmacochemistry and network pharmacology study.

This study aimed to discover novel multifunctional anticonvulsant agents through the evaluation of a series of test compounds 5d–f, 7b, and 10c–f, which were previously identified based on their potent anti-inflammatory activity in both in vitro and in vivo models in acute and chronic seizure models. Initial screening in the pentylenetetrazol (PTZ)-induced seizure model identified compounds 7b, 5f, 5e, and 10c as the most effective, with compound 7b demonstrating complete seizure protection (100%) and zero mortality, outperforming the reference drug valproic acid (VI). These four candidates were further assessed in the pilocarpine-induced temporal lobe epilepsy model. Compound 7b again showed superior efficacy, significantly delaying seizure onset by 188.6%, reducing seizure severity at all time points, and ensuring 100% survival. Mechanistic studies revealed that 7b markedly reduced hippocampal oxidative stress markers, including malondialdehyde by 67.2% and nitric oxide levels by 41.0%. It also suppressed the neuroinflammatory cytokines TNF-α and IL-6 by 56.9% and 63.0%, respectively. In addition, compound 7b attenuated excitotoxic glutamate accumulation by 61.5% and downregulated glial activation markers GFAP and Iba-1 by 73.9% and 49.8%, respectively, consistently outperforming valproic acid. Importantly, safety evaluation confirmed that high-dose administration of 7b did not induce hepatic, renal, or cardiac toxicity. Collectively, these findings establish compound 7b as a potent, safe, and multifunction anti-inflammatory and antiepileptic candidate, warranting further pharmacological and mechanistic investigation.

ObjectivesAlzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by cognitive impairment, amyloid-beta (Aβ) accumulation, tau hyperphosphorylation, and chronic neuroinflammation. Despite symptomatic treatments, no current therapies halt disease progression. Traditional Chinese Medicine (TCM) offers potential multi-targeted interventions in complex diseases like AD. In this study, we evaluated the individual and combined neuroprotective effects of curcumin and Glycyrrhiza glabra in a D-galactose sodium nitrite-induced mouse model of AD. Behavioral analysis, biochemical assays, and molecular profiling were conducted to assess cognitive function, inflammatory cytokine expression, oxidative stress, and AD-related protein levels.MethodsMice were randomly assigned to five groups: control, AD model, curcumin-treated, Glycyrrhiza glabra-treated, and combination-treated groups. Cognitive function was assessed using the Morris water maze. Levels of neuroinflammatory cytokines interleukin-6(IL-6) and tumor necrosis factor-alpha (TNF-α), AD-related proteins amyloid precursor protein (APP) and microtubule-associated protein tau (MAPT),oxidative stress (MDA), and antioxidant capacity (SOD) were evaluated via quantitative PCR and Western blotting.ResultsCurcumin alone modestly improved spatial learning and reduced IL-6 (p < 0.05), whereas Glycyrrhiza glabra had limited effects. The combination therapy yielded the strongest outcomes, significantly reducing escape latency (p < 0.01), IL-6 and TNF-α levels (p < 0.01 and p < 0.05), and downregulating APP and MAPT expression. Additionally, oxidative damage was attenuated, as indicated by decreased MDA and elevated SOD activity (p < 0.001). Although direct measurement of TLR4/NF-κB phosphorylation was not performed, the observed anti-inflammatory and antioxidant effects suggest possible modulation of this pathway.ConclusionCo-administration of curcumin and Glycyrrhiza glabra exerts synergistic neuroprotective effects by attenuating neuroinflammation, oxidative stress, and AD-related protein expression, surpassing monotherapy outcomes. These findings suggest a synergistic neuroprotective mechanism via modulation of TLR4/MyD88/NF-κB and redox pathways. This study provides preclinical evidence supporting the development of TCM-based combination strategies for AD intervention.

Metabolic and endocrine dysfunctions in traumatic brain injury: Implications for cognitive recovery and therapeutic strategies.

Syringaresinol from Cinnamomum cassia (L.) J.Presl ameliorates cognitive deficits and AD pathology via AMPK in a DM-AD mouse model.

Fustin, a photogenic flavanol found in the plant Rhus verniciflua Stokes, has been involved in multiple disease ailments and has a beneficial pharmacological effect and a history of use in traditional medicine. The present research aimed to study the impact of fustin on scopolamine (SCOP)-induced memory impairment and neurodegeneration by modulating neuroinflammation and neurotransmitters in rats. A total of 30 healthy wistar rats were allocated into five groups (n=6). Group Iserved as control and received saline solution (1mL/kg i.p.), group -II- fustin (100 mg/kg, orally), group -III -SCOP (1 mg/kg, i.p.), and group -IV and V were given fustin (50 and 100 mg/kg/p.o.) with SCOP (1 mg/kg, i.p.) for 14-days. After 14 days, 2 hours after SCOP injection, the Y-maze and Morris water maze (MWM) tests were performed. After behavioral tests rats were subsequently euthanized, and brain supernatants were used to estimate choline-acetyltransferase (ChAT), acetylcholinesterase (AChE), antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH)], and total protein, oxidative stress markers [nitrate and malondialdehyde (MDA)], pro-inflammatory markers [tumor necrosis factor (TNF-α), and Interleukins-1β (IL-1β) and IL-6]. Also, neurotransmitters such as serotonin (5-HT), dopamine (DA), ϒ-amino butyric acid (GABA), acetylcholine (Ach), and noradrenaline (NA) contents were performed. Fustin exhibited substantial behavioral improvement in the Y-maze measures spontaneous alterations percentage (SA%) and decreased latency time following the acquisition and prolonged time spent in the probe trial in the MWM test. Moreover, fustin inhibits enhanced neuroinflammatory cytokines and oxidative stress markers and improves the neurotransmitters. The findings of this study suggest that fustin inhibits SCOP impact on cognitive abilities in rats. The present investigation demonstrates that fustin, a potent phytochemical, effectively mitigated the behavioral and physiological changes induced by SCOP in rats. This was primarily achieved by modulating the levels of inflammatory response and neurotransmitters.

IntroductionPrenatal exposure to valproic acid (VPA) is a recognized risk factor for autism spectrum disorder (ASD)-like phenotypes, yet the mechanisms linking gut microbiota dysbiosis to neurodevelopmental impairments remain poorly understood. Emerging evidence implicates the microbiota-gut-brain axis as a critical mediator of neuroinflammation and cognitive deficits, but causal pathways in VPA-induced ASD models require systematic exploration. This study investigates how prenatal VPA exposure reshapes gut microbiota composition, exacerbates neuroinflammatory responses, and drives cognitive dysfunction through the microbiota-gut-brain axis in C57BL/6 mouse offspring.MethodsPrenatal VPA-exposed and control offspring underwent behavioral assessments (open field, three-chamber social interaction, marble-burying, and Morris water maze tests). Neuroinflammatory cytokines (IL-1β, IL-6, TNF-α, IL-10), oxidative stress markers (GSH, SOD, MDA), and microglial activation (Iba1 immunofluorescence) were quantified. Gut microbiota profiles were analyzed via 16S rRNA sequencing, with functional pathway predictions using PICRUSt2 and KEGG databases.ResultsVPA-exposed mice exhibited ASD-like behaviors, including social deficits, repetitive stereotypic actions, and impaired spatial memory. Neuroinflammation was marked by upregulated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and microglial hyperactivation, alongside suppressed antioxidant systems (GSH, SOD). Gut microbiota analysis revealed dysbiosis characterized by reduced Bacteroidia and enriched Clostridia, with diminished short-chain fatty acid (SCFA)-producing taxa (e.g., Oscillibacter). Co-occurrence networks highlighted disrupted microbial interactions, while functional profiling indicated impaired carbohydrate metabolism and elevated neurotoxic pathway activity.DiscussionPrenatal VPA exposure induces gut microbiota remodeling that exacerbates neuroinflammation and cognitive dysfunction via the microbiota-gut-brain axis. This study provides evidence for linkages between taxonomic and metabolic gut dysbiosis and ASD-like pathophysiology, underscoring the therapeutic potential of microbiota-targeted interventions for neurodevelopmental disorders.

Yizhi Qingxin formula (YQF) is a traditional Chinese medicine for the treatment of Alzheimer’s disease (AD). This study explored the mechanism of YQF to improve AD-related neuroinflammation in vivo and in vitro. The behavioral tests, immunohistochemical analysis and Western blot were performed. The present results showed that YQF ameliorated cognitive deficits, reduced hippocampal Aβ deposition, and decreased the number of GFAP and Iba1-positive cells. The results also indicated that YQF suppressed neuroinflammatory cytokines (TNF-α, IL-1β, IL-6) by inhibiting TLR4/NF-κB/NLRP3 pathway. In summary, YQF provides a multi-targeted strategy for AD-related neuroinflammation, which may address limitations of single-pathway therapies.

Imbalances in redox and neuroinflammation are believed to play a role in the complex causes of schizophrenia, a widespread mental disorder characterized by abnormal behaviour. In this regard, we investigated the effects of geraniol, a natural compound with various medicinal uses, on ketamine-induced schizophrenia-like behaviour, oxidative stress and neuroinflammation in mice. We conducted three sets of experiments with adult male Swiss mice (n = 7): drug alone, preventive and reversal groups. The treatments included saline (10mL/kg/p.o./day), geraniol (25, 50 and 100mg/kg/p.o./day) and risperidone (0.5mg/kg/p.o./day) for 14days, along with ketamine (20mg/kg/i.p./day) injections between days 8-14 in the preventive group, or ketamine administration for full 14days before therapeutic intervention from days 8-14 in the reversal group. We measured behavioural hyperactivity, cognition and sociability. Additionally, brain oxidative/nitrergic imbalance, inflammatory cytokines (TNF-α, IL-6) and proteins (COX-2, iNOS, NF-κB) were determined in the striatum, prefrontal cortex, and hippocampus. KET administration was associated with schizophrenia-like symptoms as characterized by increased hyperlocomotion, impaired spatial memory and social withdrawal, particularly in the reversal group. This was exacerbated by redox imbalance and neuroinflammation in specific brain regions. However, geraniol (25, 50 and 100mg/kg) treatment significantly prevented and reversed the brain's insults by restoring ketamine-induced decreases in glutathione, superoxide-dismutase and catalase activities, reduced malondialdehyde and nitrite contents along with TNF-α and IL-6 concentrations. Geraniol also suppressed NF-κB, COX-2 and iNOS expressions in the striatum, prefrontal-cortex and hippocampus. Geraniol shows neuroprotective and neurorestorative effects against schizophrenia-like symptoms by inhibiting oxidative stress, neuroinflammatory cytokines, and protein expression in mouse brains.

BackgroundAcute ischemic stroke is a disastrous disease characterized by damaging blood flow in the brain, leading to acute brain injury. Acute brain ischemia elicits severe inflammation, thus in turn, aggravates neural injury. Interferon-Induced Protein 35 (IFP35), is a 35 kDa protein, a novel type of DAMP that trigger inflammatory responses, exacerbating acute and chronic inflammatory disease. This study aimed to investigate the potential neuroinflammation role of IFP35 in acute ischemic stroke in a mouse model of MCAO.MethodsC57BL/6 male mice were subjected to middle cerebral artery occlusion (MCAO) to establish an animal model of acute ischemic stroke. Leveraging serum from stroke patients, serum and brain tissue after MCAO mice, IFP35 was released. Immunofluorescence assay was used to investigated the cell sources of IFP35 expression after MCAO. The impact of IFP35 on neuroinflammation and neural injury was assessed by siRNA-mediated cerebral IFP35 knockdown. Behavioral tests, and brain tissues were harvested for histological analysis and biochemical assays. TUNEL assays were used to evaluate neuronal damage. TTC staining was performed to assess infarction volumes. Additionally, using western blotting and immunofluorescence assays, we further assessed the contribution of TLR4/NF-κB/NLRP3 signaling in MCAO mice and BV2 cells.ResultsIFP35 was accumulated in peripheral blood of cerebral ischaemia patients, ischemia mice serum, as well as peri-infarct regions in focal cerebral ischemia mice. Although endothelial cells, microglia, and astrocytes are capable of expressing IFP35, cerebral neural cells seem to express and release more IFP35 compare to other cell types. Knockdown of IFP35 alleviated the production of neuroinflammatory cytokines, decreased neuronal death, and minimized infarct volumes, ultimately leading to improved neurological outcomes. Importantly, IFP35 triggered the activation of NF-κΒ and NLRP3 signaling, exacerbating neuroinflammation and brain injury by binding its receptor TLR4.ConclusionsThis study revealed IFP35 as a novel DAMP released during cerebral ischemia that promotes neuroinflammation and injury, expanding the current understanding of inflammatory networks following stroke.

Memory decline is a common hallmarksignal of neurodegenerative diseases marked by elevated neuroinflammatory cytokines, oxidative damage and cholinergic insufficiency in cortical regions. Studies indicate that inhibiting these cytokines and associated markers may enhance memory and provide neuroprotection. This study investigates the effects of sabinene, a neuroprotective monoterpene found in essential oils with neuroprotective and antioxidant properties, on lipopolysaccharide (LPS)-induced neuroinflammation, oxidative stress and learning/memory impairment in mice. In this study, mice ingroups 1 and 2 received normal saline, while groups 3-5 were pretreated with sabinene (5, 10, and 20mg/kg). Group 6 received donepezil (1mg/kg) orally. Groups 2-6 were additionallyinjected with LPS (0.5mg/kg, i.p.) 30min post-treatment for 7days. Behavioral consequences indicating spatial and non-spatial deficits were assessed through Y-maze and novel-object recognition tests, along with locomotor functions conducted. Biochemical markers of neuroinflammation (TNF-α, IL-6), oxidative stress (glutathione, peroxidase, malondialdehyde, nitrite), cholinergic function, and molybdenumenzymes were analyzed in the prefrontal-cortex (PFC) and hippocampus. Sabinene treatment mitigated LPS-induced memory impairments and reduced motor activity. It also significantly decreased acetylcholinesterase activity and malondialdehyde levels in the hippocampus and PFC while increasing glutathione and glutathione peroxidase levels, respectively. Moreover, sabinene reduced LPS-induced molybdenumenzyme elevation in the PFC. Compared to LPS, sabinene significantly lowered TNF-α and IL-6 levels in the PFC and hippocampus while protecting neuronal cell damage in the PFC. Overall, sabinene enhances memory function in LPS-treated mice by reducing oxidative stress and neuroinflammation while improving cholinergic activity and molybdenum enzymes in the cortical regions of mice brains.

Rotenone is a pesticide compound that selectively damages dopaminergic neurons in the substantia nigra pars compacta and produces Parkinson’s like symptoms in rodents. Deposition of iron and reactive oxygen species (ROS) generation by its oxidation are contributing factors in the etiology of Parkinson’s disease. Deferoxamine (DFO) is an iron chelator with high affinity produced by Streptomyces wadayamensis, S. malaysiense, like organisms. The present study provides insight to evaluate the protective effect of DFO in rotenone-induced neurotoxicity in rats. Rotenone (6 μg/2 μl/rat, unilaterally) was injected intranigral on day-1 using a digital stereotaxic apparatus. DFO (50 and 100 mg/kg, intraperitoneally) was given orally daily for 21 days starting from day 8 after the intranigral surgery. On day 28, animals were sacrificed, and the striatum was isolated for oxidative stress parameters (lipid peroxidation, nitrite and reduced glutathione, glutathione peroxidase, superoxide dismutase, catalase), neuroinflammatory cytokines (IL-1β, IL-6, and TNF-α), mitochondrial complexes-I and IV, neurotransmitters (brain catecholamines, gamma-aminobutyric acid, glutamate), and iron level estimation. Unilateral intranigral infusion of rotenone led to significant motor deficits as evidenced by impairments in locomotor activity in open field test, rotarod activity (motor coordination), grip strength, and narrow beam walk performance. DFO administration dose-dependently significantly improved against rotenone-induced behavioral abnormalities in rats, restored the altered level of neurotransmitters in the striatum, and attenuated oxidative stress and inflammatory response in the striatum. These findings indicate that DFO successfully achieved antioxidant and anti-inflammatory properties and protect dopaminergic neurons against rotenone-induced neurotoxicity.