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Oxidative stress-induced enteric neuropathy is a key driver of slow-transit constipation (STC), primarily through disrupted mitochondrial dynamics and neuronal degeneration. To address this, we developed a bioengineered oral delivery system that supports neuronal recovery and actively enhances mitochondrial membrane fusion. A self-assembling amphiphilic peptide (GFF) was synthesized to encapsulate rhein (RH), a natural anthraquinone with antioxidant, anti-inflammatory, and microbiota-regulating properties. A BDNF-derived tetrapeptide was integrated to further potentiate neurotrophic effects. These components were co-assembled into a therapeutic nanofiber (RFI), which was embedded in a chitosan/sodium alginate hydrogel for sustained oral delivery. In vitro and in vivo studies demonstrated that RFI significantly improved neuronal viability and gastrointestinal motility. Mechanistic investigations revealed that RFI is associated with activation of the AKT signaling pathway and enhancement of mitochondrial membrane fusion, collectively contributing to the restoration of mitochondrial network integrity and neuronal protection. This multifunctional nanoplatform offers a promising therapeutic approach to STC by combining targeted delivery with direct modulation of mitochondrial function. Show less

This study aims to investigate the radioprotective effects of melatonin (MEL) against oxidative damage that may be caused by flattening filter (FF) and flattening filter-free (FFF) beam in the cerebrum and cerebellum of rat using various genetic markers. Forty female Wistar albino rats were randomly assigned to five groups. The control group received no intervention. The FF group received a single 16 Gy fraction at 600 MU/min. The FF+MEL group received the same FF protocol, preceded by melatonin (50 mg/kg, intraperitoneal) administered 15 min before irradiation. The FFF group received a single dose of 16 Gy at 2,400 MU/min. The FFF+MEL group received the same FFF protocol with melatonin administered as above. After treatment, cerebrum and cerebellum tissues were harvested, and mRNA expression levels of BDNF, CREB, BAX, BCL2 and IL6 were measured. Both FF and FFF radiotherapy treatments significantly increased BDNF, CREB, IL6, and BAX gene expression in cerebrum and cerebellum tissues, while decreasing BCL2 levels (P < 0.05). Melatonin treatment increased BDNF and CREB expression, significantly attenuated radiation-induced increases in IL6 and BAX, and partially reversed the decrease in BCL2 (P < 0.05). The increase in the BAX/BCL2 ratio after radiotherapy was significantly attenuated by melatonin treatment. Overall, FFF irradiation induced a stronger oxidative, inflammatory, and pro-apoptotic response than FF, whereas melatonin exhibited potent neuroprotective and anti-apoptotic effects. In conclusion, MEL demonstrates potential as a protective agent for healthy tissues during irradiations, owing to its antiapoptotic, anti-inflammatory, and neurotrophic properties. Show less

Formononetin (FMN) is known for its significant neuroprotective effects, this study aims to investigate the antidepressant potential and underlying mechanisms of FMN. Antidepressant efficacy was evaluated in corticosterone (CORT)-induced depression models. In vivo, CORT-exposed mice received FMN to assess behavioral and hippocampal changes (dendritic spine density, synaptic markers: MAP-2/GAP-43). In silico, network pharmacology and molecular docking predicted FMN's binding affinity and enriched pathways. In vitro, HT22 cells pretreated with FMN (10 μM, 6 h) were subjected to CORT injury, with mechanistic validation via ERα antagonist (MPP) and ERK inhibitor (PD98059). FMN alleviated depressive-like behaviors and preserved hippocampal integrity in mice. Bioinformatics analysis revealed FMN's strong binding to ER subtypes and enrichment in estrogen/MAPK pathways. In vitro, FMN pretreatment activated the ERK-CREB-BDNF axis in CORT-injured HT22 cells, enhancing neuronal survival and synaptic function. The activation was ERα/ERK-dependent, as evidenced by the abolition of protective effects following pharmacological inhibition with MPP (ERα antagonist) or PD98059 (ERK inhibitor). Concomitantly, in vivo FMN treatment restored hippocampal p-ERK/ERK ratios in mice, directly corroborating the ERK-CREB-BDNF pathway activation and highlighting its efficacy in reversing CORT-induced signaling deficits. FMN exerts antidepressant effects via ERα-mediated neurotrophic signaling (ERK-CREB-BDNF), offering a mechanistic foundation for natural antidepressant development. Show less

To date, the burden of alcohol-related seizures is increasing, with an unexplored etiological complex, and the psychopharmacological interplay remains significantly scarce. In this study, we developed an experimental approach to investigate the contrasting impact of alcohol on pentylenetetrazol-induced seizures and the effects of diosgenin, a phytosteroid agent with neuroprotective effects. After 7 days of binge alcoholism with ethanol (2 g/kg, oral gavage) in male mice, they were subjected to maximum and sub-convulsive pentylenetetrazol-induced seizures concomitantly with diosgenin (25 and 50 mg/kg, p.o.) or diazepam (3 mg/kg, p.o) treatments from days 8-14. The interaction between ethanol and pentylenetetrazol-induced seizures was investigated, along with behavioral comorbidities, hypothalamic-adrenal-pituitary-axis (HPA-axis), neurochemical and neurotrophic dysfunctions, oxidative stress, and neuroinflammation in the hippocampus, prefrontal cortex, and striatum. Ethanol-exacerbated pentylenetetrazol-induced seizure and frequency, characterized by rearing with myoclonic jerks, and clonic-tonic convulsions. It increased anxiety, depressive behavior and impaired spatial working memory, influenced by heightened alcohol preference and corticosterone levels, which were normalized by diosgenin. Concomitant ethanol administration exacerbated reductions in GABAergic-dependent glutamic acid decarboxylase and increased glutamate levels associated with pentylenetetrazol-induced seizures, alongside depletions of serotonin and brain-derived neurotrophic factor in the hippocampus, prefrontal cortex, and striatum. Among others, diosgenin, compared to ethanol-pentylenetetrazol exacerbation, reduced levels of myeloperoxidase, TNF-α, and IL-6, nitrite and malondialdehyde in the hippocampus, prefrontal cortex, and striatum while increasing IL-10 cytokine and antioxidant system (superoxide-dismutase, glutathione, and glutathione-transferase). These findings suggest that alcoholism exacerbates seizures across brain regions, involving neurochemical imbalance, HPA-axis dysfunction, oxidative stress, and neuroinflammation, which are reversible by diosgenin. Show less

Alzheimer's disease (AD) is characterized by progressive cognitive decline and memory dysfunction, with prominent roles in cholinergic deficits and synaptic plasticity impairments. Vitisin B, a resveratrol tetramer derived from Vitis vinifera, exhibits potent antioxidant and neuroprotective properties. However, its potential to influence cognitive function in AD models remains inadequately explored. In this study, we first tested vitisin B in an in vitro model using SH-SY5Y cells exposed to scopolamine-induced cytotoxicity, where vitisin B significantly enhanced cell viability and promoted cell survival. We evaluated its therapeutic potential in vivo using both systemic administration and direct delivery into the third ventricle of the brain in a scopolamine-induced AD mouse model. Across both administration routes, vitisin B exerted a broad pro-cognitive effect, restoring multiple domains of learning and memory disrupted by scopolamine. Vitisin B recovered spatial working memory in the Y-maze, normalized exploratory activity in the open field, improved recognition memory in the novel object recognition (NOR) test, and enhanced long-term memory retention in the passive avoidance assay. This treatment restored cognitive function, alleviated cholinergic deficits, increased hippocampal brain-derived neurotrophic factor (BDNF) levels, and enhanced synaptic plasticity. These results suggest that vitisin B exerts reliable cognitive and neuroprotective effects through both systemic and cerebral administration, highlighting its potential as a promising therapeutic compound for restoring cholinergic function and enhancing hippocampal synaptic plasticity in AD. Show less

Alzheimer's disease (AD) presents a critical therapeutic gap, necessitating novel multitarget strategies. Excitotoxicity via NMDA receptor overactivation and oxidative stress is a key driver of Tau hyperphosphorylation and neuronal loss. While the tripeptide Gly-Pro-Glu (GPE) derived from IGF-1 exhibits NMDA receptor antagonism, its clinical potential is limited by poor blood-brain barrier penetration and rapid hydrolysis. Herein, we rationally designed three novel GPE-derived oligopeptide conjugates (SAC-PE, SPE, and SAR-SPE) by replacing the N-terminal glycine with antioxidant moieties (( Show less

Microplastic (MPs) pollution is widespread in the environment and poses growing risks to food safety and human health. In a 60-day oral exposure study, male Swiss mice received MPs (10 mg/kg b.wt), and the neuroprotective potential of taurine (Tau, 200 mg/kg b.wt) was evaluated. MPs exposure induced pronounced anxiety-like behavior, evidenced by increased peripheral zone activity in the open field test (+ 81.1%) and elevated anxiety index in the elevated plus maze (+ 75.9%), along with significant memory and spatial learning impairments in the Y-maze (increased trials + 31.6% and latency + 75.2%). Neurochemically, MPs increased acetylcholinesterase (AChE) activity (+ 89.4%) while reducing dopamine (-29.4%) and γ-aminobutyric acid (GABA) (-17.9%) levels. MPs also triggered marked oxidative stress, as shown by elevated reactive oxygen species (+ 107.6%) and malondialdehyde (+ 249.0%), accompanied by reduced total antioxidant capacity (-26.2%). At the molecular level, MPs downregulated CREB1 (-82.2%) and BDNF (-80.2%) while markedly upregulating AKT1 (~ fivefold) and pro-inflammatory cytokines (TNF-α, IL-6, CXCL-10, and IL-1β; 5.2-7.2-fold). Histopathological analysis revealed severe neurodegenerative alterations across the cerebrum, hippocampus, and cerebellum. Tau co-treatment significantly ameliorated MPs' induced neurotoxicity by reducing anxiety and memory deficits, lowering AChE activity (- 17.3%), restoring dopamine (+ 28.8%) and GABA (+ 14.2%) levels, attenuating oxidative stress (ROS -45.4% and MDA -44.7%), suppressing inflammatory gene expression (-51.0 to -68.1%), and partially normalizing CREB1 and BDNF expression (+239% and +240%, respectively). Collectively, these findings identify Tau as a promising natural neuroprotective agent against MPs' induced neurotoxicity. Show less

Lilium brownii is a plant that can be used for medicinal and food purposes. 1-O-p-coumaroyl-3-O-feruloyl glycerol (CF) is a phenolic acid glycerol dimer isolated from Lilium brownii. This study aims to evaluate the neuroprotective effects of CF and elucidate the possible molecular mechanisms underlying its neuroprotective effects through in vivo and in vitro models of Parkinson's disease. 1-methyl-4-phenylpyridinium ions (MPP Following CF administration, the apoptosis rate and reactive oxygen species (ROS) levels in PC12 cells were significantly reduced. CF markedly upregulated the expression of proteins including dopamine, tyrosine hydroxylase, brain-derived neurotrophic factor (BDNF), while simultaneously downregulating the expression of proteins such as α-synuclein. Molecular docking results demonstrated favorable affinity between CF and proteins including p62. This compound not only ameliorated motor and cognitive impairments in Parkinson's disease mice but also markedly increased neuronal numbers within the substantia nigra region of these animals. CF exerts a neuroprotective effect in Parkinson's disease by modulating the p62-Keap1-Nrf2 signalling pathway. Show less

Postoperative cognitive dysfunction (POCD) in older adults is strongly linked to neuroinflammation driven by microglial activation and NF-κB signaling. Runx1 has emerged as an upstream regulator of NF-κB, but its role in POCD is unknown. Dendrobine, a sesquiterpenoid alkaloid from Dendrobium species, exhibits anti-inflammatory and neuroprotective activity. POCD was induced in aged C57BL/6 mice via sevoflurane anesthesia combined with exploratory laparotomy. Dendrobine (10 or 20 mg/kg) was administered, and cognitive outcomes were evaluated by Morris Water Maze and Novel Object Recognition. RNA sequencing, Western blotting, immunofluorescence, and in vitro microglia-neuron co-culture systems were employed to investigate inflammatory responses, apoptosis, synaptic plasticity, and signaling pathway activation. Functional roles of Runx1 were validated via siRNA knockdown, pharmacological inhibition (Ro5-3335), and overexpression in BV2 cells. Dendrobine improved spatial and recognition memory in POCD mice, reduced hippocampal microglial activation, proinflammatory cytokine expression (TNF-α, IL-1β, IL-6), and neuronal apoptosis while enhancing synaptic protein levels (BDNF, PSD95, SYN1). Transcriptomic and KEGG analyses revealed suppression of NF-κB signaling by dendrobine, with Runx1 identified as an upstream modulator. Dendrobine downregulated Runx1 expression in vivo and in vitro. Runx1 inhibition enhanced dendrobine's anti-inflammatory effects, whereas RUNX1 overexpression abolished them. Dendrobine ameliorates POCD by inhibiting the Runx1/NF-κB signaling pathway, suppressing neuroinflammation, promoting synaptic resilience, and preventing neuronal apoptosis. Runx1 appears to act as a key upstream mediator of NF-κB signaling in POCD. Targeting the Runx1/NF-κB axis represents a promising strategy for perioperative neuroprotection. Show less

The pathological mechanism of Alzheimer's disease (AD) is complex. The binding of Aβ to α7 nicotinic acetylcholine receptor (α7nAChR) contributes to neuronal damage. Sinomenine (SIN) is an alkaloid extracted from the traditional Chinese medicine Qingfengteng (Sinomenium acutum). The anti-inflammatory, antioxidant, and immunomodulatory effects of SIN were confirmed to be closely associated with the α7nAChR. This study aimed to investigate whether α7nAChR serves as a pharmacological target of SIN against AD, and to evaluate the neuroprotective effects of SIN both in vivo and in vitro, focusing on the α7nAChR/Nrf2/Keap1 signaling pathway. In this study, the effects of SIN in both APP/PS1 transgenic mice and SH-SY5Y cells subjected to Aβ1-42-induced injury were assessed. The selective antagonist α-bungarotoxin ‌(α-BTX), the agonist nicotine (Nic) of α7nAChR, and α7nAChR siRNA were employed. The cognitive function, Aβ deposition, synaptic plasticity markers, the tau protein phosphorylation, mitochondrial membrane potential, oxidative stress and the α7nAChR/Nrf2/Keap1 signaling pathway were analyzed in vivo and/or in vitro. SIN significantly enhanced learning and memory abilities in APP/PS1 mice, reduced Aβ plaque deposition and synaptic dysfunction, and inhibited hyperphosphorylation of tau protein and oxidative stress in the brain. In Aβ1-42-induced neuronal injury model, SIN alleviated apoptosis, increased BDNF and ACh levels, inhibited mitochondrial damage, stabilized calcium homeostasis, and suppressed oxidative stress. Meanwhile, SIN disrupted Nrf2-Keap1 binding to promote the Nrf2/HO-1 signaling pathway. Nevertheless, SIN effects above were inhibited by α-BTX. The knockdown of α7nAChR in vitro significantly promoted Nrf2/HO-1 pathway and BDNF expression. SIN exerts neuroprotective effect in APP/PS1 transgenic mice and Aβ1-42-induced neuronal injury by inhibiting oxidative stress via α7nAChR/Nrf2/Keap1 pathway. This study provides evidence for α7nAChR as a new target and the clinical application potential of SIN in AD treatment. Show less

N-Acetylcysteine (NAC), a thiol-containing antioxidant, has demonstrated neuroprotective potential in various neurological disorders. Recently, cold atmospheric plasma (CAP) technology has emerged as a promising approach for modifying the physicochemical properties of biomolecules. This study investigated the neuroprotective effects of plasma-activated N-acetylcysteine (PAN) in a rat model of intracerebroventricular streptozotocin (icv-STZ)-induced cognitive impairment, with particular emphasis on redox homeostasis and cholinergic function. The physicochemical properties of PAN were characterized using FTIR, LC-MS/MS, and DPPH assay. Male rats received a single icv-STZ injection (3 mg/kg) on day 0, followed by oral administration of NAC or PAN (50 mg/kg) every other day for three weeks. Cognitive performance and anxiety-like behaviors were assessed using the shuttle box, novel object recognition, and elevated plus maze tests. Subsequently, oxidative stress indices (TAC, GSH, SOD, CAT, MDA, NO), cholinergic markers (AChE activity, ACh levels), and the expression of AChE, α7 nAChR, Nrf2, Keap1 and BDNF genes were quantified in the hippocampus and cerebral cortex. FTIR and LC-MS/MS analyses revealed plasma-induced chemical modifications in NAC, resulting in the generation of novel compounds. The DPPH assay further demonstrated superior radical scavenging activity of PAN compared with NAC. Behaviorally, PAN administration significantly alleviated STZ-induced cognitive deficits and anxiety-like behaviors. Biochemically, PAN normalized TAC, GSH, MDA, NO, and ACh levels, increased CAT and SOD activities, and reduced AChE activity. At the transcriptional level, PAN upregulated α7 nAChR, Nrf2 and BDNF expression while downregulating AChE and Keap1. Collectively, these findings suggest that PAN mitigates behavioral impairments in the icv-STZ rat model of Alzheimer's disease, potentially through attenuation of oxidative stress and restoration of cholinergic neurotransmission. Show less

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that, through the activation of its full length receptor, TrkB-FL, plays a pivotal role in neuroprotection, namely against neuronal toxicity mediated by amyloid-β peptide (Aβ). In astrocytes, the increase of calcium (Ca Show less

Extended periods of microgravity during orbital flights can impair astronauts' cognitive abilities, including learning and memory, posing a persistent health concern in the field of aerospace medicine. The study examined the pharmacological effects of agmatine and its influence on simulated neurobehavioral changes in rats under microgravity conditions. Rats were exposed to simulated microgravity (SMG) conditions using the hindlimb unloading (HU) model for 28 days and evaluated for behavioural alterations using the open field test, elevated plus maze, and forced swim test, and cognitive deficits using the novel object recognition test and Morris water maze. Further, brain agmatine levels, neurochemical and structural alterations in the hippocampus, and prefrontal cortex were examined. Chronic agmatine treatment dose-dependently (40 and 80mg/kg) and its endogenous modulation by l-arginine, and aminoguanidine prevented behavioral and cognitive deficits by improving exploratory behaviour, reducing anxiety-depressive-like symptoms, and enhancing cognitive performance. Our findings reported a significant reduction in agmatine levels in the hippocampus and prefrontal cortex in SMG conditions. Agmatine administration and its modulation normalized neurotransmitter imbalances, especially by restoring the reduced levels of gamma-aminobutyric acid, dopamine, and serotonin, along with a reduction of elevated levels of glutamate in SMG conditions. Moreover, agmatine decreased reactive oxygen species production, enhanced hippocampal antioxidant enzyme activities, suppressed pro-inflammatory cytokines (TNF-α, IL-6), and improved IL-10 and brain-derived neurotrophic factor levels in HU rats. Moreover, agmatine and its endogenous modulation preserved neuronal cells of the hippocampus and prefrontal cortex. In conclusion, the present study suggests that agmatine administration and modulation of endogenous agmatine levels effectively mitigate SMG-induced neurological dysregulation through neuroprotection and neuromodulation. Understanding the neurobiological mechanisms underlying these effects opens up new possibilities for creating novel interventions targeting agmatinergic signaling in spaceflight conditions and associated complications. Show less

Growing evidence highlights that long-term orbital flight may lead to structural changes in brains and cognitive impairments in astronauts. However, effective strategies to counteract these effects remain limited. Compound Gastrodia elata Formula (CGEF), composed of Gastrodia elata Bl., Polygonatum sibirium Red., and Poria cocos (Schw.) Wolf has been shown to improve learning and memory. The present study aimed to evaluate the effects and underlying mechanisms of CGEF in attenuating cognitive deficiency induced by simulated weightlessness in mice. A cognitive impairment model was induced in mice using Hindlimb unloading (HU) method. Cognitive function was assessed through Object recognition test (ORT), the Morris water maze (MWM), and the Step-down Test (SDT). Serum and hippocampus levels of inflammatory markers, including Interleukin-1 beta (IL-1β), Tumor Necrosis Factor alpha (TNF-α), and Interleukin-6 (IL-6) were evaluated using ELISA. Neurotransmitter concentrations in the hippocampus and cortex were measured using LC-MS/MS. While Brain-derived neurotrophic factor (BDNF) / Tropomyosin receptor kinase B (TrkB) protein expression signaling pathway in hippocampus was evaluated by western blot. Results showed that CGEF treatment significantly reversed the memory deficits induced by four weeks of HU exposure. Furthermore, CGEF treatment markedly suppressed the production of inflammatory factors. It also assisted in the recovery of neurotransmitter balance and regulated tryptophan metabolism to improve cognitive disorder. Western blotting analysis revealed that CGEF treatment upregulated the expression of Synaptophysin, Postsynaptic density 95 proteins, while also activating the brain-derived neurotrophic factor-Tropomyosin receptor kinase B pathway. These findings suggest that CGEF has substantial potential for development as an aerospace health product to improve memory decline associated with spaceflight. Show less

Parkinson's disease (PD) is a progressive neurological disorder characterized by the loss of dopaminergic neurons in the substantia nigra and is associated with neuroinflammation, apoptosis, oxidative stress, and motor impairment. Imipramine, a tricyclic antidepressant, has a wide range of biological effects such as anti-inflammatory, anti-apoptotic, and free radical scavenging activities. The present study was designed to investigate the neuroprotective effect of imipramine in a rat model of PD induced by 6-hydroxydopamine (6-OHDA). Male Wistar rats were treated with daily intraperitoneal administration of imipramine (20 mg/kg, for 14 days) starting 72 h after 6-OHDA injection (20 μg/rat; 4 μl in the right medial forebrain bundle (MFB)). The motor performance was assessed using the rotarod, beam, pole, and apomorphine-induced rotation tests. The protein levels of neurotrophic factors (BDNF, GDNF, and NT3) and factors involved in oxidative stress (MDA, CAT, SOD, GST, and GSH) were measured in the striatum by ELISA technique. The neuronal survival was also evaluated by Nissl staining. Our results showed that 6-OHDA caused motor impairments and neuronal cell death. It also significantly reduced the protein levels of neurotrophic factors and induced an oxidative stress response in the striatum of rats. Whereas, imipramine treatment effectively reduced 6-OHDA-induced motor deficits and neuronal cell death. This improvement was accompanied by an increase in neurotrophic factors, especially GDNF, as well as a reduction in oxidative stress through increased SOD levels. These findings provide direct evidence that imipramine treatment contributes to improve of neuronal cell death and motor deficits, perhaps by increasing the striatal levels of SOD and GDNF, which play a key role in the survival of dopaminergic neurons. Further studies are also needed to elucidate the precise underlying molecular mechanisms of neuroprotective effects of imipramine. Show less

Given the potential of polyphenols to mitigate neurodegenerative diseases (NDDs), this meta-analysis investigated whether clinical evidence supports the use of polyphenols for neuroprotection and as nutritional strategies in NDDs. We analyzed different polyphenol types across seven NDDs, 13 studies involving 849 participants were included. Prespecified outcomes comprised global cognition (Mini-Mental State Examination, MMSE), domain-specific cognition (Alzheimer's Disease Cooperative Study-Cognitive Subscale, ADCS-Cog), activities of daily living (Alzheimer's Disease Cooperative Study-Activities of Daily Living, ADCS-ADL), neuropsychiatric symptoms (Neuropsychiatric Inventory, NPI), and selected biomarkers (plasma amyloid-β40 and brain-derived neurotrophic factor, BDNF). Reporting followed PRISMA 2020 guidelines, methods conformed to the Cochrane Handbook, and certainty of evidence was assessed using GRADE. Overall, polyphenol supplementation was associated with improved global cognition (pooled MD in MMSE = 2.06; 95% CI 0.62-3.49). In subgroup analyses, flavonoids were associated with a modest but significant improvement in MMSE scores, whereas stilbenes produced a significant benefit in daily functioning (ADCS-ADL) without clear gains in MMSE or ADCS-Cog and no consistent effects on NPI. Anthocyanidins, phenolic acids, and lignans did not significantly affect cognitive outcomes (MMSE or ADCS-Cog), and polyphenol subclasses did not yield robust or consistent changes in NPI or biomarker endpoints (Aβ40 and BDNF). Specific polyphenol subclasses therefore appear to confer selective cognitive and functional benefits, with stilbenes primarily supporting functional outcomes and flavonoids potentially enhancing global cognition. Show less

Docosahexaenoic acid (DHA) is indispensable for neurological health, yet its therapeutic potential is hampered by poor bioavailability and non-specific brain distribution. We hypothesized that co-administering DHA with specific molecular carriers - eicosapentaenoic acid (EPA) or phosphatidylserine (PS) - would exploit distinct cellular transport pathways to achieve region-specific brain enrichment and associated neuroprotection. By dietary intervention using C57BL/6J mice, we employed regional lipidomics, ELISA, and western blotting to assess brain fatty acid incorporation, neurotrophic factor levels, inflammatory signaling, and transporter expression following supplementation with DHA alone or in combination with EPA or PS. Lipidomic analyses revealed striking, carrier-dependent spatial modulation of DHA. Co-administration with EPA enriched the cortex and striatum, while PS co-administration preferentially targeted the hippocampus and cortex. Mechanistically, both carrier-DHA complexes enhanced the expression of the key blood-brain barrier (BBB) transporter MFSD2A. Functionally, this precision delivery activated distinct neuroprotective programs. PS + DHA robustly upregulated the CREB-BDNF neurotrophic pathway, while EPA + DHA uniquely suppressed the NF-κB pathway, demonstrating potent anti-inflammatory effects. These results demonstrate that the choice of molecular carrier dictates both the spatial distribution of DHA and the nature of the ensuing neuroprotective response. Our findings establish that dietary co-supplementation with specific lipid carriers enables precise spatial delivery of DHA by engaging specific transporters, thereby activating distinct neuroprotective programs in a region-specific manner. This work provides a mechanistic framework for a precision nutrition strategy, tailoring DHA formulations to target specific neuroanatomical and cellular vulnerabilities in neurological disorders. Show less

Pan-apoptosis and involvement of the inflammatory process are the hallmarks of Huntington's disease (HD). Inflammation currently represents one of the potential therapeutic targets for slowing and fighting the pathological phenotype of HD. The immunomodulatory properties of natural compounds, such as resveratrol, have been demonstrated in various disease models and human clinical trials. In the present study, we evaluated the neuroprotective and anti-inflammatory effects of the daily intranasal administration of resveratrol-conjugated gold nanoparticles in awake R6/2 mice, the genetic animal model of HD. Transgenic mice were treated daily with resveratrol-conjugated gold nanoparticles (0.1 mg/kg/day) starting from 5 weeks of age corresponding to the prodromal stage of the disease. After sacrifice, histological and immunofluorescence studies were performed. We found that resveratrol treated R6/2 mice survived longer and displayed a significant partial recovery of motor performance compared with R6/2 mice that received the nanoparticles with vehicle. Primary outcome measures such as striatal atrophy, neuronal intranuclear inclusions, and modulation of microglial reaction revealed a neuroprotective effect of resveratrol conjugated gold nanoparticles. Resveratrol provided a significant increase of neuroglobin, a neuroprotective globin, along with activated CREB and BDNF in the mice medium spiny neurons, accompanied by a down modulation of neuroinflammation, which, combined, might explain the beneficial effects observed in this model. Our findings showed that nanoparticles loaded with a specific compound which acts on the mutated protein intranuclear inclusions and inflammatory components may represent a valid therapeutic strategy in slowing down the symptoms of HD neurodegeneration. Show less

The purpose of our study was to investigate the neuroprotective effects of Nigella sativa (NSt) ethanolic extract (200 mg/kg) and/or Telmisartan(Tel) (10 mg/kg) against fipronil (Fip) (9.7 mg/kg)-induced neurobehavioral toxicity in rats, besides exploring the underlying mechanistic signaling pathways. Our results showed that the phytochemical analysis of NSt ethanolic extract by ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS) revealed 43 compounds, mainly alkaloids, phenolics, terpenoids, fatty acids and flavonoids. While in our in vivo model of neurotoxicity, the combination of NSt and Tel effectively restored neurobehavioral alterations in rotarod, open field and T-maze tests. Additionally, the cotreatments of NSt and Tel significantly decreased acetylcholine, tumor necrosis factors-α, interleukin (IL)-6, IL-1β, MDA, BAX, P62, LC3B and IBA-1. Conversely, they significantly upregulated GABA, brain-derived neurotrophic factor, superoxide dismutase, catalase, glutathione peroxidase and antiapoptotic BCl2, P70S6K and miRNA137-5P without significant change in mTOR expression in hippocampus. Also, they ameliorated pathological alterations as detected by H&E staining, reduced glial fibrillary acidic protein and caspase-3 immunoreactivity. Electron microscopic examination of the combination group revealed the restoration of nuclear and mitochondrial structures with less glial activation and multivesicular bodies. In conclusion, the combination of NSt and Tel are notable agents in mitigating hippocampal neuronal necrosis and astrogliosis and reduced Fip-induced neurotoxicity. Show less

With the global population growing and aging, along with increasing environmental, metabolic, and lifestyle-related risk factors, the worldwide incidence of stroke, Alzheimer's disease (AD) and other dementias, meningitis, and other neurological disorders-along with associated mortality-has risen significantly. Proanthocyanidins (PCs), which are oligomers and polymers of flavan-3-ols, are widely distributed across the plant kingdom, including in grape seeds, cinnamon, apples, cranberries, lotus seeds, and pine bark. They represent the second most abundant class of polyphenols in nature, after lignin. A substantial body of preclinical evidence indicates that PCs exert significant neuroprotective effects through multiple mechanisms. This review provides a systematic overview of the sources, structural characteristics, and bioavailability of PCs, with a focus on their pharmacological mechanisms in nervous system disease. Specifically, it examines their roles in regulating oxidative stress, neuroinflammation, protein homeostasis, apoptosis, autophagy, and key signaling pathways, including Nrf2/HO-1, CREB/BDNF, PI3K/Akt, MAPK, and NF-κB. Furthermore, this review systematically summarized the distinct structural forms of PCs, including monomers, dimers, trimers, and polymers, and explores their structure-activity relationships (SARs) in modulating the gut-brain axis. Additionally, recent advances in PCS-based nano-delivery systems and clinical studies related to neurological disorders are summarized. Growing evidence indicates that microbial metabolism in the gut serves as a key mechanism underlying their neuroprotective effects. Finally, the potential applications of PCs as promising dietary supplements or therapeutic agents for the prevention and treatment of nervous system diseases are discussed, along with existing challenges and future perspectives. Show less

Antioxidant supplements have emerged as promising strategies to mitigate the impact of Alzheimer's disease (AD) and associated dementia. We explored the neuroprotective potential of Carvone nanoemulsion (CANO) using a rat model of AD-associated dementia. Our experimental groups comprised non-AD control rats (CON), untreated AD rats (AD), and AD rats treated with CANO at two different dosages: 40 mg/kg (CANO40) and 80 mg/kg (CANO80). We assessed various behavioral parameters, malondialdehyde (MDA) and brain-derived neurotrophic factor (BDNF) levels,ferric-reducing ability of plasma (FRAP). AD induction caused a significant reduction in step-through latency (P < 0.001), center time (P < 0.001), the number of visits (P < 0.001), and total distance traveled (P < 0.001), time spent in open arms (P < 0.001), and both FRAP (P < 0.001) and BDNF levels (P < 0.001) in comparison to the CON group, while elevating escape latency, time in target zone and platform location latency, and MDA levels (P < 0.001). Treatment with CANO, particularly at the CANO80 dosage, significantly improved these parameters compared to the AD group, resulting in decreased time in the target zone (P < 0.001), escape latency (P < 0.001), and platform location latency (P < 0.001) and higher FRAP (P < 0.05) and BDNF levels (P < 0.05), along with decreased MDA levels (P < 0.05). CANO, especially at the 80 mg/kg dosage, shows promise in alleviating symptoms associated with AD-associated dementia. However, further research is warranted to validate and expand upon these findings. Show less

Enhancing memory and alleviating amnesia are among the conditions that Ganoderma lucidum has historically been used to treat. However, there are relatively few studies on the potential therapeutic effects of active ingredients derived from Ganoderma lucidum in the treatment of memory impairment. This study investigated the ameliorative effect of Lucidenic acid A (LAA) on memory impairment via in vivo and in vitro experiments using experimental pharmacology approaches. In vivo, behavioral tests were used to evaluate memory impairment in mice. Transmission electron microscopy, Hematoxylin-Eosin (HE) staining, and Nissl staining were employed to observe pathological changes in mice. Western blotting (WB) was used for protein expression analysis. In vitro, CCK-8 assay and cell scratch test were used to evaluate changes in cell viability. Reactive oxygen species (ROS) immunofluorescence staining was used to assess intracellular oxidative stress changes. WB was also used for protein expression analysis. The results show that LAA can not only improve spatial learning and memory abilities and alleviate cholinergic system impairments in mice with memory impairment, but also mitigate oxidative stress and inflammatory responses, and reduce pathological changes in brain tissue. In addition to improving memory impairment in mice, LAA can also alleviate inflammation, oxidative stress, and neuronal apoptosis induced in cells. LAA can induce the activation of the PI3K/AKT/BDNF pathway, thereby alleviating inflammation, oxidative stress, and cholinergic system impairments caused by scopolamine (SCOP) administration, and improving memory impairment. Show less

Lactoferrin (LF) plays a positive role in attenuating aging. In this study, LF obtained using different processing methods (freeze-dried: F and spray-dried: S) and its gastrointestinal digesta (XF and XS) were supplemented in d-gal-induced mice to explore their antiaging effects. The results showed that LF and its digesta (LFs) effectively ameliorated cognitive decline. Mechanistically, LFs prevented neuronal and synaptic injury by restoring redox balance, inhibiting the activation of microglia and astrocytes, and activating the cAMP-response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF) pathway. Additionally, LFs increased the tight junction proteins and mucin-2, regulated the gut microbiota, particularly enriching bacteria in Firmicutes and restoring the Firmicutes/Bacteroidota ratio to maintain intestinal homeostasis. Meanwhile, LFs altered phospholipids (PLs) and other metabolites involved in glycerophospholipid metabolism such as arachidonic acid. Correlation analysis showed a significant association among metabolites, microbiota, and behaviors. These results indicated that LF and especially its digesta exert antiaging effects through multitarget pathways involving neuronal protection, neuroinflammation suppression, and microbiota-gut-brain axis regulation. Show less

Prosopis cineraria is traditionally used to enhance cognitive function and manage mental disorders. Its stem bark is valued in ethnomedicine, but its potential anti-Alzheimer's disease (AD) effects are scientifically unexplored. This research has examined the neuroprotective effects of the ethyl acetate fraction of P. cineraria bark (Pc-EA) against AlCl Diseased rats were treated with Pc-EA (30, 100, and 300 mg/kg) for 42 days. Cognitive and affective functions were evaluated with behavioral tests on days 29-42. Biochemical assays measured oxidative stress and cholinesterase activity, while RT-PCR quantified neuroinflammatory markers. Histopathological examination was performed to evaluate the integrity of hippocampal regions. Bioactive compounds were identified by phytochemical profiling (HPLC, GC-MS), and molecular docking was performed to assess binding interactions with acetylcholinesterase. AlCl Pc-EA demonstrated multi-targeted neuroprotection in AlCl Show less

This study investigated the neuroprotective effects and mechanisms of cycloastragenol (CAG) on oxidative stress and neurological function in cerebral ischemia-reperfusion injury (CIRI) and oxygen-glucose deprivation/reoxygenation (OGD/R) models. In vivo, rats were given oral CAG daily for 28 days before CIRI induction. Cerebral infarction and hippocampal injury were assessed using TTC, Nissl, and HE staining. Neurological scores, morris water maze, grip strength tests, and brain water content were used to evaluate functional outcomes. Oxidative stress was determined by biochemical assays, DHE staining, and transmission electron microscopy, while Western blotting was performed to measure neuroprotective proteins. In vitro, primary neurons were treated with CAG and subjected to OGD/R. Cell viability was tested by CCK-8 assay, apoptosis and mitochondrial membrane potential were analyzed by flow cytometry, ROS levels were quantified, and MDA, SOD, and GSH were measured biochemically. Western blot further evaluated BDNF and NeuN expression to confirm in vivo findings. In vivo, CAG reduced infarct volume and edema, improved neurological deficits, preserved the structural integrity of neurons in the hippocampal CA1 region. CAG also promoted motor function recovery, markedly reduced MDA levels, increased SOD and GSH activity, and upregulated BDNF and NeuN expression. In vitro, CAG enhanced cell viability in the OGD/R model, reduced apoptosis, restored mitochondrial membrane potential, and significantly suppressed oxidative stress induced by ischemia-reperfusion. CAG effectively alleviated injury caused by cerebral and cellular ischemia-reperfusion by maintaining redox homeostasis, inhibiting oxidative stress, and promoting the expression of neuroprotective proteins, demonstrating promising neuroprotective potential. Show less

Siponimod is an approved drug for secondary progressive multiple sclerosis (SPMS), and may exert neuroprotective effects beyond its established immunomodulatory properties. Brain-derived neurotrophic factor (BDNF) is a key molecule supporting neuronal survival and plasticity, and its secretion by immune cells may contribute to neuroregeneration in MS. We studied the impact of long-term siponimod therapy on the secretion of BDNF and other neurotrophic factors by immune cells in MS patients. Twenty patients diagnosed with relapsing-remitting MS (RRMS) or SPMS and receiving siponimod were assessed at baseline, 6 months, and 18 months. Peripheral blood mononuclear cells, CD3 A significant increase in BDNF secretion was observed in PBMCs and T cells after 18 months of siponimod treatment. The other neurotrophins remained below detectable thresholds. Correlation of RRMS vs. SPMS analyses (age, sex, disease duration, baseline Expanded Disability Status Scale, and disease course), and multivariable regression modelling revealed no significant associations between them and treatment-induced changes in BDNF. These findings suggest that prolonged siponimod therapy enhances BDNF secretion by immune cells, demonstrating a heretofore unreported neuroprotective mechanism contributing to siponimod's clinical efficacy in reducing disability progression in MS. Our study found that long-term treatment with siponimod, a drug for multiple sclerosis MS, led to a significant increase in the release of a BDNF by immune cells. This effect was seen after 18 months and was not influenced by patients' age, disease type, or disability level. The findings suggest that siponimod may support neuroprotection and repair in MS through a newly identified mechanism beyond its known immune effects. Show less

Luteolin, a flavonoid naturally present in a variety of fruits, vegetables, and medicinal plants, has been recognized as a potentially effective neuroprotective nutraceutical because of its remarkable anti-inflammatory, antioxidant, and neurotrophic properties. Increasing evidence suggests that neuroinflammation and oxidative stress are major contributors to cognitive decline and neuronal degeneration in several prominent neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS). Luteolin significantly inhibits microglial activation, reduces pro-inflammatory cytokine production, modulates the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, and enhances Nrf2-mediated antioxidant mechanisms. Furthermore, it promotes synaptic plasticity through brain-derived neurotrophic factor (BDNF)-associated pathways and mitigates the aggregation of pathological proteins, including Aβ, tau, α-synuclein, and mutant huntingtin. Preclinical studies consistently demonstrate substantial improvements in cognitive function, motor performance, demyelination, and neuronal viability in models of AD, PD, MS, and HD. Preliminary clinical observations also indicate prospective advantages for cognitive function, regulation of inflammatory responses, and alleviation of symptoms, particularly concerning AD and MS. Notwithstanding these encouraging outcomes, obstacles persist due to luteolin's restricted bioavailability, ideal dosing parameters, and the translational discrepancies between experimental models and human pathophysiological conditions. In summary, luteolin emerges as a noteworthy candidate for nutraceutical-oriented approaches designed to alleviate neuroinflammation and cognitive deterioration in the context of neurodegenerative diseases. Show less

Radiation-induced brain injury causes significant neurotoxicity and cognitive dysfunction in patients undergoing radiotherapy for brain tumors. This study aimed to evaluate the neuroprotective effects of intranasal ketamine on radiation-induced brain injury, specifically focusing on its modulation of perineuronal networks (PNNs), extracellular matrix components, and neuroinflammation. Eighteen male New Zealand White Rabbits were divided into three groups: normal controls, irradiation (IR) with saline (IR + saline), and IR with ketamine (IR + ketamine). Whole-brain IR (20 Gy) was applied to the IR groups, and ketamine (2 mg/kg/day) was administered intranasally for 15 days. Biochemical markers, including malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), brain-derived neurotrophic factor (BDNF), ADAMTS4, and syndecan-1 levels, were measured. Histopathological analysis of hippocampal and cerebellar regions assessed neuronal survival and astrogliosis. Magnetic resonance spectroscopy (MRS) evaluated lactate and Ketamine administration significantly reduced oxidative stress (MDA) and inflammatory markers (TNF-α) while restoring BDNF levels compared to the IR + saline group. ADAMTS4 and syndecan-1 levels were reduced, changes consistent with PNN-associated extracellular matrix dynamics, but without direct confirmation by core PNN markers such as aggrecan or WFA staining. Histopathology showed increased neuronal survival and decreased reactive astrogliosis in ketamine-treated groups. Intranasal ketamine demonstrates significant neuroprotective effects in a radiation-induced brain injury model by reducing oxidative stress and inflammation, modulating extracellular matrix components, and preserving neuronal integrity. These findings highlight ketamine's potential as a therapeutic agent, although direct PNN markers and broader cytokine panels were not assessed. Overall, ketamine showed neuroprotective effects across biochemical, histological, and MRS-supported metabolic readouts. Show less

This study was designed to explore the effects of esketamine on cognitive deficits and blood-brain barrier (BBB) dysfunction in sepsis-associated encephalopathy (SAE). An in vivo SAE model was generated through the administration of lipopolysaccharide (LPS), and LPS-induced cognitive impairment in rats was evaluated using the Morris water maze (MWM) test. BBB disruption in vivo was assessed by measuring brain water content together with Evans blue dye penetration, while LPS-induced endothelial hyperpermeability in vitro was examined through FITC-dextran leakage. The protein expression of claudin-3 and ZO-1 was determined by western blotting. In addition, the levels of pro-inflammatory cytokines, cell apoptosis, autophagy, and the activity of the BDNF/TrkB pathway were examined. Rapamycin (Rap, an autophagy inducer) and K252a (a BDNF inhibitor) were used to determine whether the protective effects of esketamine were associated with autophagy and BDNF/TrkB signaling. Esketamine treatment significantly improved the LPS-induced cognitive dysfunction and neurological injury observed in vivo, and it also inhibited the production of pro-inflammatory cytokines and reduced cell apoptosis both in vivo and in LPS-treated hCMEC/D3 cells. Importantly, esketamine alleviated BBB hyperpermeability in vivo and prevented LPS-induced endothelial leakage in vitro. Moreover, esketamine suppressed LPS-induced autophagy, and the influence of esketamine on claudin-3 and ZO-1 expression was reversed when Rap was applied. Esketamine activated the BDNF/TrkB pathway, and the protective effects of esketamine on BBB integrity and autophagy in response to LPS were abolished by K252a. Taken together, these findings indicate that esketamine protects the BBB against SAE by activating the BDNF/TrkB pathway and inhibiting autophagy, providing a potential therapeutic strategy for SAE. Show less