Search Results (364)

Background/Objectives. Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder characterized by dopaminergic neuron loss, α-synuclein pathology, neuroinflammation, and cognitive decline. Synaptamide (N-Docosahexaenoylethanolamine (DHEA)) is an endogenous lipid mediator with documented anti-inflammatory and neurogenic properties, but its effects in PD models remain unexplored. This study aimed to evaluate the neuroprotective potential of synaptamide in a subchronic MPTP-induced mouse model of PD. Methods. Male C57BL/6 mice received MPTP (30 mg/kg/day, i.p., 5 days) with or without synaptamide (10 mg/kg/day, s.c., 13 days). Behavioral tests (open field, Y-maze, elevated plus maze, novel object recognition (NOR)) were performed, followed by immunohistochemical analysis of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra, and Western blotting for α-synuclein, p-α-synuclein, TH, and IL1β in brain homogenates and serum. In vitro Neuro-2a cells were co-treated with MPP⁺ (100 µM) and synaptamide (0.1–10 µM) for cytotoxicity assessment (MTS assay). Results. Synaptamide (10 µM) significantly attenuated MPP⁺-induced cytotoxicity in Neuro-2a cells. In vivo, MPTP caused a marked loss of TH⁺-neurons in the substantia nigra, which was prevented by synaptamide treatment. Importantly, this subchronic MPTP model recapitulates early biochemical alterations (e.g., α-synuclein phosphorylation at Ser129) rather than mature Lewy body pathology, a limitation that should be considered when interpreting these findings. Although no motor deficits or anxiety-like behavior were observed, the NOR test revealed MPTP-induced long-term memory impairment, which was fully restored by synaptamide. Conclusions. These findings suggest that synaptamide may exert effects on pathological processes associated with PD, warranting further investigation into its potential role in combination or supportive therapy for this disease. Full article

Objective: Neuroinflammation contributes to cognitive impairment across neurodegenerative disorders. Prostaglandins (e.g., PGE₂, PGD₂, PGF₂α) and pro-inflammatory cytokines (TNF-α, IL-1β) are key mediators of lipopolysaccharide (LPS)-induced hippocampal dysfunction. Carvacrol (CRV), a monoterpenic phenol with anti-inflammatory and antioxidant properties, may mitigate these effects, but its impact on hippocampal prostaglandin profiles is not well-defined. Methods: BALB/c mice were randomly assigned to Control (PBS; n = 7), LPS (1 mg/kg, i.p.; n = 10), or LPS + CRV (50 mg/kg, p.o.; n = 7). Body weight was tracked daily for 7 days; rectal temperature was measured once before behavioral testing and euthanasia. Locomotion/anxiety were assessed by the open-field test (OFT; average speed, total distance, freezing, mobility rate) using ToxTrac. Spatial recognition memory was evaluated in the Y-maze novel-arm task (novel-arm entries, duration, total entries, discrimination index [DI]). Hippocampal PGE₂, PGD₂, PGF₂α, TNF-α, and IL-1β were quantified by ELISA. Data were analyzed by one-way ANOVA with Sidak’s post hoc test. Results: OFT measures did not differ among groups (p > 0.05), indicating no confounding locomotor deficits. In the Y-maze, LPS reduced novel-arm entries versus the Control (p = 0.0029), while LPS + CRV showed a nonsignificant increase versus LPS (p = 0.2406). Novel-arm duration differed among groups (p = 0.0033); LPS + CRV spent less time than LPS (p = 0.0128). Critically, DI showed a robust treatment effect (p < 0.0001): LPS markedly impaired DI versus the Control (p < 0.0001), and CRV significantly improved DI versus LPS (p < 0.0001). Biochemically, LPS elevated hippocampal PGE₂ (p < 0.0001) and PGF₂α (p = 0.0040); CRV normalized PGE₂ (p < 0.0001) but not PGF₂α (p = 0.2656). PGD₂ was unchanged. LPS increased TNF-α and IL-1β (both p < 0.0001), and CRV significantly reduced both versus LPS (both p < 0.0001). Conclusions: Acute LPS provokes prostaglandin- and cytokine-driven hippocampal inflammation with associated recognition memory deficits. Carvacrol attenuates cognitive impairment and suppresses hippocampal PGE₂, TNF-α, and IL-1β, supporting a mechanism involving modulation of the prostaglandin–cytokine axis. These findings highlight CRV as a candidate adjunct for inflammation-associated cognitive dysfunction. Full article

The potential health hazards caused by microwave exposure have attracted increasing attention. Microwave radiation has been reported to induce oxidative stress in neural tissues, which is considered one of the primary mechanisms underlying its adverse effects on central nervous system function. The hippocampus is sensitive to microwave radiation, whereas underlying cellular and molecular mechanisms remain incompletely understood. In this study, microwave-exposed mice exhibited significantly impaired performance in the Go/No-go, Y-maze, and novel object recognition tests at 6 h and 7 days post-exposure, indicating deficits in hippocampus-dependent working memory. Single-cell RNA sequencing of hippocampal tissues from control and microwave-exposed mice yielded 94,088 high-quality cells across eight major cell types. Astrocyte sub-clustering identified five transcriptionally distinct subpopulations, with Astrocyte_S100a6 and Astrocyte_Son proportions increased and Astrocyte_Serpinf1 decreased in the radiation group. Analysis of astrocyte transcriptional state transitions showed microwave-exposed astrocytes were preferentially distributed toward terminal reactive states with depletion at early homeostatic nodes. Cell–cell communication analysis revealed increased total interactions and interaction strength following radiation. Astrocyte outgoing signaling was increased for pathways associated with vascular remodeling, phagocytic regulation, and neuroinflammation, while pathways related to trophic support were decreased. Incoming signaling showed increased activity in pathways linked to phagocytic recruitment and inflammatory mediation. Taken together, these findings indicate that microwave exposure is associated with hippocampus-dependent working memory deficits accompanied by transcriptional remodeling of astrocyte subpopulation composition, directional astrocyte state transitions toward reactive phenotypes, and broad alterations in astrocyte-centered intercellular communication, providing a cellular and molecular framework for understanding astrocyte involvement in microwave radiation-associated hippocampal dysfunction. Full article

Background: Acute carbon monoxide (CO) poisoning can cause delayed neuropsychiatric sequelae (DNS) after a latent period, yet its pathophysiology remains poorly understood because of the lack of reproducible experimental models. Methods: We established a rat model of DNS using acute CO poisoning (6500 ppm for 25 min). Behavioral assessments evaluated cognition, locomotion, sensorimotor function, exploratory behavior, and reward responsiveness. Histopathological analyses assessed brain injury, and regional monoamine concentrations were quantified using high-performance liquid chromatography. Results: CO-exposed rats developed delayed and progressive behavioral abnormalities, including impaired spatial working memory, reduced locomotor activity, sensorimotor dysfunction, and diminished exploratory behavior. At 4 weeks, CO-exposed rats showed reduced Y-maze alternation (49.3% vs. 72.2%, p < 0.0001), complete loss of tape-removal success (0% vs. 100%, p < 0.001), reduced digging behavior (10.1 ± 6.9 vs. 27.4 ± 3.9, p < 0.01), and decreased locomotor activity (330.5 ± 172.1 vs. 730.5 ± 139.5 cm, p < 0.01). In contrast, olfactory discrimination, sucrose preference, and grip strength were preserved. Histopathology demonstrated persistent neuronal and inflammatory alterations. Dopamine concentrations were significantly reduced in the cortex and basal ganglia, whereas thalamic serotonin levels were increased following CO poisoning. Conclusion: Acute CO poisoning induces a reproducible DNS characterized by progressive behavioral impairment, persistent histopathological abnormalities, and regional monoaminergic dysregulation. These findings support the concept that DNS is an evolving neuropathological process and identify dopaminergic pathways as potential therapeutic targets. Full article

Alzheimer’s disease (AD) and metabolic syndrome often occur together, sharing characteristics such as insulin resistance, dyslipidemia, and chronic inflammation. Metabolic dysfunction frequently precedes cognitive decline, indicating that early intervention might alter the disease’s progression. We investigated whether the GLP-1 receptor agonist semaglutide (SMGL) influences metabolic impairment and AD pathology in an AD mouse model. Male and female 5xFAD and wild-type (WT) mice on regular (RD) or high-fat diets (HFD) were administered SMGL for 13 weeks. SMGL-treated groups exhibited significant, context-dependent effects. In metabolically challenged 5xFAD HFD mice, treatment led to reduced body weight, improved glucose tolerance, normalized cholesterol levels, and a restored balance of adiponectin and leptin. These improvements were associated with reduced Aβ40 and Aβ42 levels, restored GLP-1 receptor expression, increased synaptophysin and βIII-tubulin levels, and enhanced spatial memory. SMGL also decreased Iba1 and CD68 immunoreactivity in the hippocampus and cortex, reduced macrophage infiltration, and lowered CD36 expression in visceral adipose tissue (VAT), indicating coordinated anti-inflammatory effects. WT RD mice showed minimal metabolic responses and a modest decline in Y-maze performance, suggesting that excessive GLP-1 receptor activation may disrupt neuronal homeostasis when metabolic status is normal. SMGL acts as a context-specific metabolic and neuroprotective agent, offering the greatest benefits under conditions of metabolic dysfunction. These findings in a preclinical model suggest that targeting early metabolic disturbances provides a testable hypothesis for attenuating AD-related neurodegeneration, though further translational studies are required. Full article

Bacopa monnieri (BM) is a traditional medicinal herb that has been reported to have neuroprotective and cognitive-enhancing properties. In this study, the antioxidant, safety, and neuroprotective properties of BM extract (BME) were assessed in a lipopolysaccharide (LPS) model of cognitive impairment. Ethanol was used for extraction, after which the ethanolic extract was profiled to characterize total phenolic and flavonoid content and major bioactive constituents. The assessment of antioxidant activity was done through several in vitro tests (DPPH, ABTS, FRAP, NBT, OARC, and metal chelation). Toxicity was assessed in Caenorhabditis elegans using pharyngeal pumping and food clearance tests. For in vivo evaluation, rats were pre-treated with BME, and then LPS was administered, followed by evaluation of cognitive performance by the Morris water maze and Y-maze test. Phytochemical examination revealed the existence of phenolics and flavonoids, as well as bacoside A components. The extract showed good antioxidant activity, mainly via hydrogen atom transfer and single-electron transfer, suggesting effective radical scavenging and reducing ability, but no metal chelating activity was observed. Toxicity tests demonstrated that lower concentrations of the extract were well tolerated, and higher concentrations resulted in temporary inhibition of feeding behavior, indicating mild, dose-dependent effects. In the LPS-induced rat model, the inflammatory challenge produced significant cognitive deficits relative to normal controls, validating the model. Pre-treatment with BME at 70 mg/kg did not produce statistically significant rescue of any behavioral endpoint compared with the LPS-only group, although small-to-medium effect sizes in the protective direction were observed for several measures. Additionally, BME modulated LPS-induced neuroinflammatory responses by reducing cortical IL-1β, TNF-α, iNOS, and COX-2 levels while enhancing hippocampal AChE and PGE2 activity, suggesting region-specific anti-inflammatory and cholinergic regulatory effects. The most robust positive findings of this study are therefore the phytochemical characterization and the in vitro antioxidant profile of this standardized extract, which support its potential as a candidate for further investigation in inflammation-related cognitive impairment; the in vivo findings are preliminary and warrant confirmation in larger-scale, dose-ranging studies. Full article

Background/Objectives: Neuroinflammation is increasingly recognized as an important contributor to Alzheimer-like cognitive impairment. Lipopolysaccharide (LPS) is commonly used in experimental models to trigger systemic immune activation and behavioral alterations associated with neuroinflammation. This study aimed to validate a subacute LPS-induced model of recall-phase impairment and to compare the effects of donepezil and tacrine on recall-related exploratory behavior in rats. Methods: Male Wistar rats were tested in a two-trial Y-maze paradigm consisting of an acquisition trial followed by a recall trial 24 h later. In the validation experiment, rats received saline or LPS 1 mg/kg intraperitoneally for four consecutive days. In the intervention experiment, rats received saline, LPS, or LPS combined with donepezil 1 or 3 mg/kg or tacrine 3 or 5 mg/kg. The primary recall-phase outcome was the unknown/known arm time ratio (U/K time ratio). Additional outcomes included arm times, arm entries, U/K entry ratios, discrimination indices, and mean time per entry. Results: Repeated LPS administration significantly reduced the U/K time ratio, decreased time- and entry-based discrimination indices, reduced time spent in the unknown arm, and decreased unknown-arm entries, without significantly altering acquisition-phase behavior, total entries, or mean time per entry. In the intervention experiment, donepezil 1 mg/kg and tacrine 5 mg/kg significantly increased the U/K time ratio compared with LPS. Discrimination indices and entry-based measures further supported a treatment-related shift toward novelty-directed exploration, while total arm entries and mean time per entry were not significantly changed. Conclusions: Subacute LPS administration produced a measurable recall-phase exploratory impairment in the Y-maze. Donepezil and tacrine attenuated several components of this impairment, with partially distinct dose-related behavioral profiles. Full article

Alzheimer’s disease (AD) lacks effective disease-modifying therapies, and extracellular vesicles (EVs) derived from adipose-derived mesenchymal stromal cells (ADMSCs) have emerged as promising therapeutic candidates. In this study, we investigated the brain biodistribution and dose-dependent effects of intranasally administered ADMSC-EVs in female APP/PS1 mice, with age-matched wild-type mice and vehicle-treated transgenic mice serving as controls. EV biodistribution was assessed using PKH26 labeling, cognitive performance was evaluated using the Morris water maze, Y-maze, and novel object recognition tests, and hippocampal amyloid pathology and plasma AD-related biomarkers were analyzed. Intranasally delivered ADMSC-EVs rapidly reached multiple brain regions, including the hippocampus, improved learning and memory performance, and reduced hippocampal amyloid-β 1-42 (Aβ42) deposition and plaque burden. These effects followed a nonlinear dose–response pattern, with reduced efficacy at low doses and no additional benefits at high doses. Notably, partial behavioral and pathological benefits persisted after treatment cessation. Together, these findings show that intranasal ADMSC-EVs exert therapeutic effects in APP/PS1 mice and support the importance of dose optimization and post-treatment durability in the development of EV-based interventions for AD. Full article

Background: Postmenopausal women are at high risk of Alzheimer’s disease (AD) incidence and progression. Irisin, an exercise-induced myokine, has neuroprotective and antiaging effects against AD, especially in menopausal women suffering from insulin resistance (IR). For the first time, the novel role of irisin induced by melatonin (MTN) or/and physical exercise (PHE) was investigated in the current ovariectomized (OVX)/AD rat model by modulating brain neuroinflammation and IR-related markers. Methods: Fifty female Wistar rats were divided into five groups, with one representing a sham group. AD was induced in the other four bilateral OVX rat groups by daily intraperitoneal injection of D-galactose/AlCl₃ (60 and 10 mg/kg, respectively) for 42 days. Group III–V: Animals were exposed to MTN (10 mg/kg/day; i.p.), PHE, and a combination of these, respectively, in the final 14 days of the experiment. Results: The OVX/AD rats showed significant deterioration in learning, memory, neurochemical, and histopathological examinations, while the MTN or/and PHE treatments significantly increased serum and brain irisin, improving memory in a Y-maze assessment. Thus, hippocampal histopathological alterations and IR-related markers decreased. In addition, suppressed hippocampal amyloid-beta protein expression and neuroinflammatory content of tumor necrosis factor-alpha (TNF-α), p38 mitogen-activated protein kinase (p38 MAPK), and NOD-like receptor protein-3 (NLRP3) were associated with an increase in peroxisome proliferator-activated receptor-gamma (PPAR-γ) protein expression and insulin-like growth factor-1 content in hippocampal tissues, collectively suppressing glial fibrillary acidic protein (GFAP) content, leading to an increase in brain-derived neurotrophic factor expression. Conclusions: Irisin induction may serve as a novel avenue in AD/menopause treatment and prevention via modulating the TNF-α/p38 MAPK/PPAR-γ/NLRP3/GFAP pathway. Full article

Background: To evaluate the neuroprotective effect of nicotinamide mononucleotide (NMN), an NAD⁺ precursor, in a D-galactose-induced aging mouse model. Chronic D-galactose administration is widely used to establish age-related cognitive impairment driven by oxidative stress. Methods: Mice received subcutaneous D-galactose for six weeks, concomitantly with oral NMN (300 or 500 mg/kg). Cognitive function was assessed using the Y-maze test and the Elevated Plus Maze test. Oxidative stress indicators, inflammatory cytokines, and Nrf2/HO-1 pathway components were measured by ELISA, Western blotting, and Immunohistochemistry. Gut microbiota composition was analyzed via 16S rRNA sequencing. Results: NMN supplementation improved spatial memory without affecting anxiety-related behavior. NMN enhanced the activities of antioxidant enzymes (SOD, GSH, CAT), reduced malondialdehyde and pro-inflammatory cytokine levels and decreased microglial activation in the hippocampus. Furthermore, NMN remodeled the gut microbiota by increasing butyrate-producing taxa (such as Butyrivibrio_A and Clostridium_T) and activated the Nrf2/HO-1 signaling pathway. Conclusions: NMN alleviates age-related cognitive decline in mice by reducing oxidative stress, suppressing neuroinflammation, and modulating the gut microbiota. Targeting the gut–brain axis and the Nrf2/HO-1 pathway may therefore represent a promising therapeutic strategy for age-related neurodegeneration. Full article

Dietary factors play an important role in cognitive health during aging. Dark tea has shown potential cognitive benefits, but its key bioactive component and underlying mechanisms remain unclear. In a naturally aged C57BL/6J mouse model, instant dark tea (IDT) samples with different fermentation degrees were evaluated together with behavioral outcomes using composition–effect relationship analysis. This analysis identified theabrownin (TB) as the component most strongly associated with improved cognitive performance. Compared with aged controls, TB increased Y-maze spontaneous alternation from 51.91% to 71.59% and reduced escape latency on day 5 of the Morris water maze from 44.84 s to 26.59 s. In contrast, the corresponding TB-depleted fraction produced no comparable cognitive improvement. TB also alleviated hippocampal injury and neuroinflammation. Antibiotic treatment abolished the cognitive benefits of TB, whereas fecal microbiota transplantation partially restored them. Multi-omics analyses suggested that TB treatment was associated with gut microbiota remodeling and increased serum acetate and 3-hydroxybutyrate; both metabolites partially recapitulated these benefits. Together, these findings show that TB attenuates age-related cognitive decline in naturally aged mice and suggest that modulation of gut microbiota and metabolites may contribute to this effect, supporting its potential as a functional food ingredient for healthy brain aging. Full article

This study addresses the problem of robust video-based tracking of laboratory rats in open-field and Y-maze experiments under challenging acquisition conditions, including non-uniform illumination, low contrast, and heterogeneous recording setups. Existing approaches based on classical image processing or deep learning often fail to maintain stable localization under such conditions or require large, annotated datasets. We propose a hybrid tracking framework that combines an improved motion–appearance voting mechanism with consistency-constrained optimization for open-field experiments, together with a comparative deep learning-based detection strategy for Y-maze analysis. The proposed method introduces (i) adaptive dual-threshold motion extraction, (ii) directionally constrained temporal validation, and (iii) a robustness-driven fusion of motion and appearance cues. Experimental results demonstrate that the proposed approach achieves reliable tracking with a maximum localization error below 10 pixels under severe illumination variations. In the Y-maze scenario, a comparative evaluation of multiple detectors (YOLOv5, YOLOv9, YOLO12, Faster R-CNN) highlights the trade-off between accuracy and inference time, with YOLOv9 providing the best balance. The main contribution consists of enabling robust behavioral quantification in low-quality experimental conditions using limited training data, bridging the gap between classical tracking robustness and deep learning flexibility. Full article

Aluminum chloride (AlCl₃)-induced rat models are widely used to investigate Alzheimer-like neurodegeneration, yet substantial methodological variability limits cross-study comparability. A structured synthesis focused specifically on the methodological architecture of these models, including dose, exposure duration, route of administration, and behavioral assessment, remains lacking. This review aimed to synthesize the behavioral paradigms used to assess learning and memory in rat models of aluminum chloride-induced Alzheimer’s disease, with particular emphasis on dose, duration, and route of administration. A structured narrative review incorporating systematic elements was conducted following PRISMA-informed procedures using PubMed, Web of Science, and Scopus. The reviewed literature showed a predominance of oral administration, low-to-moderate AlCl₃ doses and subchronic exposure durations, most commonly 31–60 days. Behavioral assessment was dominated by hippocampal-dependent paradigms, particularly the Morris water maze and Y-maze. Across studies, AlCl₃ exposure was associated with multidomain behavioral impairment accompanied by consistent hippocampal and cortical histopathological abnormalities and convergent biochemical and molecular changes, including cholinergic dysfunction, oxidative stress, neuroinflammation, and amyloid- and tau-related alterations. Overall, the available literature does not support a standardized experimental protocol or a clear overall dose–effect or duration–effect relationship. Greater harmonization of study design is needed to improve reproducibility and translational relevance. Full article

According to the most recent data published by the World Health Organization (WHO), it is estimated that approximately 332 million persons worldwide suffer from depression. The relationship between depression and alcohol consumption is complex and bidirectional. This study aimed to investigate the effects of cannabidiol (CBD) on behavior and malondialdehyde (MDA) imbalance in female Wistar rats exposed to chronic stress and alcohol. Sixteen intact cycle female 5-month-old Wistar rats were randomly assigned to two groups: the Control group (n = 8), and the CBD group (n = 8), which received CBD at a dose of 10 mg/kg. Following chronic stress induction, during the three-week treatment period, the animals were exposed to alcohol on three separate occasions. CBD-treated females showed increased freezing time in the Open Field test with no clear anxiolytic effect. In the Y maze and Morris Water Maze, they exhibited improved memory-related performance. Brain MDA levels were reduced, while plasma MDA was unchanged. Cortisol tended to be higher in the CBD group. CBD administration showed potential cognitive and central antioxidant effects, but no clear anxiolytic effect. Full article

Background: Standardized and ethically compliant animal models remain essential for improving translational research in Alzheimer’s disease. Although Aβ_1–42-induced rodent models are widely used, methodological variability continues to limit reproducibility. Methods: We explored the feasibility of a stereotactic intrahippocampal Aβ_1–42 rat model established by bilaterally injecting pre-aggregated peptide into the hippocampus of adult Sprague Dawley rats. Model feasibility and targeting accuracy were assessed intraoperatively. Cognitive performance was evaluated using the Y-maze for spatial recognition memory and the novel object recognition (NOR) test. Histological examination was performed using hematoxylin–eosin (H&E) and Congo red staining to assess cytoarchitecture and to provide supportive evidence of amyloid-like deposits. Results: The surgical procedure was well-tolerated, and the injected animals showed reduced performance in behavioural testing, including reduced spatial recognition memory in the Y-maze and decreased discrimination indices in the NOR test. The animals also showed histological changes, including Congo red-positive birefringent structures consistent with amyloid-like congophilic material. Conclusions: This study presents a feasible experimental framework for intrahippocampal Aβ_1–42 administration, showing behavioural and histological changes under the present experimental conditions. However, further validation, including sham-operated controls and molecular characterization, will be required before these findings can be interpreted as specific to Aβ-driven pathology. Full article