Search Results (429)

Functional recovery after traumatic brain injury (TBI) is hindered by progressive neurodegeneration resulting from neuroinflammation and other secondary injury processes. Dexamethasone (DX), a synthetic glucocorticoid, has been shown to reduce inflammation, but its systemic administration can cause a myriad of other medical issues. We aim to provide a local, sustained treatment of DX for TBI. Previously, we demonstrated that PEG-bis-AA/HA-DXM hydrogels composed of polyethyleneglycol-bis-(acryloyloxy acetate) (PEG-bis-AA) and dexamethasone-conjugated hyaluronic acid (HA-DXM) reduced secondary injury and improved motor functional recovery at 7 days post-injury (DPI) in a rat moderate controlled cortical impact (CCI) TBI model. In this study, we evaluated the effect of PEG-bis-AA/HA-DXM hydrogel on cognitive function and secondary injury at 14 DPI. Immediately after injury, hydrogel disks were placed on the surface of the injured cortex. Cognitive function was evaluated using the Morris Water Maze test, and secondary injury was evaluated by histological analysis. The hydrogel treatment group demonstrated significantly shorter latency to target, decreased distance to find the hidden target, increased number of target crossings, increased number of entries to the platform zone, and decreased latency to first entry of target zone compared to untreated TBI rats for probe test. We also observed reduced lesion volume, inflammatory response, and apoptosis in the hydrogel treatment group compared to the untreated TBI group. Full article

Background/Objectives: Lactobacillus kefiranofaciens HL1, isolated from kefir, exhibits antioxidant and anti-aging activities, defined here as improved cognitive function and reductions in oxidative stress and inflammatory markers. However, its poor milk viability limits application. This study developed a novel fermented milk by co-culturing HL1 with Lactococcus lactis subsp. cremoris APL015 (APL15) to enhance fermentation and health benefits. Methods: HL1 and APL15 were co-cultured to produce fermented milk (FM), and fermentation performance, microbial viability, texture, and syneresis were evaluated. A D-galactose-induced aging BALB/c mouse model was used to assess cognitive function, oxidative stress, inflammation, antioxidant enzyme activity, and gut microbiota after 8 weeks of oral administration. Results: FM reached pH 4.6 within 16 h, with high viable counts (~10⁹ CFU/mL) for both strains. HL1 viability and texture were maintained, with smooth consistency and low syneresis. In vivo, FM improved cognitive behavior (Y-maze, Morris water maze), reduced oxidative damage (MDA), lowered IL-1β and TNF-α, and enhanced brain SOD levels. FM-fed mice exhibited increased short-chain fatty acid producers, higher cecal butyrate, and reduced Clostridium perfringens. Conclusions: The co-cultured fermented milk effectively delivers HL1 and provides antioxidant, anti-inflammatory, and anti-aging effects in vivo, likely via gut–brain axis modulation. It shows promise as a functional food for healthy aging. Full article

Background/Objectives: The hippocampus is an essential part of the central nervous system (CNS); it plays a significant role in social–cognitive memory processing. Prenatal exposure to valproic acid (VPA) can lead to impaired hippocampal functions. In this study, we evaluated the effect of plumbagin (PLB) as a natural product on spatial learning and memory, neuro-morphological changes, and inflammation levels in a VPA-induced autism model during adolescence. Methods: Pregnant Wistar rats received a single intraperitoneal (i.p.) injection of VPA (600 mg/kg) or saline on gestational day 12.5. The male offspring were then categorized and assigned to five groups: Saline+DMSO-, VPA+DMSO-, and VPA+PLB-treated groups at doses of 0.25, 0.5, or 1 mg/kg. Spatial learning and memory were evaluated using the Morris water maze. Histopathological evaluations of the hippocampus were performed using Nissl and hematoxylin–eosin staining, as well as immunofluorescence. The pro-inflammatory cytokine levels were also quantified by quantitative real-time PCR. Results: The findings revealed that a VPA injection on gestational day 12.5 is associated with cognitive impairments in male pups, including a longer escape latency and traveled distance, as well as decreased time spent in the target quadrant. Treatment with PLB significantly enhanced the cognitive function, reduced dark cells, and ameliorated neuronal–morphological alterations in the hippocampus of VPA-exposed rats. Moreover, PLB was found to reduce astrocyte activation and the expression levels of pro-inflammatory cytokines. Conclusions: These findings suggest that PLB partly mitigates VPA-induced cognitive deficits by ameliorating hippocampal inflammation levels. Full article

Background and Objectives: Alzheimer’s disease (AD) has become a serious health problem. Agomelatine (Ago) is a neuroprotective antidepressant. This study aimed to assess how Ago influences behavioral outcomes in AD-like rat model. Materials and Methods: Forty-eight Wistar albino rats were allocated into four groups: Control (C), Alzheimer’s disease-like model (AD), Alzheimer’s disease-like model treated with Ago (ADAgo), and Ago alone (Ago). Physiological saline was injected intrahippocampally in C and Ago animals, whereas Aβ peptide was delivered similarly in AD and ADAgo rats. On day 15, 0.9% NaCl was administered to the C and AD groups, and Agomelatine (1 mg/kg/day) was infused into ADAgo and Ago rats via osmotic pumps for 30 days. Behavioral functions were evaluated using Open Field (OF), Forced Swim (FST), and Morris Water Maze (MWM) tests. Brain tissues were examined histopathologically. Neuritin, Nestin, DCX, NeuN, BDNF, MASH1, MT1, and MT2 transcripts were quantified by real-time PCR. Statistical analyses were performed in R 4.3.1, with p < 0.05 deemed significant. Results: In the FST, swimming, climbing, immobility time, and mobility percentage differed significantly among groups (p < 0.05). In the MWM, AD rats exhibited impaired learning and memory that was ameliorated by Ago treatment (p < 0.05). DCX expression decreased in AD rats but was elevated by Ago (p < 0.05). Nestin levels differed significantly between control and AD animals; MT1 expression varied between control and AD cohorts; and MT2 transcript levels were significantly lower in AD, ADAgo, and Ago groups compared to C (all p < 0.05). Conclusions: Ago exhibits antidepressant-like activity in this experimental AD model and may enhance cognitive function via mechanisms beyond synaptic plasticity and neurogenesis. Full article

Alzheimer’s disease (AD) is a neurodegenerative condition in which amyloid-beta (Aβ) plaques trigger oxidative stress (OS) and neuroinflammation, causing memory loss. OS and neurodegeneration can also be caused by reactive astrocytes, thereby promoting AD via toxic metabolite accumulation in the astrocytic urea cycle. However, the effect of molecular hydrogen (H₂) on this cycle remains unknown. Therefore, we investigated whether H₂ treatment could reduce OS-induced neurodegeneration and memory loss. 5xFAD (n = 14) and wild-type (n = 15) mice were randomized into four groups and treated with either 3% hydrogen gas (H₂) or vehicle for 60 days. Cognitive behaviors were evaluated using the Morris water maze and Y-maze tests. In addition, we used biochemical assays to measure ammonia and hydrogen peroxide (H₂O₂) levels in the hippocampi of the mice and AβO-treated primary mouse astrocytes. Aβ, γ-aminobutyric acid (GABA), and the expression of inflammatory markers were evaluated using immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT-PCR). We observed that H₂ treatment significantly prevented cognitive deficits, oxidative stress, the accumulation of toxic metabolites, and the increase in inflammatory markers in 5xFAD mice. These results suggest that H₂ therapy can mitigate toxic metabolites in the astrocytic urea cycle, thereby reducing neurodegeneration and memory loss in AD. Full article

The spatial orientation of mammals and birds has been intensively studied for many years, but the cognitive mechanism of spatial orientation and memory used by squamates remains poorly understood. Our study evaluated the learning and memory abilities of leopard geckos (Eublepharis macularius) in an adapted Morris water maze. The animals learned during the training phase consisted of 20 trials. To assess long-term memory, we retested geckos twice after several months. The geckos remembered the learned information in a short re-test after two months, but after four months, they required retraining to find the platform. We hypothesise that the duration of memory corresponds with short-term changes in semi-desert environments within one season, while disruption of memory performance after a six-month gap may simulate the more extensive seasonal change in spatial relationships in their natural environment. Moreover, during the winter period, geckos exhibit low activity, which can be connected with decreased frequency of foraging trips. Therefore, the memory loss after four months may reflect the low level of memory jogging. The motivation during the experiment was the crucial parameter of learning and memory processes. In later phases, geckos were less motivated to perform the task. Finally, they relearned the spatial orientation task, but they moved more slowly as the experiment progressed. Full article

Background/Objectives: Creatine monohydrate supplementation has gained popularity in the fitness industry due to its ability to enhance athletic performance and has sparked curiosity about other possible effects of the supplement. The purpose of this study was to examine the effect of creatine supplementation on spatial working memory, body weight, and food intake in male and female rats. Methods: Experimental rats, six male and six female, were administered creatine while six male and six female rats served as controls. The Morris water maze (MWM) was employed to assess spatial working memory. Body weight and food intake were measured daily. Results: Neither male control nor experimental animals demonstrated positive working memory upon initial exposure (week 1) to the MWM, whereas the initial exposure of female control and experimental animals resulted in positive working memory. By week 2 of the experimental period, all animals in both the control and experimental groups showed significant working memory with no significant differences among the groups. These effects were unrelated to creatine supplementation. Gender-specific differences were found for body weight, with higher weight gain observed in male rats compared to female rats. Weight gain was not directly influenced by creatine supplementation; however, food intake was lower in the experimental male rats receiving the supplement as compared to the control rats. No difference was observed in female rats. Conclusions: Because of the popularity of creatine, further research about the effects of this supplement on different mechanisms in the body influencing cognitive processing and appetitive behavior is warranted. Full article

This study aims to investigate the mechanism by which the total flavones of Rhododendron (TFR) protect against cerebral ischemic injury through the endothelial-derived H₂S-mediated regulation of RhoA phosphorylation at the Ser188 and Rho kinase 2 (ROCK₂) phosphorylation at Thr436. For experimental design, mouse or rat cerebrovascular endothelial cells (ECs) were cultured with or without neurons and subjected to hypoxia/reoxygenation (H/R) injury. The vasodilation of the cerebral basilar artery was assessed. Cerebral ischemia/reperfusion (I/R) injury was induced in mice by bilateral carotid artery ligation, followed by Morris water maze and open field behavioral assessments. The protein levels of cystathionine-γ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (3-MST), RhoA, ROCK₂, p-RhoA (RhoA phosphorylated at Ser188), and p-ROCK₂ (ROCK₂ phosphorylated at Thr436) were quantified. Additionally, the activities of RhoA and ROCK₂ were measured. Notably, TFR significantly inhibited H/R-induced H₂S reduction and suppressed the increased expression and activity of RhoA and ROCK₂ in ECs, effects attenuated by CSE or 3-MST knockout. Moreover, TFR-mediated cerebrovascular dilation was reduced by RhoA or ROCK₂ inhibitors, while the protective effect of TFR against cerebral I/R injury in mice was markedly attenuated by the heterozygous knockout of ROCK₂. In the ECs-co-cultured neurons, the inhibition of TFR on H/R-induced neuronal injury and decrease in H₂S level in the co-culture was attenuated by the knockout of CSE or 3-MST in the ECs. TFR notably inhibited the H/R-induced upregulation of neuronal RhoA, ROCK₂, and p-ROCK₂ protein levels, as well as the activities of RhoA and ROCK₂, while reversing the decrease in p-RhoA. However, the knockout of CSE or 3-MST in the ECs significantly attenuated the inhibition of TFR on these increases. Furthermore, 3-MST knockout in ECs attenuated the TFR-mediated suppression of p-RhoA reduction. Additionally, CSE or 3-MST knockout in ECs exacerbated H/R-induced neuronal injury, reduced H₂S level in the co-culture system, and increased RhoA activity and ROCK₂ expression in neurons. In summary, TFR protected against ischemic cerebral injury by endothelial-derived H₂S promoting the phosphorylation of RhoA at Ser188 but inhibited the phosphorylation of ROCK₂ at Thr436 to inhibit the RhoA-ROCK₂ pathway in neurons. Full article

Cognitive problems are associated with impaired learning ability and memory dysfunction. Neuroinflammation has been identified as an important factor in the progression of anxiety and depressive disorders. Zingerone is a phenolic alkanone derived from ginger (Zingiber officinale Roscoe), which is known for its antioxidant and anti-inflammatory properties. A number of studies have investigated the effect of zingerone on neuroinflammation and cognitive impairment. However, this evidence has not been systematically reviewed. This study sought to systematically review the effect of zingerone on neuroinflammation and neurobehavioural changes associated with memory and learning impairment and anxiety-like and depressive-like behaviours. A systematic review was conducted using pre-defined search criteria on Google Scholar, Scopus and Web of Science. The records obtained were screened based on inclusion criteria, and data was extracted from the included studies. Out of the 482 studies that were identified, only 9 studies met the inclusion criteria. Neuroinflammatory markers such as interleukin 1β (IL-1β), interleukin 6 (IL-6), tumour necrosis factor-alpha (TNF-α) and ionized calcium binding adaptor molecule (IBA-1), as well as behavioural parameters including Morris water maze, Y-Maze, recognition test, passive avoidance test, elevated plus maze, sucrose preference test and forced swimming test were measured. Zingerone exhibited anti-neuroinflammatory effects by improving IL-1β, IL-6 and TNF-α levels. However, zingerone did not show any significant changes on activated microglia. The anti-neuroinflammatory mechanisms of zingerone were linked to the inhibition of nuclear factor kappa B (NF-kB) activation and the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome, as well as the reduction in neuronal nitric oxide synthase (nNOS). The anxiolytic and anti-depressive effects of zingerone were also associated with an improvement in cortical cholinergic transmission, the mitigation of oxidative stress and the upregulation of neurotransmitters such as serotonin and dopamine. This review provides scientific evidence on the cognitive enhancing and neuroprotective mechanisms of zingerone, which may be beneficial for future experimental investigations. Full article

Neuroinflammation, triggered by lipoxygenase (LOX), contributes to Alzheimer’s disease (AD) progression. Overexpression of LOX-5 in patients with AD serum highlights its role. This study assessed the efficacy of the LOX-inhibitor-peptide YWCS in an AD rat model induced by Aβ_25–35 injection. Cognitive tests, magnetic resonance imaging (MRI) scans, and molecular analyses were conducted. YWCS treatment significantly improved cognitive function, as evidenced by improved performance in the open field, novel object recognition, elevated plus maze, and Morris water maze tests. MRI scans revealed hippocampal shrinkage in AD rats and no changes were observed from YWCS treatment. Molecular analysis revealed altered expression of LOX-5, LOX-12, Aβ, γ-secretase components, p-Tau¹⁸¹, Akt, p-Akt, and p53 in AD rats. Immunofluorescence staining confirmed increased expression of LOX, Aβ, and p-Tau¹⁸¹ in the hippocampus of AD rats, which was reduced by YWCS treatment. Serum LOX levels were elevated in AD rats and significantly decreased after YWCS treatment, aligning with previous findings in human AD patients and AD cell models. YWCS offered improvements in behavioral and inflammatory marker regulation and also prevented progression of the disease, as shown by MRI results. These results suggest that YWCS, by targeting LOX, has the potential to be a promising therapeutic agent for AD. Full article

Perioperative neurocognitive disorder (PND) is a concern following anesthesia, particularly in individuals at risk for Alzheimer’s disease (AD). This study compared the cognitive and pathological effects of propofol and remimazolam in a mouse model with AD following surgery. Five-month-old male ApoE4-KI mice underwent abdominal surgery under either propofol (170 mg/kg) or remimazolam (85 mg/kg) anesthesia. Cognitive function was assessed using the Morris water maze and Y-maze, and neuronal apoptosis and amyloid-beta (Aβ) deposition in the CA3 and dentate gyrus (DG) of the hippocampus were evaluated preoperatively and at 2, 4, and 7 days postoperatively. Both groups showed similar postoperative cognitive functions, with increased relative escape latency at day 2 and decreased relative spontaneous alternation at days 4 and 7. However, the neuropathological analysis revealed that propofol-induced significantly more neuronal death in the CA3 (days 4 and 7) and DG (days 2, 4, and 7), and greater Aβ accumulation in the CA3 (days 2 and 4) and DG (days 2 and 7) compared to remimazolam (p < 0.05). Propofol was associated with more pronounced neuropathologic changes in the hippocampus compared to remimazolam. These findings suggest remimazolam may be a safer anesthetic for patients at risk for neurodegenerative disorders, as it is associated with less severe hippocampal pathology, which is characteristic of AD. Full article

Suk-SaiYasna (SSY) is a well-documented traditional Thai herbal formula in the Royal Scripture of King Narai’s Traditional Medicine. SSY contains Cannabis sativa leaves as a key ingredient and has traditionally been used to promote sleep, alleviate stress-related symptoms, and stimulate appetite. This study aimed to investigate the neuroprotective effects of SSY in a mouse model of unpredictable chronic mild stress (UCMS)-induced cognitive impairment and explore the underlying mechanisms, particularly antioxidant enzyme pathways. Behavioral tests, including the Y-maze test, novel object recognition test, and Morris water maze test, demonstrated that UCMS-exposed mice exhibited cognitive impairment compared to non-stress mice. However, SSY treatment significantly improved learning and memory performance in UCMS-exposed mice. Mechanistic studies revealed that SSY reduced lipid peroxidation in the hippocampus and frontal cortex, key brain regions affected by chronic stress. Furthermore, UCMS significantly reduced the activity of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), whereas SSY treatment restored their activity, indicating antioxidative and neuroprotective effects in vivo. Gene expression analysis further revealed that SSY regulates oxidative stress via the Nrf2/Keap1 signaling pathway. In vitro studies using 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay confirmed the radical scavenging activities of SSY and its herbal components, demonstrating significant antioxidant potential. Phytochemical analysis identified delta-9-tetrahydrocannabinol, delta-9-tetrahydrocannabinolic acid A, and cannabinoids as bioactive compounds in SSY, along with potent antioxidants such as gallic acid, myricetin, myristicin, piperine, costunolide, and gingerol. These findings suggest that the SSY formula mitigates UCMS-induced cognitive function through its antioxidant properties via multiple pathways, including radical scavenging activities, modulating the Nrf2-Keap1 pathway, inducing the expression of HO-1, NQO1 mRNAs, and other antioxidant enzymes. This work bridges traditional Thai medicine with modern neuropharmacology. Full article

Background: Alzheimer’s disease (AD) is the most common dementia, characterized by significant cognitive impairments and neural network dysfunction. Currently, multiple therapeutic strategies are being developed to design effective anti-AD drugs. Among them, Withaferin A (WA), a natural steroidal lactone extracted from Withania somnifera leaves, has been shown to reduce amyloid-β (Aβ) peptide levels in vitro. However, its potential to improve cognitive function in AD remains unclear. Methods: In this study, 5xFAD mice were administered WA (2 mg/kg intraperitoneally every 2 days) for 14 days, and its neuroprotective effects were evaluated through behavioral tests, wide-field imaging, immunohistochemistry, and ELISA. Results: WA significantly improved short-term memory, as evidenced by enhanced performance in the Novel Object Recognition Test (NORT) (p < 0.001, n = 10), Novel Location Recognition Test (NLRT) (p < 0.01, n = 14), and Three-Chamber Social Test (TCST) (p < 0.001, n = 8). WA also ameliorated long-term memory deficits in the Morris Water Maze Test (MWMT) (p < 0.05, n = 7). Furthermore, cortical wide-field Ca²⁺ imaging revealed that WA treatment rescued slow-wave impairments by enhancing long-range coherence (0.8363 ± 0.0185, p < 0.01, n = 8) and reducing the frequency of slow-wave activity (0.6578 ± 0.0512 Hz, p < 0.01, n = 8). Additionally, WA treatment significantly reduced Aβ plaque deposition in both cortical and hippocampal regions. Conclusions: These findings suggest that WA may be a promising therapeutic agent for AD, exerting neuroprotective effects. Full article

Mild traumatic brain injury (mTBI), a leading cause of disability in young adults, often results from external forces that damage the brain. Cellularly, mTBI induces oxidative stress, characterized by excessive reactive oxygen species (ROS) and diminished antioxidant capacity. This redox imbalance disrupts hippocampal glutamatergic transmission and synaptic plasticity, where NMDA receptors (NMDARs) are crucial. The exocyst, a vesicle tethering complex, is implicated in glutamate receptor trafficking. We previously showed that Exo70, a key exocyst subunit, redistributes within synapses and increases its interaction with the NMDAR subunit GluN2B following mTBI, suggesting a role in GluN2B distribution from synaptic to extrasynaptic sites. This study investigated whether Exo70 could mitigate mTBI pathology by modulating NMDAR trafficking under elevated oxidative stress. Using a modified Maryland mTBI mouse model, we overexpressed Exo70 in CA1 pyramidal neurons via lentiviral transduction. Exo70 overexpression prevented mTBI-induced cognitive impairment, assessed by the Morris water maze. Moreover, these mice exhibited basal and NMDAR-dependent hippocampal synaptic transmission comparable to sham animals, preventing mTBI-induced deterioration. Preserved long-term potentiation, abundant synaptic GluN2B-containing NMDARs, and downstream signaling indicated that Exo70 overexpression prevented mTBI-related alterations. Our findings highlight Exo70’s crucial role in NMDAR trafficking, potentially counteracting oxidative stress effects. The exocyst complex may be a critical component of the machinery regulating NMDAR distribution in health and disease, particularly in pathologies featuring oxidative stress and NMDAR dysfunction, like mTBI. Full article

As the average age of the population increases, memory impairment has become an increasingly prevalent issue. This study investigates the effects of 14 days of oral birch sap administration on memory functions in healthy rats using the Morris water maze (MWM) test and explores the underlying mechanisms. A compositional analysis revealed that birch soap is rich in polysaccharides, specifically a low-molecular weight polysaccharide (MW 1.29 kDa), and exhibits no hepatotoxicity or renal toxicity at the tested dose. The results from the MWM test demonstrated that the time and distance required to reach the platform were significantly shorter in the birch sap-treated group compared to the control group, suggesting that birch sap supports memory preservation. Moreover, rats treated with birch sap showed improved cerebral blood flow compared to the control rats. Additionally, in hippocampal nerve terminals (synaptosomes), rats treated with birch sap exhibited a significant increase in evoked glutamate release, as well as elevated levels of presynaptic proteins, including vesicular glutamate transporter 1 (VGluT1), synaptophysin, synaptobrevin, synaptotagmin, syntaxin, synapsin I, and the 25 kDa synaptosome-associated protein (SNAP-25). Transmission electron microscopy also revealed a notable increase in the number of synaptic vesicles in hippocampal synaptosomes of the birch-sap-treated rats. These findings suggest that birch sap enhances hippocampal presynaptic glutamatergic functions and cerebral blood flow, contributing to its memory-preserving effects in rats. Full article