Water Maze Test Research Articles

Hippocampal iron overload and spatial reference memory impairment: Insights from a rat model

BackgroundBrain iron overload may induce neuronal death and lead to cognitive impairment. The hippocampus is a critical limbic structure involved in memory. This study aimed to investigate iron overload and its role in hippocampal damage and memory impairment using a rat model. MethodsYoung rats (2 weeks old) received intraperitoneal injections of high-dose iron solution (Group H, n = 10), low-dose iron solution (Group L, n = 10) and normal saline as control (Group D, n = 5). The Morris water maze (MWM) test was performed on all rats to evaluate their spatial reference memory by assessing their escape latency time and number of platform crossing. The iron content and neuronal damage in hippocampal tissue sections of the rats were assessed semi-quantitatively using diaminobenzidine (DAB)-enhanced Perl’s Prussian blue (PPB) staining, and their correlation with spatial reference memory performance was evaluated. ResultsThe escape latency in Group H was significantly longer compared to Groups L and D (P < 0.05). The number of platform crossings was significantly lower in Group H than in Group L or D (P < 0.001). The neuronal cells in Group H had more brown iron deposits than those of Groups L and D. There were significant correlations between the severity of structural damage in the hippocampal tissue and the number of platform crossings (P1 = 0.001 for Group H; P2 = 0.043 for Group L). ConclusionThis study showed an association between hippocampal iron-induced structural damage and spatial reference memory impairment in a rat model. This work should advance our understanding of hippocampal iron overload on cognitive functioning.

TFEB agonist clomiphene citrate activates the autophagy-lysosomal pathway and ameliorates Alzheimer's disease symptoms in mice

Autophagy is a conserved eukaryotic cellular clearance and recycling process through the lysosome-mediated degradation of damaged organelles and protein aggregates to maintain homeostasis. Impairment of the autophagy-lysosomal pathway is implicated in the pathogenesis of Alzheimer’s disease (AD). Transcription factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis. Therefore, activating TFEB and autophagy provides a novel strategy for AD treatment. We previously described that clomiphene citrate (CC) promotes nuclear translocation of TFEB and increases autophagy and lysosomal biogenesis. In this study, 7 and 3-month-old APP/PS1 mice were treated with TFEB agonist CC and assessed. The behavioral tests were performed using Morris water maze and open field test. Additional changes in Aβ pathology, autophagy and inflammatory response were determined. We found that CC activated TFEB and the autophagy-lysosomal pathway in neuronal cells. Moreover, using mouse model of Alzheimer's disease, CC treatment promoted clearance of Aβ plaques and ameliorated cognitive function in both 7 and 3-month-old APP/PS1 mice. The CC-induced activation of TFEB occurs by promoting acetylation of TFEB for nuclear translocation. These findings provide a molecular mechanism for the TFEB-mediated activation of the autophagy-lysosome pathway by CC, which has the potential to be repurposed and applied in the treatment or prevention of AD.

Anti-viral Effects of Pavetta indica Methanolic Extract and Acyclovir on Behavioral and Biochemical Parameters in Streptozotocin-induced Alzheimer's Disease in Rats.

Alzheimer's disease is a neurological dysfunction of the brain caused by neurodegeneration and oxidative stress. Some viruses, such as herpes viruses, HSV-1, and HSV-2, are causative agents of Alzheimer's disease and result in β-amyloid peptide and tau protein accumulation in the brain. Some antiviral drugs, such as valacyclovir, acyclovir, and foscarnet, reduce amyloid-beta and P-tau. Pavetta indica leaves are also reported for their antiviral properties. The current study aimed to find out the significance of using Pavetta indica methanolic extract and acyclovir against Alzheimer's disease induced by streptozotocin. Wistar rats received acyclovir and Pavetta indica methanolic extract orally at different dose ranges (50, 150, 450 mg/kg) and (125, 250, 500 mg/kg), respectively. The standard therapy, Rivastigmine (2 mg/kg), was given orally. Intracerebroventricular-streptozotocin produced significant alternations in behavioral assessments, including locomotor activity test, Morris water maze test, and elevated plus maze test. Moreover, intracerebroventricular-streptozotocin ameliorated the antioxidant defense activity by decreasing levels of catalase, superoxide dismutase, and reduced glutathione while enhancing the oxidative stress markers, including malondialdehyde, and total nitrite levels. Finally, the main findings showed that intracerebroventricular-streptozotocin significantly increased the inflammatory marker, tumor necrosis factor-α, and disturbed neurotransmitter mediators, including levels of acetylcholinesterase, glutamate, and γ-amino butyric acid. In a dose-dependent manner, acyclovir and Pavetta indica methanolic extract treatments abrogated the streptozotocin-induced behavioral and neurological abnormalities in rats. The potential therapeutic effects of PIME and acyclovir administration in intracerebroventricular-streptozotocin-treated rats may be attributed to its potential antiviral, antioxidant, and anti-inflammatory effects. The current study suggests that Pavetta indica methanolic extract and acyclovir are promising therapeutic targets against Alzheimer's disease.

The effects of apelin-13 in a mouse model of post-traumatic stress disorder.

The objective is to investigate the effects of apelin-13 in models of post-traumatic stress disorder (PTSD). Mature male CD1 mice were subjected to the single prolonged stress method to induce PTSD-related behaviors. These behaviors were then evaluated using the elevated plus maze test, Morris water maze test, and open field test. Hippocampal neural cell death was assessed using propidium iodide labeling. The expression of hippocampal autophagy pathway-associated proteins was determined through immunoblotting analysis, and LC3 levels were also measured via quantitative real-time reverse transcription-PCR. The results demonstrate that administration of apelin-13 suppressed PTSD-induced hippocampal neural cell death and alleviated PTSD-related behaviors in mice. Additionally, PTSD led to an up-regulation of LC3 and FoxO3a, and down-regulation of P62, p-PI3K, p-Akt, and p-FoxO3a in the hippocampus. However, these changes were reversed by apelin-13 treatment. These findings support the hypothesis that apelin-13 prevents the development of PTSD-like behavior and inhibits autophagy of neuronal cells in a mouse model of PTSD. Apelin-13 may hold potential as a therapeutic agent for PTSD in clinical applications.

Atractylodes macrocephala polysaccharides shield a D-galactose-induced aging model via gut microbiota modulation

This study explored the effect of a heteropolysaccharide (RAMP) on aging model mice and the importance of changes in the gut microbiota mediated by RAMP for the first time. The findings revealed that RAMP exerted protective effects on cognitive decline and oxidative stress in mice subjected to D-gal-induced aging, potentially by regulating the intestinal flora, according to the results of the Morris water maze test; brain and immune organ indices; hematoxylin and eosin-stained cerebral cortex images; transmission electron microscopy analysis of cortical neurons; and biochemical index measurements. In addition, 16S rRNA sequencing revealed notable changes in the abundance of Acidobacteriota, Anaerovoracaceae, and GCA-900066575 in the mouse model, all of which were abrogated by RAMP. These findings confirm that RAMP regulates the composition of mouse intestinal microorganisms. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) functional analyses linked these changes to 27 metabolic pathways, including those of the nervous system. Furthermore, metabolomics analysis revealed four RAMP-regulated metabolites related to lipid metabolism (2-dodecylbenzenesulfonic acid, N-undecylbenzenesulfonic acid, aspartyl-isoleucine, and 1-palmitoyl-2-(5-oxo-valeroyl)-sn-glycero-3-phosphate), suggesting that the mechanism potentially associated with lipid metabolism regulation. This study provides novel insights into the antiaging mechanisms of RAMP, suggesting its potential use in antiaging treatments.

SARS-CoV-2 spike S1 protein induces microglial NLRP3-dependent neuroinflammation and cognitive impairment in mice

Cognitive impairment is often found at the acute stages and sequelae of coronavirus disease 2019 (COVID-19), and the underlying mechanisms remain unclear. The S1 protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be a cause of cognitive impairment associated with COVID-19. The nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome and neuroinflammation play important roles in Alzheimer's disease (AD) with cognitive impairment. However, their roles remain unknown in COVID-19 with cognitive impairment. We stimulated BV2 cells with S1 protein in vitro and injected the hippocampi of wild-type (WT) mice, NLRP3 knockout (KO), and microglia NLRP3 KO mice in vivo with S1 protein to induce cognitive impairment. We assessed exploratory behavior as associative memory using novel object recognition and Morris water maze tests. Neuroinflammation was analyzed using immunofluorescence and western blotting to detect inflammatory markers. Co-localized NLRP3 and S1 proteins were investigated using confocal microscopy. We found that S1 protein injection led to cognitive impairment, neuronal loss, and neuroinflammation by activating NLRP3 inflammation, and this was reduced by global NLRP3 KO and microglia NLRP3 KO. Furthermore, TAK 242, a specific inhibitor of Toll-like receptor-4, resulted in a significant reduction in NLRP3 and pro-IL-1β in BV2 cells with S1 protein stimulation. These results reveal a distinct mechanism through which the SARS-CoV-2 spike S1 protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses.

Safety Evaluation of a Potential Anti-Rheumatoid Arthritis Candidate, Levamisole.

Given the limitations and adverse effects of current rheumatoid arthritis (RA) treatments, there is an urgent need for safer and more effective therapeutic options. Levamisole (LVM) is a non-specific immunomodulator with potential for treating skin diseases, tumors, and autoimmune disorders. Recognizing LVM's potential despite its controversial reputation, this study aimed to investigate its safety profile and therapeutic efficacy towards RA. To evaluate the potential toxicity of LVM, a 28-day oral administration was conducted in SD rats, assessing general toxicity and neurotoxicity using serum biochemical indicators, the Morris water maze test, transmission electron microscopy, and H&E staining. Subsequently, the therapeutic effects of LVM on RA were evaluated. The results showed that 30 mg/kg LVM has promising therapeutic effects in the treatment of RA with negligible toxicity from 45 mg/kg to 180 mg/kg. This study provides valuable preclinical data on the safety and efficacy of LVM, laying the groundwork for future clinical applications and potentially offering a safer and more effective treatment option for RA patients.

Global genomic profile of hippocampal endothelial cells by single-nuclei RNA sequencing in female diabetic mice is associated with cognitive dysfunction.

Type II diabetes mellitus (T2D) is a chronic metabolic disease and a risk factor for cardiovascular disease and cerebrovascular dysfunction including vascular dementia. Sex differences in the prevalence of T2D, dementia, and global genomic changes in the brain have been observed; however, most studies have been performed in males. Therefore, our aim was to evaluate the consequence of T2D on cognitive function and decipher the underlying molecular transcriptomic mechanisms of endothelial cells in an important brain memory center, the hippocampus, using a female murine diabetes model. We assessed cognitive function, metabolic parameters, and then performed hippocampal single-nuclei RNA sequencing (snRNA seq) in adult female db/db and control wild-type (WT) mice. db/db mice exhibited characteristic T2D metabolism with hyperglycemia, hyperinsulinemia, and hyperlipidemia when compared with WT mice. Female db/db mice presented cognitive decline compared with wild-type mice, as determined by open field and Morris water maze tests. snRNAseq showed that T2D induced significant changes in the global transcriptomic profile of hippocampal endothelial cells by modulating the expression of not only protein-coding genes but also long noncoding RNAs. These genes regulate cell-cell junctions, cell chemotaxis, actin cytoskeleton organization, and cell adhesion, suggesting that diabetes increases endothelial cell permeability. Observed genomic changes also correlated with the genetics of persons with clinical Alzheimer's disease and vascular dementia. In conclusion, T2D, by transcriptional and posttranscriptional regulation, regulates endothelial cell dysfunction predictive of increased vascular permeability, and negatively impacts cognitive function. Our work has implications for sex-specific molecular therapeutic targets for dementia in females.NEW & NOTEWORTHY Female db/db mice presented cognitive decline as determined by open field and Morris water maze tests. snRNAseq showed that T2D induced changes in the global transcriptomic profile of hippocampal endothelial cells by modulating the expression of not only protein-coding genes but also long noncoding RNAs. These genes regulate cell-cell junctions, cell chemotaxis, or cell adhesion, suggesting increased endothelial permeability. Genomic changes correlated with the genetics of persons with clinical Alzheimer's disease and vascular dementia.

Lead Acetate Exposure and Cerebral Amyloid Accumulation: Mechanistic Evaluations in APP/PS1 Mice.

The role of environmental factors in Alzheimer's disease (AD) pathogenesis remains elusive. Mounting evidence suggests that acute and past exposure to the environmental toxicant lead (Pb) is associated with longitudinal decline in cognitive function, brain atrophy, and greater brain -amyloid () deposition. However, the nature of Pb-induced amyloid deposition and how it contributes to AD development remain unclear. This study investigates the role of Pb in the pathogenesis of cerebral amyloid angiopathy (CAA) and whether plasminogen activator inhibitor-1 (PAI-1) contributes to this process in the APP/PS1 mouse model. Female APP/PS1 mice at 8 wk of age were administered either Pb-acetate (PbAc) (i.e., ) or an equivalent molar concentration of sodium acetate (NaAc) via oral gavage once daily for 8 wk. Amyloid deposition and vascular amyloid were determined by immunostaining. In addition, perivascular drainage, vascular binding assay, and microglial endocytosis were examined to determine underlying mechanisms. Furthermore, magnetic resonance imaging demyelination imaging was performed invivo measure the level of demyelination. Finally, Y-maze and Morris water maze tests were assessed to evaluate the cognitive function of mice. APP/PS1 mice (an AD mice model) exposed to PbAc demonstrated more vascular amyloid deposition less neocortical myelination, and lower cognitive function, as well as greater vascular binding to , higher ratios, strikingly lower levels in the perivascular drainage, and microglial endocytosis. Importantly, exposure to a specific PAI-1 inhibitor, tiplaxtinin, which previously was reported to lower CAA pathology in mice, resulted in less CAA-related outcomes following PbAc exposure. Our findings suggest that PbAc induced CAA/AD pathogenesis via the PAI-1 signaling in the APP/PS1 mouse model, and the inhibition of PAI-1 could be a potential therapeutic target for PbAc-mediated CAA/AD disorders. https://doi.org/10.1289/EHP14384.

AGMATINE ADMINISTRATION ALLEVIATES NERVE DAMAGE AND IMPROVES NERVE FUNCTION IN METHOTREXATE INDUCED PERIPHERAL NEUROPATHY IN RATS

Objective: Chemotherapeutic agents can produce neurodegenerative changes. This study was conducted to assess the therapeutic potential of agmatine, a neuromodulator, on methotrexate induced neurodegeneration in sciatic nerve. Materials and Methods: 40 male Wistar albino rats were assigned into four groups at random as control, methotrexate, agmatine and methotrexate-agmatine. Methotrexate was injected intraperitoneally at a 37.5 mg/kg/week dose for 3 weeks. Afterwards, agmatine was administered intraperitoneally twice a day at a 40 mg/kg dose for 7 days. Sciatic functional index, nociceptive pain perception and behavioral changes were analyzed every week. Nerve conduction velocity was evaluated. Apoptotic activity and mitophagy, histopathological changes in sciatic nerves were examined. Results: Methotrexate administration resulted in a prolonged escape time to the platform and decreased the time spent in the quadrant in the water maze test; elevated nociceptive latencies; decreased the number of frames passed in the open field test; reduced sciatic NCV and SFI score. Besides, methotrexate administration caused a reduction in myelin thickness and axon diameter in sciatic nerve and a more intense glial fibrillary acidic protein immunoreactivity. Methotrexate administration triggered an increase in the Bax/Bcl-2 protein expression ratio without changing the expression level of Parkin, indicating a slight apoptotic activation. agmatine administration improved methotrexate induced changes in behavioral performances, nociceptive pain perception, nerve conduction, SFI scores and histopathological changes. Conclusion: Agmatine has been demonstrated to possess a therapeutic potential in methotrexate induced degeneration and peripheral neuropathy in the rat sciatic nerve.

Danggui Shaoyao San Alleviates Early Cognitive Impairment in Alzheimer's Disease Mice Through IRS1/GSK3β/Wnt3a-β-Catenin Pathway.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by Amyloid plaques and neurofibrillary tangles. We explored the potential mechanism by which Danggui Shaoyao San (DSS) modulates central glucose metabolism via the insulin receptor substrate 1 (IRS1)/glycogen synthase kinase-3β (GSK3β)/Wnt3a-β-catenin pathway, thereby exerting protective effects on cognitive functions. In vitro, HT22 cells were induced with streptozotocin (STZ) to investigate the impact of GSK3β on pathway transduction. The active components in the DSS stock solution were validated using mass spectrometry. Subsequently, an AD model in C57BL/6J mice was established through STZ injection into both ventricles. The success of the model was validated behaviorally and pathologically. The Morris Water Maze (MWM) test, immunohistochemistry, Western blotting, quantitative reverse transcription-PCR, and 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) were employed to evaluate the influence of DSS on memory and pathological changes in AD. The DSS stock solution, rich in active components, ameliorated the memory deficits in AD mice in the MWM. In vitro, GSK3β exhibited regulatory control over Wnt and β-catenin, with GSK3β inhibition mitigating β-amyloid and tau redundancies at protein and gene levels, facilitating signal transduction. In vivo, DSS impacted key targets in the IRS1/GSK3β/Wnt3a-β-catenin pathway, mitigated senile plaques resulting from amyloid β (Aβ) deposition and neurofiber tangles induced by tau hyperphosphorylation, and alleviated the decline in central glucose metabolism observed in FDG-PET. Our findings suggest that DSS potentially confers cognitive protection by alleviating central hypoglycemia through the IRS1/GSK3β/Wnt3a-β-catenin pathway. This may serve as a promising therapeutic avenue for AD.

Behavioral Assessment Reveals GnRH Immunocastration as a Better Alternative to Surgical Castration.

Castration is often employed in animal management for reproductive control. However, it is important to evaluate its impact on animal welfare. In this study, we developed rat models for both surgical (n = 6) and GnRH immunocastration (n = 6) to assess the effects of these castration methods on physiological and behavioral characteristics. The novel GnRH-based vaccine significantly increased serum GnRH antibody levels and drastically reduced testosterone, with the testes shrinking to one-fifth the size of those in the control group, thereby halting spermatogenesis at the secondary spermatocyte stage. Behavioral evaluations demonstrated that sexual behavior was significantly suppressed in both surgically and immunologically castrated groups compared to the control, confirming the effectiveness of both methods. However, psychological tests revealed significant signs of depression and social deficits in the surgically castrated group, whereas the behavior of the GnRH-immunocastrated group did not significantly differ from the control. Furthermore, no significant differences in learning and memory were observed among the three groups in the water maze test. Compared to surgical castration, GnRH immunocastration offers effective results and better animal welfare, providing a more humane alternative for livestock management.

Neuroprotective Properties of Rutin Hydrate against Scopolamine-Induced Deficits in BDNF/TrkB/ERK/CREB/Bcl2 Pathways.

Background/Objectives: Alzheimer's disease (AD) is an age-related degenerative brain disorder characterized by a progressive decline in cognitive function and memory. This study aimed to evaluate whether rutin hydrate (RH) has neuroprotective effects in an AD-like learning and memory impairment rat model induced by scopolamine (SCO). Methods: The rats were administered with RH (100 mg/kg) and SCO (1.5 mg/kg) and underwent behavioral tests, including the Morris water maze test, Y-maze test, and passive avoidance test, to evaluate their learning and memory abilities. Additionally, long-term potentiation (LTP) was induced to observe changes in the field excitatory postsynaptic potential (fEPSP) activity. Results: RH treatment attenuated the SCO-induced shortening of step-through latency in the passive avoidance (PA) test, increased the percentage of alternation in the Y-maze, and increased the time spent in the target zone in the Morris water maze (MWM). Moreover, RH increased the total activity of fEPSP following theta burst stimulation and attenuated the SCO-induced blockade of fEPSP. RH also ameliorated the SCO-induced decrease in the expression levels of the BDNF, TrkB, ERK, CREB, and Bcl-2 proteins and the increase in the Bax protein level in the rat hippocampus. This demonstrates that RH has beneficial neuroprotective effects in the brain, improving learning, memory, and synaptic plasticity in rats. Conclusions: Our results highlight the molecular and cellular mechanisms through which RH exerts its neuroprotective effects in the prevention and treatment of learning and memory deficit disorders. RH could potentially be used as a therapeutic strategy for the restoration of learning and memory function and the prevention of the progression of AD.

Exploring Liraglutide in Lithium-Pilocarpine-Induced Temporal Lobe Epilepsy Model in Rats: Impact on Inflammation, Mitochondrial Function, and Behavior.

Background/Objectives: Glucagon-like peptide-1 receptor agonists such as liraglutide are known for their neuroprotective effects in neurodegenerative disorders, but their role in temporal lobe epilepsy (TLE) remains unclear. We aimed to investigate the effects of liraglutide on several biological processes, including inflammation, antioxidant defense mechanisms, mitochondrial dynamics, and function, as well as cognitive and behavioral changes in the TLE model. Methods: Low-dose, repeated intraperitoneal injections of lithium chloride-pilocarpine hydrochloride were used to induce status epilepticus (SE) in order to develop TLE in rats. Fifty-six male Sprague Dawley rats were subjected and allocated to the groups. The effects of liraglutide on inflammatory markers (NLRP3, Caspase-1, and IL-1β), antioxidant pathways (Nrf-2 and p-Nrf-2), and mitochondrial dynamics proteins (Pink1, Mfn2, and Drp1) were evaluated in hippocampal tissues via a Western blot. Mitochondrial function in peripheral blood mononuclear cells (PBMCs) was examined using flow cytometry. Cognitive-behavioral outcomes were assessed using the open-field, elevated plus maze, and Morris water maze tests. Results: Our results showed that liraglutide modulates NLRP3-mediated inflammation, reduces oxidative stress, and triggers antioxidative pathways through Nrf2 in SE-induced rats. Moreover, liraglutide treatment restored Pink1, Mfn2, and Drp1 levels in SE-induced rats. Liraglutide treatment also altered the mitochondrial function of PBMCs in both healthy and epileptic rats. This suggests that treatment can modulate mitochondrial dynamics and functions in the brain and periphery. Furthermore, in the behavioral aspect, liraglutide reversed the movement-enhancing effect of epilepsy. Conclusions: This research underscores the potential of GLP-1RAs as a possibly promising therapeutic strategy for TLE.

Parthenolide ameliorates 3-nitropropionic acid-induced Huntington’s disease-like aberrations via modulating NLRP3 inflammasome, reducing microglial activation and inducing astrocyte shifting

BackgroundHuntington’s disease (HD) is a progressive neurodegenerative disease that causes motor, cognitive, and psychiatric abnormalities, with no satisfying disease-modifying therapy so far. 3-nitropropionic acid (3NP) induces behavioural deficits, together with biochemical and histological alterations in animals’ striata that mimic HD. The role of nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome in HD pathogenesis remains largely uncharacterized. Parthenolide (PTL), a naturally occurring nuclear factor kappa B (NF-κB) inhibitor, is also known to inhibit NLRP3 inflammasome. Whether PTL is beneficial in HD has not been established yet.AimThis study evaluated the possible neuroprotective effects of PTL against 3NP-induced behavioural abnormalities, striatal biochemical derangements, and histological aberrations.MethodsMale Wistar rats received PTL (0.5 mg/kg/day, i.p) for 3 weeks and 3NP (10 mg/kg/day, i.p) was administered alongside for the latter 2 weeks to induce HD. Finally, animals were subjected to open-field, Morris water maze and rotarod tests. Rat striata were examined histologically, striatal protein expression levels of glial fibrillary acidic protein (GFAP), cluster of differentiation 45 (CD45) and neuron-specific enolase (NSE) were evaluated immunohistochemically, while those of interleukin (IL)-1β, IL-18, ionized calcium-binding adapter molecule-1 (Iba1) and glutamate were determined by ELISA. Striatal nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein (Keap1), NF-κB, NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, S100 calcium-binding protein A10 (S100A10) and complement-3 (C3) were assessed by gene expression analysis.ResultsPTL improved motor, locomotor, cognitive and anxiety-like behaviours, restored neuronal integrity, upregulated Nrf2, and inhibited NLRP3 inflammasome, NF-κB and microglial activation. Additionally, PTL induced astrocyte shifting towards the neuroprotective A2 phenotype.ConclusionPTL exhibits neuroprotection against 3NP-induced HD, that might be ascribed, at least in part, to its modulatory effects on Keap1/Nrf2 and NF-κB/NLRP3 inflammasome signaling.

Dysregulated mTOR networks in experimental sporadic Alzheimer's disease.

Beyond the signature amyloid-beta plaques and neurofibrillary tangles, Alzheimer's disease (AD) has been shown to exhibit dysregulated metabolic signaling through insulin and insulin-like growth factor (IGF) networks that crosstalk with the mechanistic target of rapamycin (mTOR). Its broad impact on brain structure and function suggests that mTOR is likely an important therapeutic target for AD. This study characterizes temporal lobe (TL) mTOR signaling abnormalities in a rat model of sporadic AD neurodegeneration. Long Evans rats were given intracerebroventricular injections of streptozotocin (ic-STZ) or saline (control), and 4 weeks later, they were administered neurobehavioral tests followed by terminal harvesting of the TLs for histopathological study and measurement of AD biomarkers, neuroinflammatory/oxidative stress markers, and total and phosphorylated insulin/IGF-1-Akt-mTOR pathway signaling molecules. Rats treated with ic-STZ exhibited significantly impaired performance on Rotarod (RR) and Morris Water Maze (MWM) tests, brain atrophy, TL and hippocampal neuronal and white matter degeneration, and elevated TL pTau, AβPP, Aβ, AChE, 4-HNE, and GAPDH and reduced ubiquitin, IL-2, IL-6, and IFN-γ immunoreactivities. In addition, ic-STZ reduced TL pY1135/1136-IGF-1R, Akt, PTEN, pS380-PTEN, pS2448-mTOR, p70S6K, pT412-p70S6K, p/T-pT412-p70S6K, p/T-Rictor, and p/T-Raptor. Experimental ic-STZ-induced sporadic AD-type neurodegeneration with neurobehavioral dysfunctions associated with inhibition of mTOR signaling networks linked to energy metabolism, plasticity, and white matter integrity.

Safflower Improves Memory, Learning, and Behavior in Rats Subjected to Sleep Deprivation.

Sleep is a physiological process that provides the body with a window for recovery and restoration. Intriguingly, even short-term sleep deprivation can impair brain memory, emotional capacity, information processing, and attention. Safflower (Carthamus tinctorius L.) has been shown to attenuate memory loss and improve anxiety and depression. This study aims to study the possible therapeutic effect of safflower on sleep deprivation-dependent effects on memory and behavior. Thirty young male Wistar albino rats were acclimatized, trained, and then assigned to three random groups: control (C), sleep-deprived (SD), and sleep-deprived Safflower-treated (SD+Sf) groups. Morris Water Maze (MWM) and Elevated Plus Maze (EPM) tests were used to study spatial memory and learningand anxiety-related behavior, respectively, in the study groups. There was a significant deterioration in learning and memory, as tested by the MWM in the SD group, compared to the C group. This included prolonged test duration, reduced average speed, and longer travel distance. Treatment with safflower significantly improved MWM test performance in the SD+Sf group when compared to the SD group. When compared to the C group, rats in the SD group demonstrated altered EPM test parameters suggestive of anxiety-like behavior. These included spending more time in the closed arms, spending less time in the open arms, and having fewer entries in the open arms. Rats in the SD+Sf group showed improved EPM test parameters when compared to the SD group. Safflower significantly ameliorated sleep deprivation induced by memory loss and altered behavior. Safflower supplementation may provide potential memory-enhancing and preserving, anxiolytic, and antidepressant therapeutic roles.

Platycodin D and voluntary running synergistically ameliorate memory deficits in 5 × FAD mice via mediating neuromodulation and neuroinflammation.

Alzheimer's disease (AD) is the leading cause of dementia, and currently, no effective treatments are available to reverse or halt its progression in clinical practice. Although a plethora of studies have highlighted the benefits of physical exercise in combating AD, elder individuals often have limited exercise capacity. Therefore, mild physical exercise and nutritional interventions represent potential strategies for preventing and mitigating neurodegenerative diseases. Our research, along with other studies, have demonstrated that platycodin D (PD) or its metabolite, platycodigenin, derived from the medicinal plant Platycodon grandiflorus, exerts neuroprotective effects against amyloid β (Aβ)-induced neuroinflammation. However, the combined effects of PD and physical exercise on alleviating AD have yet to be explored. The current study aimed to investigate whether combined therapy could synergistically ameliorate memory deficits and AD pathology in 5 × FAD mice. Five-month-old 5 × FAD mice were randomly assigned to four groups, and received either PD (5 mg/kg/day, p.o.), voluntary running, or a combination of both for 47 days. Nest building test, locomotion test, and Morris water maze test were used to evaluate the cognitive function. Immunohistochemical and ELISA analysis was performed to determine Aβ build-up, microglia and astrocytes hyperactivation, and survival neurons in the hippocampus and perirhinal cortex. Real-time quantitative PCR analysis was used to assess the polarization of microglia and astrocytes. HPLC analysis was performed to measure monoamine neurotransmitters in the hippocampus. The combination of PD and voluntary running synergistically restored nest-building behavior, alleviated recognition and spatial memory deficits, and showed superior effects compared to monotherapy. In addition, the PD and voluntary running combination reduced Aβ build-up, decreased hyperactivation of microglia and astrocytes in the hippocampus and perirhinal cortex, promoted the polarization of inflammatory M1 microglia and reactive astrocytes toward beneficial phenotypes, and lowered systemic circulating pro-inflammatory cytokines while increasing anti-inflammatory cytokines in 5 × FAD mice. Furthermore, combined therapy effectively protected neurons and increased levels of 5-hydroxytryptamine (5-HT) and dopamine (DA) in the hippocampus of 5 × FAD mice. In conclusion, the combination of PD and voluntary running holds great potential as a treatment for AD, offering promise for delaying onset or progression of AD.

Therapeutic Efficacy of Extracellular Vesicles Derived from Stem Cell for Alzheimer's Disease: A Meta-Analysis Study.

Alzheimer's disease (AD) poses a significant public health challenge, increasingly affecting patients' finances, mental health, and functional abilities as the global population ages. Stem cell-derived extracellular vesicles (SC-EVs) have emerged as a promising cell-free therapeutic approach for AD, although their precise mechanisms remain unclear. This meta-analysis aims to evaluate the effectiveness of SC-EVs in treating AD. We systematically searched PubMed, EMBASE, and Web of Science databases up to December 31, 2023, identifying studies investigating SC-EVs therapy in AD rodent models. Outcome measures included Morris water maze and Y maze tests, β-amyloid pathology, and inflammatory markers. Statistical analyses utilized Stata 15.1 and R software. This meta-analysis of 16 studies (2017-2023, 314 animals) demonstrates significant efficacy of SC-EVs therapy in AD models. Pooled analyses demonstrated that SC-EVs therapy significantly increased the learning function as measured by Morris water maze tests (MWM) by -1.83 (95% CI = -2.51 to -1.15, p < 0.0001), Y maze test by 1.66 (95% CI = 1.03 to 2.28, p < 0.0001), decreased Aβ plaques in the hippocampal by -2.10 (95% CI = -2.96 to -1.23, p < 0.0001), and proinflammatory cytokines Tumor necrosis factor alpha (TNFα) by -2.61 (95% CI = -4.87 to -0.35, p < 0.05), Interleukin-1 beta (IL-1β) by -2.37 (95% CI = -3.68 to -1.05, p < 0.001). SC-EVs therapy shows promise in enhancing cognitive function and mitigating AD progression in preclinical models. Future research should focus on standardizing methodologies and comparing SC-EVs isolation techniques and dosing strategies to facilitate clinical translation.

Inhibition of GZMB activity ameliorates cognitive dysfunction by reducing demyelination in diabetic mice

BackgroundDiabetic cognitive dysfunction (DCD) has attracted increased attention, but its precise mechanism remains to be explored. Oligodendrocytes form myelin sheaths that wrap around axons. Granzyme B (GZMB) can cause axonal degeneration of the central nervous system. However, the role of GZMB in diabetic cognitive dysfunction (DCD) has not been reported. This study aimed to investigate whether GZMB promotes demyelination and participates in DCD by regulating the endoplasmic reticulum stress function of oligodendrocytes. MethodsStreptozotocin was injected intraperitoneally to establish a diabetic model in C57BL/6 mice. The mice were randomly divided into four groups: control group, diabetic group, diabetic + SerpinA3N group, and diabetic + saline treatment group. We performed the Morris water maze test to assess the learning and memory abilities of the mice. An immunofluorescence assay was performed to detect the expression sites of GZMB and OLIG2 in the hippocampal CA1 region. Luxol Fast Blue staining and electron microscopy were performed to detect the myelin number and myelin plate densities. Immunohistochemistry was used to detect the expression levels of MBP and CNPase. Protein blotting was used to assess the expression levels of GZMB, PERK, p-PERK, eIF2α, p-eIF2α, NLRP3, Caspase-1, GSDMD-N, IL-1β, and IL-18 as well as MBP and CNPase. ResultsThe GZMB inhibitor SerpinA3N reduces escape latency and increases the traversing platforms and residence time in the target area, improving DCD in mice. It also reduces endoplasmic reticulum stress in hippocampal oligodendrocytes and focal prolapse, further promoting MBP and CNPase expression and reducing demyelination. ConclusionsOur findings suggest that inhibition of GZMB activity modulates oligodendrocyte endoplasmic reticulum stress and pyroptosis, reduces demyelination, and ameliorates diabetes-related cognitive impairment.