Water Maze Research Articles

Astrocytic Acid-Sensing Ion Channel 1a Contributes to the Development of Epileptic Cognitive Impairment

Reactive astrogliosis and acidosis, common features of epileptogenic lesions, express a high level of astrocytic acid-sensing ion channel-1a (ASIC1a), a proton-gated cation channel and key mediator of responses to neuronal injury. This study investigates the role of astrocytic ASIC1a in cognitive impairment following epilepsy. Status epilepticus (SE) in C57/BL6 mice was induced using lithium–pilocarpine; the impact of ASIC1a on astrocytes was assessed using rAAV–ASIC1a–NC and rAAV–ASIC1a–shRNA, injected in the CA3 region of mice. Behavioral assessments were conducted using the Morris water maze (MWM). Western blotting and immunofluorescence were applied to evaluate ASIC1a and Gfap expression while analyzing intracellular calcium and extracellular glutamate (Glu) concentrations in primary cultured astrocytes isolated from the brains of 1 to 3-day-old mice and treated LPS. Results showed enhanced astrocyte proliferation and ASIC1a expression in the dentate gyrus of epileptic mice 7, 21, and 28 days post-SE (all p < 0.05). Escape latency in the MWM further suggested that ASIC1a regulates cognitive function in mice with chronic epilepsy. LPS stimulation in vitro mimicked inflammatory responses, increasing ASIC1a after 24 h, which increased the concentration of intracellular calcium and extracellular expression of Glu; inhibition of ASIC1a expression reversed this process. To sum up, these data confirm that astrocytic ASIC1a may facilitate cognitive dysfunction post-epilepsy, presenting a potential therapeutic target.

Carotid Endarterectomy Ameliorates Cognitive Impairment in Clinical and Experimental Unilateral Carotid Artery Stenosis.

Carotid endarterectomy (CEA) is widely used to treat carotid artery stenosis (CAS). However, the effects of CEA on unilateral CAS-induced cognitive impairment and the underlying mechanism remain poorly understood. Thirteen patients diagnosed with unilateral severe CAS underwent pre- and post-CEA assessments, including 18fluoro-2-deoxy-d-glucose positron emission tomography/magnetic resonance imaging, cognitive assessments, and routine blood tests before and after CEA. Unilateral carotid common artery occlusion and ligation release (reperfusion) surgeries were performed in mice to mimic CAS and CEA. Cognitive function, cerebral blood flow, and white matter damage were evaluated in mice using the Morris water maze test, Doppler flowmetry, laser-speckle imaging, diffusion tensor imaging, Luxol fast blue staining, transmission electron microscopy, and western blot assays post unilateral carotid common artery occlusion and reperfusion. Genomic sequencing of the white matter was performed to explore the potential underlying mechanism. CEA significantly enhanced the Montreal Cognitive Assessment scores in patients with CAS and preoperative cognitive impairment. Moreover, CEA led to notable improvements in cerebral blood flow, energy metabolism, and white matter integrity, while concurrently reducing blood inflammation. In the mouse model, reperfusion surgery alleviated cognitive deficits, increased cerebral blood flow, and alleviated white matter damage following unilateral carotid common artery occlusion. Furthermore, transcriptional surveys have revealed substantial alterations in the upregulation of Nrf2 signaling and metabolic pathways, coupled with the inhibition of neuroinflammation, cellular communication, and immune cell population signaling following reperfusion. CEA ameliorated CAS-induced cognitive dysfunction by improving the cerebral functional structure. These beneficial effects may be attributed to their antioxidant and anti-inflammatory properties.

Exploring Azithromycin’s Neuroprotective Role in Traumatic Brain Injury: Insights into Cognitive and Motor Recovery and Neuroinflammatory Modulation

Background: Traumatic brain injury (TBI) is a leading cause of mortality worldwide and often results in substantial cognitive, motor, and psychological impairments, triggering oxidative stress, neuroinflammation, and neurodegeneration. This study examined the neuroprotective effects of azithromycin (AZI) in TBI. Methods: TBI was induced in rats using the weight-drop method. Subsequently, rats received a daily intraperitoneal (I.P.) dose of AZI (150 mg/kg) for 28 days. Behavioral tests (Morris water maze, rotarod, and open field tests) were performed to assess cognitive and motor functions. Neurochemical analyses included oxidative stress markers (GSH, SOD, MDA, catalase), inflammatory cytokines (TNF-α, IL-1β), apoptotic markers (caspase-3, Bax, Bcl-2), mitochondrial complexes (complex I, II, III, IV, and V), and the transforming growth factor- beta (TGF-β) as a neurofilament marker. Histological evaluations focused on neuronal integrity in the cortex, hippocampus, and striatum. Results: Treatment with AZI significantly facilitated motor and cognitive function recovery in TBI-affected rats. At the molecular level, AZI effectively reduced oxidative stress markers, ameliorated neuroinflammation by decreasing TNF-α, IL-1β, and neuronal apoptosis, and differentially modulated mitochondrial complexes. Histological assessments revealed enhanced neuronal integrity and fewer pathological changes in AZI-treated rats compared to untreated TBI controls. Conclusion: AZI was shown to interfere with several pathways involved in TBI’s pathophysiology. While preclinical results are promising, further studies are necessary to establish the long-term safety and efficacy of AZI in a clinical setting. This research supports the potential re-purposing of AZI as a novel treatment strategy for TBI and related neurodegenerative disorders.

Amauroderma rugosum Extract Improves Brain Function in d‐Galactose‐Induced Aging Mouse Models via the Regulatory Effects of Its Polysaccharides on Oxidation, the mTOR‐Dependent Pathway, and Gut Microbiota

ABSTRACTThe pharmacological effects of Amauroderma rugosum (AR), an edible mushroom found mainly in Southeast Asia, are not well studied, particularly its neuroprotective properties. This study investigated the neuroprotective effects of AR aqueous extract (ARW) in a d‐galactose‐induced accelerated aging mouse model and senescent SH‐SY5Y neuronal cells. Behavioral tests (open field, Morris water maze, Y‐maze, and rotarod) demonstrated that d‐galactose‐induced aging mice exhibited impaired cognitive function, memory loss, anxiety, and reduced locomotor ability, all of which were alleviated by ARW treatment. Histological analysis showed that ARW reduced neuropathological lesions in the hippocampus. In SH‐SY5Y neuronal cells, ARW and AR polysaccharide extract (ARP) enhanced cell viability and decreased intracellular reactive oxygen species (ROS) levels in a concentration‐dependent manner. ARW and ARP also reduced cellular senescence and apoptosis in d‐galactose‐treated cells. Western blot analysis indicated that ARW and ARP upregulated the phosphorylation of mTOR and increased the expression of antioxidant enzymes, including superoxide dismutase 1 and heme‐oxygenase‐1. Additionally, ARW altered the gut microbiota, increasing the relative abundance of beneficial bacteria such as Lactobacillus reuteri and decreasing harmful bacteria like Clostridium scindens. These findings suggest that AR exerts neuroprotective effects primarily through its polysaccharides by modulating oxidative stress, activating the mTOR‐dependent pathway, and influencing the gut microbiota. Consequently, AR could serve as a potential dietary supplement for the prevention and treatment of neurodegenerative diseases.

Comparison of two independent populations of compositional data with positive correlations among components using a nested dirichlet distribution.

Compositional data are multivariate data made up of components that sum to a fixed value. Often the data are presented as proportions of a whole, where the value of each component is constrained to be between 0 and 1 and the sum of the components is 1. There are many applications in psychology and other disciplines that yield compositional data sets including Morris water maze experiments, psychological well-being scores, analysis of daily physical activity times, and components of household expenditures. Statistical methods exist for compositional data and typically consist of two approaches. The first is to use transformation strategies, such as log ratios, which can lead to results that are challenging to interpret. The second involves using an appropriate distribution, such as the Dirichlet distribution, that captures the key characteristics of compositional data, and allows for ready interpretation of downstream analysis. Unfortunately, the Dirichlet distribution has constraints on variance and correlation that render it inappropriate for some applications. As a result, practicing researchers will often resort to standard two-sample t test or analysis of variance models for each variable in the composition to detect differences in means. We show that a recently published method using the Dirichlet distribution can drastically inflate Type I error rates, and we introduce a global two-sample test to detect differences in mean proportion of components for two independent groups where both groups are from either a Dirichlet or a more flexible nested Dirichlet distribution. We also derive confidence interval formulas for individual components for post hoc testing and further interpretation of results. We illustrate the utility of our methods using a recent Morris water maze experiment and human activity data. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Restoration of Memory Potential by Piper betel Leaves Extract in High-Fat Diet (HFD)-Induced Dementia in Mice

The present study has been designed to evaluate the effect of ethanolic extract of leaves of Piper betel in high fat diet (HFD) induced dementia and memory restoration effect in Albino mice by various parameters like Morris water maze (MWM) test, Elevated Plus Maze etc. and Estimation of serum total cholesterol using commercially available kit. Dementia is a syndrome in which the deterioration of cognitive functions occurs. The results of this study indicate that the administration of a high-fat diet to the Swiss mice produces a severe deterioration of spatial memory as determined by the Morris water maze (MWM) test, Elevated Plus Maze, T Maze delayed alteration task performed. Administration of ethanolic extract of Piper betel (250 and 500 mg/kg, p.o.) for 14 days significantly attenuated high-fat diet-induced memory deficits. Moringa Oleifera treatment to HFD induced mice improves cognition by virtue of its results support that the protective effect obtained with Piper betel may be through the activation of pregnane x receptors. ethanolic extract of Piper betel treatment to HFD induced mice improves cognition by virtue of its results, supports that the protective effect obtained with Piper betel may be through the activation of pregnane x receptors. Keywords: Dementia, Piper betel, high fat diet, Morris water maze, Elevated plus Maze, T Maze and Piracetam.

Icariin improves learning and memory function by enhancing HRD1-mediated ubiquitination of amyloid precursor protein in APP/PS1 mice.

One of the hallmark pathological characteristics of Alzheimer's disease (AD) is amyloid-β (Aβ) accumulated in brain, which is mainly derived from the proteolytic processing of amyloid-β protein precursor (AβPP). The ubiquitin-proteasome system is able to reduce Aβ generation by ubiquitination and degradation of AβPP. Icariin (ICA), a flavonoid isolated from Epimedium brevicornum Maxim., has been reported that it could regulate the metabolism of AβPP and reduce the Aβ level in AD in vivo and in vitro models. To investigate whether the effect of ICA on AβPP and Aβ is related to AβPP ubiquitination. We used in vivo and in vitro models to observe the effect of ICA on AβPP ubiquitination as well as to investigate the effect of HMG-CoA reductase degradation protein 1 (HRD1), an E3 ubiquitin-protein ligase, on the processing of AβPP ubiquitination. This study showed that ICA improved the cognitive abilities of APP/PS1 AD mice in Morris Water Maze and Y-maze tests, upregulated HRD1 expression, subsequently elevated the total ubiquitination and K48-linked polyubiquitination of AβPP level, as well as increased AβPP degradation. Moreover, silenced HRD1 gene abolished the aforementioned effects of ICA. Furthermore, ICA decreased the location of AβPP in the early endosome, where AβPP is cleaved into Aβ, evidenced by reducing the co-localization of AβPP and early endosome antigen 1 (EEA1). This study demonstrated that ICA increased AβPP degradation by upregulating HRD1 mediated ubiquitination.

Neuroprotective effects of hypidone hydrochloride (YL-0919) after traumatic brain injury in mice.

Neurological dysfunction is a common complication of traumatic brain injury (TBI), and early treatments are critical for the long-term prognosis. This study aimed to investigate whether hypidone hydrochloride (YL-0919) improves neurological function impairment in mice with TBI. TBI was induced in adult male C57BL/6J mice using the controlled cortical impact (CCI) method. First, the modified neurological severity score (mNSS), rotarod test, and Morris water maze (MWM) test were conducted to assess the impact of YL-0919 on neurological function in mice with TBI. Next, immunofluorescence and laser speckle contrast imaging were utilized to measure the number and activation of microglia and cerebral blood flow (CBF) after TBI. Enzyme-linked immunosorbent assays (ELISAs) were employed to assess the inflammatory factors. Finally, Western blotting was performed to measure the expression of proteins. Golgi-Cox staining was utilized to investigate the structure of pyramidal neurons. YL-0919significantly alleviated neurological dysfunction in TBI+YL-0919mice compared with TBI+Vehicle mice, increased the time spent on the rotarod (F=1.297, P <0.05), and partially relieved cognitive dysfunction in TBI mice (for mNSS, F=5.540, P <0.01; for MWM test, F=30.78, P <0.05). Additionally, YL-0919 effectively inhibited the proliferation and activation of microglia (both P<0.01), promoted the recovery of CBF around the brain injury site and inhibited the expression of tumor necrosis factor-α (F=9.142, P <0.05) and IL-1β (F=4.662, P <0.05), and increased the concentration of IL-4 (F=5.172, P <0.05). Furthermore, continuous gavage of YL-0919 (2.5mg/kg) for seven days effectively increased the protein expression of brain-derived neurotrophic factor (BDNF), promoted the phosphorylation of mammalian target of rapamycin (mTOR), increased postsynaptic density protein 95 (PSD95) and synapsin1 levels, and increased the neuronal dendritic complexity and the dendritic spine density around the brain injury site (all P <0.05). Our findings indicated that YL-0919 can ameliorate neurological dysfunction in mice after TBI through the suppression of inflammation and the stimulation of the BDNF-mTOR signaling pathway. These findings provide an insightful perspective on the potential pharmacological mechanism involved in the neuroprotective effect of YL-0919.

TeMac™ ameliorates memory impairment and cholinergic dysfunction in rats induced by scopolamine.

Alzheimer's disease (AD) is associated with cognitive impairments which are linked to a deficit in cholinergic function. The objective of this study was to evaluate the ability of TeMac™ to prevent memory impairment in scopolamine-rats model of Alzheimer's disease and by in silico approaches to identify molecules in TeMac™ inhibiting acetylcholinesterase. The cholinergic cognitive dysfunction was induced by intraperitoneal injection of scopolamine (1mg/kg daily) in male Wistar rats for seven consecutive days. TeMac™ at 400mg/kg body weight was orally administrated 60min after scopolamine. Donepezil was used as a reference drug. The cognitive deficits were assessed by the Morris Water Maze and novel object recognition tests. After killing the rats, brains were immediately collected and used to carry out cholinesterase enzyme activity and histopathological analyses. Liquid chromatography-mass spectrometry (LC-MS) characterization of the TeMac™ was carried out and the identified molecules were tested in silico for their ability to cross the Blood-Brain Barrier (BBB) and inhibit acetylcholinesterase using molecular docking. The administration of the TeMac™ led to the prevention of memory deficits in rats by reducing significantly the cholinesterase enzymes activities and protecting against morphological alterations and loss of neurons in hippocampus. Seven major compounds were identified in TeMac™. Molecular docking simulations confirm the ability of oleaterminaloic acid B and stigmasterol to cross the BBB and interact with peripheral site and the acyl pocket of acetylcholinesterase. All these observations suggest that TeMac™ can therefore be used as an alternative for the management of AD-related cognitive impairments.

The ER protein CANX (calnexin)-mediated autophagy protects against alzheimer disease

ABSTRACT Although the relationship between macroautophagy/autophagy and Alzheimer disease (AD) is widely studied, the underlying mechanisms are poorly understood, especially the regulatory role of the initiation signaling of autophagy on AD. Here, we find that the ER transmembrane protein CANX (calnexin) is a novel interaction partner of the autophagy-inducing kinase ULK1 and is required for ULK1 recruitment to the ER under basal or starved conditions. Loss of CANX results in the inactivity of ULK1 kinase and inhibits autophagy flux. In the brains of people with AD and APP-PSEN1 mice, the interaction of CANX and ULK1 declines. In mice, the lack of CANX in hippocampal neurons causes the accumulation of autophagy receptors and neuron damage, which affects the cognitive function of C57BL/6 mice. Conversely, overexpression of CANX in hippocampal neurons enhances autophagy flux and partially contributes to improving cognitive function of APP-PSEN1 mice, but not the CANX variant lacking the interaction domain with ULK1. These findings reveal a novel role of CANX in autophagy activity and cognitive function by cooperating with ULK1. Abbreviation: AD: Alzheimer disease; APEX: ascorbate peroxidase; APP: amyloid beta precursor protein; APP-PSEN1 mice: amyloid beta precursor protein-presenilin 1 transgenic mice; ATG: autophagy related; Aβ: amyloid-β; BiFC: bimolecular fluorescence complementation; CANX: calnexin; EBSS: Earle’s balanced salt solution; EM: electron microscopy; IP: immunopurification; KO: knockout; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MWM: Morris water maze; PLA: proximity ligation assay; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; SQSTM1/p62, sequestosome 1.

Low-dose intranasal deferoxamine modulates memory, neuroinflammation, and the neuronal transcriptome in the streptozotocin rodent model of Alzheimer’s disease

IntroductionIntranasal (IN) deferoxamine (DFO) has emerged over the past decade as a promising therapeutic in preclinical experiments across neurodegenerative and neurovascular diseases. As an antioxidant iron chelator, its mechanisms are multimodal, involving the binding of brain iron and the consequent engagement of several pathways to counter pathogenesis across multiple diseases. We and other research groups have shown that IN DFO rescues cognitive impairment in several rodent models of Alzheimer Disease (AD).MethodsThis study was designed to probe dosing regimens to inform future clinical trials, while exploring mechanisms within the intracerebroventricular (ICV) streptozotocin (STZ) model.ResultsFive weeks of daily IN dosing of Long Evans rats with 15 μL of a 1% (0.3 mg), but not 0.1% (0.03 mg), solution of DFO rescued cognitive impairment caused by ICV STZ administration as assessed with the Morris Water Maze (MWM) test of spatial memory and learning. Furthermore, IN DFO modulated several aspects of the neuroinflammatory milieu of the ICV STZ model, which was assessed through a novel panel of brain cytokines and immunohistochemistry. Using RNA-sequencing and pathway analysis, STZ was shown to induce several pathways of cell death and neuroinflammation, and IN DFO engaged multiple transcriptomic pathways involved in hippocampal neuronal survival.DiscussionTo our knowledge this study is the first to assess the transcriptomic pathways and mechanisms associated with either the ICV STZ model or DFO treatment, and the first to demonstrate efficacy at this low dose.

Aluminum Induces Neurotoxicity through the MicroRNA-98-5p/Insulin-like Growth Factor 2 Axis.

Aluminum is a well-known and widely distributed environmental neurotoxin. This study aimed to investigate the effect of miR-98-5p targeting insulin-like growth factor 2 (IGF2) on aluminum neurotoxicity. Thirty-two Sprague-Dawley rats were randomly divided into four groups and administered 0, 10, 20, and 40 μmol/kg maltol aluminum [Al(mal)3], respectively. They were intraperitoneally injected every other day for three months. PC12 cells were divided into four dose groups: 0, 100, 200, and 400 μmol/L Al(mal)3, and four intervention groups: inhibitor NC, Al(mal)3 + inhibitor NC, miR-98-5p inhibitor, and Al(mal)3 + miR-98-5p inhibitor. The Morris water maze was used to test the learning and memory abilities of rats. Hematoxylin and eosin staining was used to observe the arrangement and quantity of neurons in the CA1 area of the rat hippocampus. Cell viability was detected using the Cell Counting Kit-8. Cell apoptosis was detected using flow cytometry and the 5-ethynyl-2'-deoxyuridine assay. Real-time polymerase chain reaction and Western blotting were used to detect the expression levels of miR-98-5p, IGF2 mRNA, IGF2/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway proteins, and apoptosis-related proteins caspase3 and cleaved caspase3. The dual-luciferase assay was used to determine the targeting relationship between miR-98-5p and IGF2 mRNA. As the dose of aluminum exposure increased, the escape latency of rats gradually prolonged, and the target quadrant residence time and the number of crossing platforms gradually decreased. The arrangement of neurons in the hippocampal CA1 area was significantly loose, and their number gradually decreased. The total and early apoptosis rates of PC12 cells gradually increased, and the cell proliferation rate slowed down. Both in vivo and in vitro experimental results showed that with the increase of aluminum exposure dose, the relative expression levels of miR-98-5p and caspase3 and cleaved caspase3 proteins gradually increased, while the relative expression levels of IGF2 mRNA and IGF2, p-JAK2 (Tyr1007/1008), and p-STAT3 (Tyr705) proteins gradually decreased. After inhibiting miR-98-5p in the aluminum exposure group, the cell apoptosis rate and expression of apoptosis-related proteins decreased, and the expression of IGF2 mRNA and IGF2/JAK2/STAT3 proteins increased. These results indicate that miR-98-5p plays a vital role in aluminum-induced neurotoxicity by targeting IGF2.

CEST imaging combined with 1H-MRS reveal the neuroprotective effects of riluzole by improving neurotransmitter imbalances in Alzheimer’s disease mice

BackgroundThe imbalance of glutamate (Glu) and gamma-aminobutyric acid (GABA) neurotransmitter system plays a crucial role in the pathogenesis of Alzheimer’s disease (AD). Riluzole is a Glu modulator originally approved for amyotrophic lateral sclerosis that has shown potential neuroprotective effects in various neurodegenerative disorders. However, whether riluzole can improve Glu and GABA homeostasis in AD brain and its related mechanism of action remain unknown. This study utilized chemical exchange saturation transfer (CEST) imaging combined with proton magnetic resonance spectroscopy (1H-MRS) to monitor the dynamic changes of Glu and GABA in riluzole-treated AD mice, aiming to evaluate the efficacy and mechanism of riluzole in AD treatment.MethodsGluCEST, GABACEST and 1H-MRS were used to longitudinally monitor Glu and GABA levels in 3xTg AD mice treated with riluzole (12.5 mg/kg/day) or vehicle for 20 weeks. Magnetic resonance measurements were performed at baseline, 6, 12, and 20 weeks post-treatment. Cognitive performance was assessed using the Morris Water Maze (MWM) at baseline, 10, and 20 weeks. At the study endpoint, immunohistochemistry, Nissl staining, and Western blot were used to evaluate the brain pathology, neuronal survival, and protein expression.ResultsGluCEST, GABACEST and 1H-MRS consistently revealed higher levels of Glu and GABA in the brain of riluzole-treated AD mice compared to untreated controls, which were associated with improvements in spatial learning and memory. The cognitive improvements significantly correlated with the increased GluCEST signals and Glu levels. Immunohistochemistry and Nissl staining demonstrated that riluzole treatment reduced amyloid-beta (Aβ) deposition, tau hyperphosphorylation, GFAP-positive astrocyte activation, and prevented neuronal loss. Moreover, riluzole upregulated the expression of excitatory amino acid transporter 2 (EAAT2), glutamic acid decarboxylase 65/67 (GAD65/67), and glutamine synthetase (GS), suggesting enhanced neurotransmitter metabolism.ConclusionsCEST imaging combined with 1H-MRS demonstrated the effectiveness of riluzole in modulating Glu- and GABA-related changes and improving cognitive function in 3xTg AD mice, potentially through regulating key proteins involved in neurotransmitter metabolism. These findings suggest riluzole as a therapeutic agent for Alzheimer’s disease and highlight the utility of multimodal MR imaging in monitoring treatment response and exploring disease mechanisms.

Blackcurrant (Ribes nigrum L.) and Its Association with Donepezil Restore Cognitive Impairment, Suppress Oxidative Stress and Pro-inflammatory Responses, and Improve Purinergic Signaling in a Scopolamine-Induced Amnesia Model in Mice.

Purinergic signaling plays a major role in aging and neurodegenerative diseases, which are associated with memory decline. Blackcurrant (BC), an anthocyanin-rich berry, is renowned for its antioxidant and neuroprotective activities. However, evidence on the effects of BC on purinergic signaling is lacking. This study investigated the effects of BC and its association with Donepezil (DNPZ) on learning and memory, on the modulation of purinergic signaling, pro-inflammatory responses, and oxidative markers in a mouse model of cognitive impairment chronically induced by scopolamine (SCO). Animals were divided into twelve groups and treated with BC (50 or 100mg/kg), and/or DNPZ (5mg/kg), and/or SCO (1mg/kg). Results showed that SCO decreased spatial learning and memory as assessed by the Morris Water Maze test, and treatment with BC and/or DNPZ restored these effects. Furthermore, BC and/or DNPZ treatments also prevented changes in ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) and adenosine deaminase (ADA) activities and restored the increased density of P2X7 and A2A receptors in synaptosomes of the cerebral cortex of SCO-induced mice. Moreover, the increased Nod-like receptor protein 3 (NLRP3) and interleukin-1β expression, and the oxidative stress markers levels were reduced by BC and/or DNPZ treatments, compared with the SCO group. Overall, BC and/or DNPZ treatments ameliorated SCO-induced cognitive decline, alleviated oxidative stress and pro-inflammatory responses, and improved purinergic signaling. These findings underscore the potential of BC, especially when in combination with DNPZ, as a therapeutic agent for the prevention of memory deficits associated with aging or neurological diseases.

Anxiolytic, Antidepressant, and Anticholinesterase Effects of Essential Oil from Myrcia sylvatica (G.Mey.) DC

Aromatic plants are rich sources of essential oils (EOs), recognized for their therapeutic properties due to their diversity of phytochemicals. This study investigated the anxiolytic and antidepressant effects of Myrcia sylvatica essential oil (MsEO) through inhalation in an animal model and its in vitro anticholinesterase (AChE) activity. The EO was obtained by hydrodistillation, and its volatile constituents were analyzed by GC-MS. Swiss mice were exposed to doses of 0.1%, 1%, and 2% of the EO via an inhalation apparatus. The anxiolytic activity was assessed using the elevated plus maze and light–dark box tests, while antidepressant activity was evaluated using the tail suspension and forced swimming tests. To examine potential side effects, the animals were subjected to rotarod, Y-maze, and Morris water maze tests to assess motor coordination, memory, and learning. Anticholinesterase activity was determined by direct bioautography and colorimetry based on the Ellman method. The results demonstrated that inhalation of MsEO at doses of 0.1% and 1% significantly reduced anxiety and depressive-like behaviors without impairing memory, learning, or motor coordination in the animals. Moreover, MsEO inhibited acetylcholinesterase with an IC50 of 0.47 μg/mL. These findings suggest that MsEO has potential therapeutic applications for anxiety and depression disorders, with additional anticholinesterase activity warranting further investigation in cognitive-related conditions.

Trehalose Inhibits ferroptosis Through Activating SIRT3/SOD2 Signaling Axis and Alleviates Brain Injury After Traumatic Brain Injury.

Trehalose has neuroprotective effects in neurodegenerative diseases. This study aimed to explore the impact of trehalose on traumatic brain injury (TBI) by investigating its role in neuroprotection. The TBI mice model was established utilizing the cortical impact technique followed by trehalose treatment. Traumatic neuronal injury induced by scratch followed by trehalose treatment was performed to mimic TBI in vitro. Memory function was assessed using the Water maze test. Brain damage was evaluated through various methods including brain water content analysis, Nissl staining, Evans blue exudation, and TUNEL staining. Biochemical and morphological changes related to ferroptosis post-TBI were also examined. The results showed that trehalose was found to enhance spatial memory, reduce brain injury, and inhibit ferroptosis in TBI mice, similar to ferroptosis inhibitors. The influence of trehalose on TBI was reversed by the SIRT3 inhibitor. Trehalose upregulated SIRT3 to increase SOD activity in TBI, which could also be counteracted by the SIRT3 inhibitor. Combining trehalose with a ferroptosis inhibitor had a more significant effect on reducing brain injury and inhibiting ferroptosis. Furthermore, in TBI mice treated with trehalose and SIRT3 inhibitors, the effect of trehalose was reversed by SIRT3 inhibitors, but the addition of ferroptosis inhibitors reversed the effect of SIRT3 inhibitors, as shown by decreased ferroptosis and neuronal apoptosis in damaged brain tissue. In summary, this study provides initial evidence that trehalose plays a crucial role in neuroprotection post-TBI through the SIRT3/SOD2 pathway-mediated ferroptosis.

Protection of Alzheimer’s disease progression by a human-origin probiotics cocktail

Microbiome abnormalities (dysbiosis) significantly contribute to the progression of Alzheimer’s disease (AD). However, the therapeutic efficacy of microbiome modulators in protecting against these ailments remains poorly studied. Herein, we tested a cocktail of unique probiotics, including 5 Lactobacillus and 5 Enterococcus strains isolated from infant gut with proven microbiome modulating capabilities. We aimed to determine the probiotics cocktail’s efficacy in ameliorating AD pathology in a humanized AD mouse model of APP/PS1 strains. Remarkably, feeding mice with 1 × 1011 CFU per day in drinking water for 16 weeks significantly reduced cognitive decline (measured by the Morris Water Maze test) and AD pathology markers, such as Aβ aggregation, microglia activation, neuroinflammation, and preserved blood-brain barrier (BBB) tight junctions. The beneficial effects were linked to a reduced inflammatory microbiome, leading to decreased gut permeability and inflammation in both systemic circulation and the brain. Although both male and female mice showed overall improvements in cognition and biological markers, females did not exhibit improvements in specific markers related to inflammation and barrier permeability, suggesting that the underlying mechanisms may differ depending on sex. In conclusion, our results suggest that this unique probiotics cocktail could serve as a prophylactic agent to reduce the progression of cognitive decline and AD pathology. This is achieved by beneficially modulating the microbiome, improving intestinal tight junction proteins, reducing permeability in both gut and BBB, and decreasing inflammation in the gut, blood circulation, and brain, ultimately mitigating AD pathology and cognitive decline.

Quercetin can improve anesthesia induced neuroinflammation and cognitive dysfunction by regulating miR-138-5p/ LCN2

BackgroundAnesthesia can lead to functional cognitive impairment, which can seriously affect postoperative recovery. To investigate the effect and mechanism of quercetin (Que) in anesthetized rats, the study provided a new therapeutic idea for the prevention of cognitive dysfunction caused by anesthesia.MethodsCognitively impaired rats were constructed using Isoflurane (ISO) anesthesia and treated with Que. The capacity of the rats to learn and remember was tested using the Morris water maze test. Rat hippocampal tissues were collected and analyzed for inflammatory factor concentration and miR-138-5p expression using ELISA and qRT-PCR, respectively, and the targeting link between miR-138-5p and LCN2 was verified by dual luciferase reporter.ResultsQue treatment was found to improve ISO-induced cognitive dysfunction and inhibit the level of hippocampal inflammatory factors in rats. miR-138-5p was down-regulated in rats with cognitive dysfunction, while Que treatment increased miR-138-5p expression. The study found that knockdown miR-138-5p can reverse the positive effects of Que therapy, aggravate cognitive dysfunction, and promote the secretion of TNF-α, IL-1β, and IL-6 in the hippocampus. In addition, LCN2, a target gene of miR-138-5p, was significantly up-regulated in the hippocampus after ISO induction.ConclusionQue may inhibit ISO-induced hippocampal neuroinflammation and ameliorate functional cognitive deficits in rats by modulating miR-138-5p/ LCN2.

Mechanism of sodium nitroprusside regulating ginseng quality

The roots of Panax ginseng C. A. Meyer (ginseng) are one of the traditional medicinal herbs in Asian countries and is known as the “king of all herbs”. The most important active components of ginseng are the secondary metabolite saponins, which are closely related to ecological stress. Unsuitable ecological stress can generate a large amount of reactive oxygen species (ROS), by which the secondary metabolism is regulated, and the quality of herbs can be significantly improved. The purpose of this study was to investigate the effect of sodium nitroprusside (SNP) treatment on the quality of fresh ginseng roots. In this study, 5-year-old fresh ginseng was exposed to 0.1, 0.5, and 2 mmol/L SNP, a nitric oxide (NO) donor for five consecutive days. SNP significantly increased the levels of O2·−, H2O2, malondialdehyde (MDA), NADPH oxidase (NOX), superoxide dismutase (SOD), catalase (CAT), peroxides (POD), ascorbate peroxidase (APX), glutathione reductase (GR), ascorbate (AsA) and GSH/GSSG. The main root treated by 0.5 mmol/L SNP for three days was the best, with the activities of the key enzymes of the ginsenoside synthesis pathway, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), farnesyl pyrophosphate synthase (FPS), squalene synthase (SS), squalene epoxidase (SE), and dammarane diol-II synthase (DS) activities increased markedly; the ginsenosides Rg1 + Re, Rb1, Rf, Rc, Rg2 + Rh1 and the total ginsenoside contents increased by 51.0%, 77.7%, 44.6%, 26.8%, 63.2% and 48.2%, respectively, but only a trace amount of the ginsenoside monomer Rb2 decreased 23.4%. The fibrous roots treated by 0.1 mmol/L SNP for four days showed the best effect, HMGCR, FPS, SS, SE, and DS also increased significantly; ginsenosides Rg1 + Re, Rb1, Ro, Rc, Rf, Rb3, Rb2, and total saponin contents increased 37.6%, 47.8%, 34.2%, 75.1%, 51.0%, 49.4%, 28.3%, and 20.4%, respectively. The 1,3-diphosphoglycerate (1,3-DPG) and phosphoenolpyruvate carboxylase (PEPC), related to primary metabolism, were also significantly elevated. The Morris water maze (MWM), histopathological analysis and oxidative stress indexes in brain tissues were used to evaluate the anti-aging effect, indicating that the SNP-treated ginseng further ameliorated D-gal-induced the impaired memory function and oxidative stress in mice, implying the efficacy of SNP-treated ginseng was better than untreated ginseng’s. SNP can build the physiological state of ginseng under ecological stress, stimulate the antioxidant protection mechanism, increase the secondary metabolites, and improve the quality of ginseng.

Impaired cerebral microvascular reactivity and endothelial SK channel activity in a streptozotocin-treated mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a complex neurodegenerative disease marked by increased amyloid-β (Aβ) deposition, tau hyperphosphorylation, impaired energy metabolism, and chronic ischemia-type injury. Cerebral microvascular dysfunction likely contributes to AD pathology, but its precise pathogenic role has been poorly defined. To examine microvascular reactivity to endothelium-dependent vasodilators and small conductance calcium-activated potassium (SK) channel activity in an intracerebral streptozotocin (STZ)-induced AD mouse model. Control and STZ-AD mice underwent Morris Water Maze and Barnes testing, after which cerebral microvascular and brain microvascular endothelial cells (MBMECs) were dissected to assess microvascular reactivity, responses to SK channel activator NS309, and ion-channel current recordings using whole-cell patch clamp methodology. Control mouse cerebral microvascular and human brain microvascular endothelial cells (HBMECs) were treated with soluble Aβ1-42 peptide to characterize microvascular reactivity and endothelial potassium currents. STZ-AD mice exhibited impaired performance vs control mice in behavioral testing. STZ-AD mice also exhibited diminished cerebral microvascular responsiveness and MBMECs potassium current augmentation in response to NS309 compared with control mice. Incubation of control mouse cerebral micro-vessels and HBMECs with soluble Aβ (1 µM) for 2 h attenuated relaxation responses to NS309 and diminished NS309-sensitive endothelial potassium currents. STZ-AD mice exhibited impaired microvascular relaxation responses to endothelium-dependent vasodilators; SK/IK channel dysfunction may be involved in the mechanism of this impairment. Acute treatment with Aβ produced dysregulated cerebrovascular endothelial SK/IK channels. Further elucidation of the role of microvascular dysfunction in AD is needed to prevent the chronic ischemia-type injury that contributes to cognitive decline.