Y-maze Research Articles

In silico, In vitro, and In vivo Evaluation of the Anti-alzheimer’s Activity of Berberine

Background: Alzheimer’s disease (AD), a progressive neurodegenerative disease for which there is no effective cure is among the leading causes of death worldwide. Objectives: To investigate the potential anti-AD activity of berberine (BBR). Methods: In silico assessment included molecular docking and ADMET prediction. BBR’s in vitro inhibitory activity of the target selected from docking results was assessed via colorimetric inhibitor screening assay. BBR’s LC50 in adult zebrafish was determined via an Acute Toxicity Study. ZnCl2 concentration for AD induction was determined via toxicity study and T-maze test. Finally, zebrafish were treated with ZnCl2 alone or simultaneously with either BBR or donepezil and assessed via the inhibitory avoidance task, followed by ELISA of AD-related biomarker levels in brain tissue. Results: The in silico assessment showed BBR’s desirable drug properties and binding affinity on selected AD-related targets, which was the greatest docking score with AChE. The in vitro IC50 on AChE was 3.45 μM. The LC50 in adult zebrafish was calculated at 366 ppm. In the T-maze test, ZnCl2 at 2.5 ppm caused the greatest cognitive impairment accompanied by moderate freezing. In the inhibitory avoidance test, fish treated with either 100 ppm BBR or 2.5 ppm donepezil had significantly better performance than ZnCl2-treated fish. ZnCl2-treated zebrafish brain tissue had the highest Aβ levels and AChE activity of all groups, but these were significantly lower in donepeziland BBR-treated fish. ZnCl2- and donepezil-treated fish had similar TNF-α levels, whereas BBR treatment significantly lowered them close to those of untreated fish. Conclusion: BBR showed anti-amyloidogenic, anti-AChE, and anti-inflammatory effects, which support its potential use in AD therapy.

Blood glucose and β-hydroxybutyrate predict significant brain injury after hypoxia-ischemia in neonatal mice.

The Vannucci procedure is widely used to model cerebral hypoxic-ischemic (HI) injury in neonatal rodents. Identifying minimally invasive biomarkers linked to brain injury would improve stratification of pups to experimental treatments. We hypothesized that extreme blood glucose (BG) and β-hydroxybutyrate (bHB) levels immediately after HI will correlate with severity of brain injury in this model. C57BL6 mice of both sexes underwent the Vannucci procedure with BG and bHB measured immediately after hypoxia. GFAP and α-fodrin were measured to assess injury severity at 4h, P11, P18 and P40. Open field (OF), Y-maze (YM), and Object-location task (OLT) were tested at P40. Clinical seizures-like stereotypies during hypoxia were associated with lower post-hypoxia BG in HI-injured mice. Low BG after HI was related to higher GFAP expression, higher α-fodrin breakdown, lower residual regional volume, and worse working memory. BG was superior to bHB in ROC analysis with BG threshold of <111 mg/dL providing 100% specificity with 72% sensitivityfor hippocampal HI-injury. Post-hypoxic BG is a minimally invasive screening tool to identify pups with significant HI brain injury in the Vannucci model modified for mice improving our ability to stratify pups to experimental treatments to assess effectiveness. End hypoxic-ischemic blood glucose levels are a reliable and inexpensive biomarker to detect hypoxic-ischemic brain injury in mice. Screening with blood glucose levels post-hypoxia allows appropriate stratification of those mouse pups most likely to be injured to experimental treatments improving validity and translatability of the results. These findings provide biological plausibility to the clinical observation that extreme blood glucose levels relate to worse outcomes after hypoxia-ischemia.

Neurological recovery in rats with portocaval anastomosis-induced hepatic encephalopathy treated with leuprolide acetate, a GnRH agonist.

Hepatic encephalopathy (HE) is a neuropsychiatric complication of acute liver failure or chronic liver injury. Liver dysfunction impairs ammonia detoxification, allowing it to cross the blood-brain barrier (BBB) and disrupt brain function. The hippocampus becomes a crucial target during elevated ammonia levels, causing spatial memory impairment and decreased learning ability. Leuprolide acetate (LA), a GnRH agonist, has been implicated in neuroprotection and neuroregeneration in several regions of the central nervous system (CNS) including hippocampus. In this study, we aim to evaluate the effects of LA treatment on hippocampus of rats with HE induced by portocaval anastomosis (PCA) trough cognitive tests, histology analysis and expression of neuronal recovery marker proteins, such as neurofilament (NF200) and neurabin II, and astrocyte marker glial fibrillary acidic protein (GFAP). Rats were divided into three groups: SHAM, portocaval anastomosis with saline solution (PCA + SS) and portocaval anastomosis treated with LA (PCA + LA). To evaluate learning and spatial memory elevated T-maze (ETM) and Y-maze test (YMT) were respectively used. Results indicated that LA-treated rats performed significantly better in ETM and YMT than untreated rats. Histological analysis of hippocampus showed increased neuron density, nuclear area, and layer thickness in dentate gyrus of PCA + LA group compared to PCA + SS. Additionally, neurabin II and NF200 expression were higher in LA-treated rats, while GFAP expression was elevated in the PCA + SS group compared to control and PCA + LA groups. In conclusion, LA enhances hippocampal neuron recovery and reduces astrogliosis, suggesting its potential as a therapeutic intervention for attenuating hippocampal damage during HE.

Chloride intracellular channel 4 blockade improves cognition in mice with Alzheimer's disease: CLIC4 protein expression and tau protein hyperphosphorylation

Numerous academic literature suggests that amyloid-β (Aβ) deposition, tau protein phosphorylation, and irreversible neuronal death are the three major causes of AD. The chloride intracellular channel (CLIC) protein family not only regulates the polarisation of neurons, but also has important implications for neuronal survival. Chloride intracellular channel 4 (CLIC4) can be pathologically activated by cyclin-dependent kinase 5 (Cdk5), which causes a significant increase in the expression of CLIC4 and mediates neuronal apoptosis. CLIC4 knockdown inhibits H2O2-induced neuronal apoptosis; however, the relationship between CLIC4 and AD remains unknown. In the present study, we showed that CLIC4 expression was elevated in the hippocampus of AD mice; knockdown of hippocampal CLIC4 alleviated Aβ25–35-induced cognitive impairment in mice; overexpression of hippocampal CLIC4 accelerated Aβ deposition and tau protein hyperphosphorylation in young AD mice (APP/PS1 mice at three months of age). CLIC4 overexpressing mice had a longer escape latency compared to controls in behavioural testing (Morris water maze and T-maze tests). By Co-immunoprecipitation/mass spectrometry (Co-IP/MS) of HT22 cells to identify proteins that specifically bind to CLIC4, we found interactions with CCAAT enhancer binding protein (C/EBPβ); a critical pathway involved in the development of various neurodegenerative diseases. In addition, the knockdown of hippocampal CLIC4 alleviated AD-like pathology by inhibiting the C/EBPβ/AEP signaling pathway. These data suggest an essential role for high CLIC4 expression in the pathophysiology of AD and reveal that inhibition of CLIC4 expression may provide an opportunity for treatment.

Interneuron-selective HCN channel knockdown in prelimbic cortex of female rats mimics effects of chronic ethanol exposure

Our laboratory has previously shown that chronic ethanol exposure elicits enhanced working memory performance in female, but not male, adult Sprague–Dawley rats, indicative of a fundamental sex difference in cortical plasticity. Recent studies have furthermore revealed that females display markedly reduced HCN-mediated channel activity in inhibitory Martinotti interneurons after chronic ethanol exposure that is similarly not observed in males. From these observations we hypothesized that alcohol induces facilitated working memory performance via down-regulation of these channels’ activity specifically within interneurons. To test this hypothesis, we employed a Pol-II compatible shRNA expression system to elicit targeted knockdown of HCN channel activity in these cells, and measured performance on a delayed Non-Match-to-Sample (NMS) T-maze test to gauge effects on working memory performance. A significant baseline enhancement of working memory performance with HCN channel knockdown was observed, indicative of a critical role for interneuron-expressed HCNs in maintaining optimal cortical network activity during cognitively-demanding tasks. Consistent with previous observations, ethanol exposure resulted in enhanced NMS T-maze performance, however elevated working memory performance was observed in both scram- and hcn-shRNA infected groups after alcohol administration. We therefore conclude that interneuron-expressed HCN channels, despite representing a minor population of total cortical HCN expression, contribute substantially to maintaining working memory processes. Downregulated HCN channel activity, though, does not alone appear sufficient to manifest alcohol-induced enhancement of working memory performance observed in female rats during acute withdrawal.

Formulation and Characterization of Silibinin Entrapped Nano-Liquid Crystals for Activity against Aβ1-42 Neurotoxicity in In-Vivo Model.

Silibinin (SIL) Encapsulated Nanoliquid Crystalline (SIL-NLCs) particles were prepared to study neuroprotective effect against amyloid beta (Aβ1-42) neurotoxicity in Balb/c mice model. Theses NLCs were prepared through hot emulsification and probe sonication technique. The pharmacodynamics was investigatigated on Aβ1-42 intracerebroventricular (ICV) injected Balb/c mice. The particle size, zeta potential and drug loading were optimized to be 153 ± 2.5nm, -21mV, and 8.2%, respectively. Small angle X-ray (SAXS) and electron microscopy revealed to crystalline shape of SIL-NLCs. Thioflavin T (ThT) fluroscence and circular dichroism (CD) techniquewere employed to understand monomer inhibition effect of SIL-NLCs on Aβ1-4. In neurobehavioral studies, SIL-NLCs exhibited enhanced mitigation of memory impairment induced on by Aβ1-42 in T-maze and new object recognition test (NORT). Whereas biochemical and histopathological estimation of brain samples showed reduction in level of Aβ1-42 aggregate, acetylcholine esterase (ACHE) and reactive oxygen species (ROS). SIL-NLCs treated animal group showed higher protection against Aβ1-42 toxicity compared to free SIL and Donopezil (DPZ). Therefore SIL-NLCs promises great prospect in neurodegenerative diseases such as Alzheimer's disease.

Naringenin mitigates nanoparticulate-aluminium induced neuronal degeneration in brain cortex and hippocampus through downregulation of oxidative stress and neuroinflammation

Alumunium usage and toxicity has been a global concern especially an increased use of nanoparticulated aluminum (Al-NPs) products from the environment and the workplace. Al degrades in to nanoparticulate form in the environment due to the routine process of bioremediation in human body. Al-NPs toxicity plays key role in the pathophysiology of neurodegeneration which is characterised by the development of neurofibrillary tangles and neuritic plaques which correlates to the Alzheimer's disease. This study evaluated the Al-NPs induced neurodegeneration and causative behavioral alterations due to oxidative stress, inflammation, DNA damage, β-amyloid aggregation, and histopathological changes in mice. Furthermore, the preventive effect of naringenin (NAR) as a potent neuroprotective flavonoid against Al-NPs induced neurodegeneration was assessed. Al-NPs were synthesized and examined using FTIR, XRD, TEM, and particle size analyzer. Mice were orally administered with Al-NPs (6 mg/kg b.w.) followed by NAR treatment (10 mg/kg b.w. per day) for 66 days. The spatial working memory was determined by novel object recognition, T-maze, Y-maze, and Morris Water Maze tests. We measured nitric oxide, advanced oxidation of protein products, protein carbonylation, lipid peroxidation, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, reduced glutathione, oxidised glutathione, and acetylcholine esterase, as well as cytokines analysis, immunohistochemistry, and DNA damage. Al-NPs significantly reduced the learning memory power, increased oxidative stress, reduced antioxidant enzymatic activity, increased DNA damage, altered the levels of cytokines, and increased β-amyloid aggregation in the cortex and hippocampus regions of the mice brain. These neurobehavioral impairments, neuronal oxidative stress, and histopathological alterations were significantly attenuated by NAR supplementation. In conclusion, Al-NPs may be potent neurotoxic upon exposure and that NAR could serve as a potential preventive measure in the treatment and management of neuronal degeneration.

Development of an Experimental Animal Screening Model for Induction of type-3 Diabetes Mellitus using High-fat Diet, Streptozotocin, and Nicotinamide

ABSTRACT Purpose: To develop a screening method for the induction of type-3 diabetes mellitus (T3DM) in experimental animals. Materials and Methods: Twelve Albino Wistar rats were divided into normal control (NC) and disease control (DC) group. Animals of NC were fed with high-fat diet (HFD) for four weeks followed by intraperitoneal administration of nicotinamide (230 mg/kg) and streptozotocin (STZ) (65 mg/kg). Body weight (BW) and blood glucose levels (BGL) were measured from week 1 to 4. Glycosylated hemoglobin (HbA1C) levels were estimated on week 4. Behavioral parameters including Morris water maze test (MWMT), T-maze test, and rota-rod test were recorded. Estimation of acetylcholine (ACh) and acetylcholinesterase (AChE) was conducted on week 4. Histopathological analysis of brain hippocampus was undertaken in three animals of each group. Results: DC group showed significant elevation in levels of BW and BGL with P value &lt; 0.05. Levels of HbA1C increased significantly in DC group with P value &lt; 0.0001. DC group showed a significant increase (P value &lt; 0.05 [week 1] and P value &lt; 0.001 [weeks 2–4]) in escape latency and elapsed time in MWMT and T-maze test, respectively. In DC group, elapsed time decreased significantly (P value &lt; 0.05 [week 1] and P value &lt; 0.001 [weeks 2–4]) in rota-rod test. A significant deviation in the levels of ACh and AChE was recorded with P value &lt; 0.0001. Histopathology of hippocampus part of DC group showed notable increase in the number of β-amyloid plaque. Conclusion: Animals administered with HFD, nicotinamide, and STZ showed dementia along with the diabetic condition suggesting the induction of T3DM.

Dental stem cells improve memory and reduce cell death in rat seizure model.

Epilepsy is a common neurological disorder that significantly affects the quality of life of patients. In this study, we aim to evaluate the effectiveness of dental pulp stem cell (DPSC) transplantation in decreasing inflammation and cell death in brain cells, thus reducing seizure damage. We induced seizures in rats using intraperitoneal injections of pentylenetetrazole (PTZ). In the PTZ + DPSC group, we conducted bilateral hippocampal transplantation of DPSCs in PTZ-lesioned rat models. After 1 month, we performed post-graft analysis and measured some behavioral factors, such as working memory and long-term memory, using a T-maze test and passive avoidance test, respectively. We investigated the immunohistopathology and distribution of astrocyte cells through light microscopy and Sholl analysis. Additionally, we employed the Voronoi tessellation method to estimate the spatial distribution of the cells in the hippocampus. Compared to the control group, we observed a reduction in astrogliosis, astrocyte process length, the number of branches, and intersections distal to the soma in the hippocampus of the PTZ + DPSC group. Further analysis indicated that the grafted DPSCs decreased the expression of caspase-3 in the hippocampus of rats with induced seizures. Moreover, the DPSCs transplant protected hippocampal pyramidal neurons against PTZ toxicity and improved the spatial distribution of the hippocampal neurons. Our findings suggest that DPSCs transplant can be an effective modifier of astrocyte reactivation and inflammatory responses.

Histological and Memory Alterations in an Innovative Alzheimer's Disease Animal Model by Vanadium Pentoxide Inhalation.

Previous work from our group has shown that chronic exposure to Vanadium pentoxide (V2O5) causes cytoskeletal alterations suggesting that V2O5 can interact with cytoskeletal proteins through polymerization and tyrosine phosphatases inhibition, causing Alzheimer's disease (AD)-like hippocampal cell death. This work aims to characterize an innovative AD experimental model through chronic V2O5 inhalation, analyzing the spatial memory alterations and the presence of neurofibrillary tangles (NFTs), amyloid-β (Aβ) senile plaques, cerebral amyloid angiopathy, and dendritic spine loss in AD-related brain structures. 20 male Wistar rats were divided into control (deionized water) and experimental (0.02 M V2O5 1 h, 3/week for 6 months) groups (n = 10). The T-maze test was used to assess spatial memory once a month. After 6 months, histological alterations of the frontal and entorhinal cortices, CA1, subiculum, and amygdala were analyzed by performing Congo red, Bielschowsky, and Golgi impregnation. Cognitive results in the T-maze showed memory impairment from the third month of V2O5 inhalation. We also noted NFTs, Aβ plaque accumulation in the vascular endothelium and pyramidal neurons, dendritic spine, and neuronal loss in all the analyzed structures, CA1 being the most affected. This model characterizes neurodegenerative changes specific to AD. Our model is compatible with Braak AD stage IV, which represents a moment where it is feasible to propose therapies that have a positive impact on stopping neuronal damage.

Marrubium vulgare Extract Improves Spatial Working Memory and Oxidative Stress Damage in Scopolamine-Treated Rats.

The cholinergic neuronal loss in the basal forebrain and increasing brain oxidative stress are one of the main features of the brain suffering from Alzheimer's disease. Marrubium vulgare (M. vulgare), commonly known as 'white horehound,' possesses a variety of valuable properties, such as antioxidative, anti-inflammatory, and antidiabetic activities. Moreover, it possesses neuromodulatory properties that could potentially impact short-term memory functions. The present study was undertaken to investigate the preventive effects of water M. vulgare extract on working memory, cholinergic neurotransmission, and oxidative stress in rats with scopolamine (Sco)-induced dementia. Male Wistar rats (200-250 g) were divided into four experimental groups. The plant extract was administered orally for 21 days, and Sco (2 mg/kg) was administered intraperitoneally for 11 consecutive days. The behavioral performance of the animals was evaluated by the T-maze test. The effect of the extract on acetylcholinesterase (AChE) activity and antioxidant status in cortex and hippocampus were also monitored. Our experimental data revealed that treatment with M. vulgare significantly increased the percentage of correct choices of rats with Sco-induced dementia in the T maze test (by 38%, p < 0.05). Additionally, it reduced AChE activity in the hippocampus (by 20%, p < 0.05) and alleviated oxidative stress induced by Sco, particularly in the cortex. M. vulgare water extract demonstrated working memory preserving effect in rats with Sco-induced dementia, AChE inhibitory activity and in vivo antioxidant potential, and deserve further attention.

LRP1 in GABAergic neurons is a key link between obesity and memory function

ObjectiveLow-density lipoprotein receptor-related protein-1 (LRP1) regulates energy homeostasis, blood–brain barrier integrity, and metabolic signaling in the brain. Deficiency of LRP1 in inhibitory gamma-aminobutyric acid (GABA)ergic neurons causes severe obesity in mice. However, the impact of LRP1 in inhibitory neurons on memory function and cognition in the context of obesity is poorly understood. MethodsMice lacking LRP1 in GABAergic neurons (Vgat-Cre; LRP1loxP/loxP) underwent behavioral tests for locomotor activity and motor coordination, short/long-term and spatial memory, and fear learning/memory. This study evaluated the relationships between behavior and metabolic risk factors and followed the mice at 16 and 32 weeks of age. ResultsDeletion of LRP1 in GABAergic neurons caused a significant impairment in memory function in 32-week-old mice. In the spatial Y-maze test, Vgat-Cre; LRP1loxP/loxP mice exhibited decreased travel distance and duration in the novel arm compared with controls (LRP1loxP/loxP mice). In addition, GABAergic neuron-specific LRP1-deficient mice showed a diminished capacity for performing learning and memory tasks during the water T-maze test. Moreover, reduced freezing time was observed in these mice during the contextual and cued fear conditioning tests. These effects were accompanied by increased neuronal necrosis and satellitosis in the hippocampus. Importantly, the distance and duration in the novel arm, as well as the performance of the reversal water T-maze test, negatively correlated with metabolic risk parameters, including body weight, serum leptin, insulin, and apolipoprotein J. However, in 16-week-old Vgat-Cre; LRP1loxP/loxP mice, there were no differences in the behavioral tests or correlations between metabolic parameters and cognition. ConclusionsOur findings demonstrate that LRP1 from GABAergic neurons is important in regulating normal learning and memory. Metabolically, obesity caused by GABAergic LRP1 deletion negatively regulates memory and cognitive function in an age-dependent manner. Thus, LRP1 in GABAergic neurons may play a crucial role in maintaining normal excitatory/inhibitory balance, impacting memory function, and reinforcing the potential importance of LRP1 in neural system integrity.

FNDC5/irisin mediates the protective effects of Innovative theta-shaking exercise on mouse memory

As a passive motion and non-invasive treatment, theta-shaking exercise is considered an alternative to traditional active exercise for slowing down brain ageing. Here, we studied the influence of theta-shaking exercise on fibronectin type III domain containing 5/irisin (FNDC5/irisin) in the anterior nucleus of the thalamus, hippocampus, and medial prefrontal cortex (ATN–HPC–MPFC). Further, we assessed memory in senescence-accelerated prone mice (SAMP-10 mice) using a behavioural test to confirm the protective effect of theta-shaking exercise against age-related memory decline. SAMP-10 mice were subjected to theta-shaking exercise for 9–30 weeks. Mice then performed the T-maze test and passive avoidance task. Immunohistochemical analysis and ELISA were used to assess FNDC5/irisin, nerve growth factor (NGF), and neurotrophin 4/5 (NT4/5) expression in the ATN–HPC–MPFC. In the shaking group, FNDC5 was locally upregulated within the hippocampus and MPFC area rather than exhibiting even distribution throughout brain tissue. Irisin levels were generally higher in the control group. Meanwhile, hippocampal NGF levels were significantly higher in the shaking group, with no differences noted in neurotrophin levels. Theta-shaking preserved normal neurons in certain sub-regions. However, no beneficial changes in neuronal density were noted in the ATN. Theta-shaking exercise positively affects memory function in SAMP-10 mice. FNDC5 upregulation and higher levels of NGF, along with the potential involvement of irisin, may have contributed to the preservation of normal neuronal density in the hippocampus and MPFC subregions.

Ameliorative potential of Astaxanthin on glyphosate-induced neurocognitive functional changes in adult zebrafish via acid phosphatase and annexin A2 dysfunction

Glyphosate (GYP) is a phosphonate type of herbicide and potentially causes neurodegenerations. Astaxanthin (AST) is a red pigment and it is a group of carotenoids. It possesses the potential antioxidants and neuroprotective actions. However, the ameliorative role of AST in GYP- induced neurocognitive dysfunction has not been studied yet. Hence, the present study is designed to investigate the ameliorative potential of AST in GYP-induced cognitive dysfunction via regulations of acid phosphatase (AP) and annexin A2 (AXA2) actions in the zebrafish model. The cognitive dysfunction was induced by exposure to GYP (0.5 mg/L for 30 minutes/day) for 14 consecutive days. The AST (50, 75, and 100 mg/L for 30 minutes/day) and reference drug i.e., donepezil (DP; 1 µg/mL for 30 minutes/day) were exposed for 14 consecutive days before GYP exposure. On the 14th day, cognitive changes i.e., three horizontal compartment test,optokinetic motor response (OMR), startle response (SR), and T-maze tests were assessed. The changes of biomarkers i.e., acetylcholinesterase (AChE) activity, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), AP, and AXA2 levels were estimated in brain tissue. The administration of AST ameliorates the GYP-induced neurocognitive dysfunctions via the antioxidant, regulation of AP and AXA2 actions. Hence, it can be used for neurocognitive disorders against the phosphonate type of herbicide (GYP) toxicity.

Neuroprotective impact of Ximenia americana aqueous bark extract on Diazepam-induced memory impairment in mice via its antioxidant potential

In traditional medicine, Ximenia americana (XA) is used to treat mental disorders, and headaches. The current study aimed to show the preventive and biochemical impacts of XA aqueou’s extract on diazepam-induced amnesia. Mice were randomized as follows: distilled water (10 mL/kg); diazepam (3 mg/kg); piracetam (PIR) (150 mg/kg); and XA experimental groups (25, 50 and 75 mg/kg). Mice were then treated in groups, 14 straight days. Radial arm maze (RAM) and T-maze were employed to assess different behaviours 30 min after each treatment. After the test was completed, the brains were isolated for histological and biochemical examinations. The results obtained showed that XA extract seriously (p &lt; 0.001) reversed mistakes in working remembrance in the radial arm maze test contrasted to the normal control factions. In the T-maze test, pretreatment of mice with XA extract seriously (p &lt; 0.001) expanded the time spent in the preferred arm when contrasted to the DZP-only treated faction. The XA-treated DZP groups showed subsequent (p &lt; 0.001) improvement in catalase (CAT) and reduced glutathione (GHS). A diminish in malondialdehyde (MDA) level was observed in brain homogenates of mice treated with the extract contrasted with the DZP- group. These few results regarding the neuroprotective and antioxidant effects of XA extract at least partially demonstrate its empirical use in the treatment of certain pathologies.

Short Working Memory Impairment Associated with Hippocampal Microglia Activation in Chronic Hepatic Encephalopathy.

Hepatic encephalopathy (HE) is a major neuropsychological condition that occursas a result of impaired liver function. It is frequently observed in patients with advanced liver disease or cirrhosis. Memory impairment is among the symptoms of HE; the pathophysiologic mechanism for this enervating condition remains unclear. However, it is possible that neuroinflammation may be involved, as recent studies have emphasized such phenomena. Therefore, the aim of the present study is to assess short working memory (SWM) and examine the involvement of microglia in a chronic model of HE. The study was carried out with male Wistar rats that were induced by repeated thioacetamide (TAA) administration (100 mg/kg i.p injection for 10 days). SWM function was assessed through Y-maze, T-Maze, and novel object recognition (NOR) tests, together with an immunofluorescence study of microglia activation within the hippocampal areas. Our data showed impaired SWM in TAA-treated rats that was associated with microglial activation in the three hippocampal regions, and which contributed to cognitive impairment.

Liraglutide versus pramlintide in protecting against cognitive function impairment through affecting PI3K/AKT/GSK-3β/TTBK1 pathway and decreasing Tau hyperphosphorylation in high-fat diet- streptozocin rat model.

The American Diabetes Association guidelines (2021) confirmed the importance of raising public awareness of diabetes-induced cognitive impairment, highlighting the links between poor glycemic control and cognitive impairment. The characteristic brain lesions of cognitive dysfunction are neurofibrillary tangles (NFT) and senile plaques formed of amyloid-β deposition, glycogen synthase kinase 3 beta (GSK3β), and highly homologous kinase tau tubulin kinase 1 (TTBK1) can phosphorylate Tau proteins at different sites, overexpression of these enzymes produces extensive phosphorylation of Tau proteins making them insoluble and enhance NFT formation, which impairs cognitive functions. The current study aimed to investigate the potential contribution of liraglutide and pramlintide in the prevention of diabetes-induced cognitive dysfunction and their effect on the PI3K/AKT/GSK-3β/TTBK1 pathway in type 2 diabetic (T2D) rat model. T2D was induced by administration of a high-fat diet for 10weeks, then injection of a single dose of streptozotocin (STZ); treatment was started with either pramlintide (200μg/kg/day sc) or liraglutide (0.6mg/kg/day sc) for 6weeks in addition to the HFD. At the end of the study, cognitive functions were assessed by novel object recognition and T-maze tests. Then, rats were sacrificed for biochemical and histological assessment of the hippocampal tissue. Both pramlintide and liraglutide treatment revealed equally adequate control of diabetes, prevented the decline in memory function, and increased PI3K/AKT expression while decreasing GSK-3β/TTBK1 expression; however, liraglutide significantly decreased the number of Tau positive cells better than pramlintide did. This study confirmed that pramlintide and liraglutide are promising antidiabetic medications that could prevent associated cognitive disorders in different mechanisms.

Motor, Cognitive, and Behavioral Impairment in TLR3 and TLR9 Deficient Male Mice: Insights into the Non-Immunological Roles of Toll-Like Receptors

Toll-like receptors (TLRs) play a critical role in initiating the innate immune response to infection or injury. Recent studies have uncovered their intriguing functions as moonlighting proteins involved in various biological processes, including development, learning, and memory. However, the specific functions of individual TLRs are still largely unknown. We investigated the effects of TLR3 and TLR9 receptor deficiency on motor, cognitive, and behavioral functions during development using genetically modified male mice of different ages. We evaluated the motor coordination, anxiety-like behavior, spatial learning, and working memory of male mice lacking the TLR3 and TLR9 genes at different ages (two, four, six, and eight months) using the rotarod, open field, water maze, and T-maze tests. We observed that the deletion of either TLR3 or TLR9 resulted in impaired motor performance. Furthermore, young TLR3-deficient mice exhibited reduced anxiety-like behavior and spatial learning deficits; however, their working memory was unaffected. In contrast, young TLR9-knockout mice showed hyperactivity and a tendency toward decreased working memory. These findings provide valuable insights into the broader roles of the TLR system beyond the innate immune response, revealing its involvement in pathways associated with the central nervous system. Importantly, our results establish a strong association between the endosomal receptors TLR3 and TLR9 and the performance of motor, cognitive, and behavioral tasks that change over time. This study contributes to the growing body of research on the multifaceted functions of TLRs and enhances our understanding of their participation in non-immune-related processes.

The Evaluation of Neuroprotective Effect of Nigella sativa Linn Seed Using Zebrafish Model

Naturally occurring materials that can serve as preservatives in foodstuffs are substances found in their composition. Nigella sativa Linn, a member of the Ranunculaceae family, is a widely recognized medicinal herb with global usage. For centuries, N. sativa L., seeds have been employed to address various ailments and health issues. In behavioral research, the bioactive compound derived from N. sativa L., namely Kaempferol 3-(2-galloyl-alpha-L-arabinopyranoside), has gained significant attention. The escalating prevalence of Alzheimer's disease among elderly individuals worldwide necessitates exploration beyond traditional mammalian and rodent models. This has led to the adoption of zebrafish (Danio rerio) as a unique model organism in biomedical research, behavior analysis and human disorders. Experiments involving scopolamine-induced T-maze, escape, place preference and bite tests have strongly suggested that behavior in zebrafish is governed by conserved regulatory processes. The results of the behavior tests demonstrated that N. sativa L., enhances learning and memory, which was otherwise affected by scopolamine treatment. Notably, a thorough analysis of histoarchitecture revealed no adverse effects of Kaempferol 3-(2-galloyl-alpha-L-arabinopyranoside), which might be a promising therapeutic option for such a multi-factorial Alzheimer's disease.

Chronic alcohol-induced long-lasting working memory deficits are associated with altered histone H3K9 dimethylation in the prefrontal cortex.

Epigenetic modifications have emerged as key contributors to the enduring behavioral, molecular and epigenetic neuroadaptations during withdrawal from chronic alcohol exposure. The present study investigated the long-term consequences of chronic alcohol exposure on spatial working memory (WM) and associated changes of transcriptionally repressive histone H3 lysine 9 dimethylation (H3K9me2) in the prefrontal cortex (PFC). Male C57BL/6 mice were allowed free access to either 12% (v/v) ethanol for 5 months followed by a 3-week abstinence period or water. Spatial WM was assessed through the spontaneous alternation T-maze test. Alcoholic and water mice received daily injections of GABAB agonist baclofen or saline during alcohol fading and early withdrawal. Global levels of histone modifications were determined by immunohistochemistry. Withdrawal mice displayed WM impairments along with reduced prefrontal H3K9me2 levels, compared to water-drinking mice. The withdrawal-induced decrease of H3K9me2 occurred concomitantly with increased level of permissive H3K9 acetylation (H3K9ac) in the PFC. Baclofen treatment rescued withdrawal-related WM deficits and fully restored prefrontal H3K9me2 and H3K9ac. Alcohol withdrawal induced brain region-specific changes of H3K9me2 and H3K9ac after testing, with significant decreases of both histone marks in the dorsal hippocampus and no changes in the amygdala and dorsal striatum. Furthermore, the magnitude of H3K9me2 in the PFC, but not the hippocampus, significantly and positively correlated with individual WM performances. No correlation was observed between H3K9ac and behavioral performance. Results also indicate that pre-testing intraperitoneal injection of UNC0642, a selective inhibitor of histone methyltransferase G9a responsible for H3K9me2, led to WM impairments in water-drinking and withdrawal-baclofen mice. Collectively, our results demonstrate that alcohol withdrawal induced brain-region specific alterations of H3K9me2 and H3K9ac, an effect that persisted for at least three weeks after cessation of chronic alcohol intake. The findings suggest a role for long-lasting decreased H3K9me2 specifically in the PFC in the persistent WM impairments related to alcohol withdrawal.