Maze Test Research Articles

The impact of early-life exercise on CREB-signaling pathway and hippocampus neuroplasticity in diabetic adult male rats; the study of developmental model.

Childhood exercise enhances brain structure, while diabetes detrimentally affects it. This study examines early-life exercise's influence on adult diabetic rats' memory and neuroplasticity. Male Wistar pups were divided into Control, Diabetes, Exercise Training, and Diabetes exercise groups. Diabetes was induced on day 23 with Alloxan (200 mg/kg). A 3-week regimen included aerobic and resistance training thrice weekly. The aerobic intensity was 70%, and resistance varied from 50% to 100% of the maximal carrying capacity (MCC). Following the last training sessions, spatial memory and retrieval tests were performed in infancy, childhood, and emerging adulthood using the Morris Water Maze test (MWM). The hippocampus was excised to measure protein and gene expression of brain-derived neurotrophic factor (BDNF), calmodulin-dependent protein kinase (CAMKII), N-methyl-D-aspartate receptors (NMDAR), and cAMP-response element-binding protein (CREB) by western blotting and reverse transcription-polymerase-chain reaction (RT-PCR) methods. Blood samples were collected during each developmental stage to measure glucose levels, at the study's conclusion, to assess Interleukin-1β levels using the ELISA method. The Nissel staining assessed dead hippocampal cells in CA1. Post-natal exercise improved spatial memory (p < 0.05) and glucose levels (p < 0.05) in diabetic rats during adolescence and emerging adulthood. Despite reduced mRNA expression (NMDAR 40%, BDNF 62%, CREB 43%, CAMKII 66%), diabetic rats, by study end, showed increased BDNF, NMDARR, CAMKII, CREB protein/gene expression (p < 0.05) in emerging adulthood for both training groups. Early-life exercise influenced hippocampal BDNF/NMDAR-CAMKII/CREB pathways in a diabetic rat model, highlighting post-natal exercise's role in neuroplasticity memory enhancement and improved glucose level.

Association of synaptic density and cognitive performance in temporal lobe epilepsy: Humans and animals PET imaging study with [18F]SynVesT-1.

Cognitive impairment is a common comorbidity in individuals with temporal lobe epilepsy (TLE), yet the underlying mechanisms remain unknown. This study explored the putative association between in vivo synaptic loss and cognitive outcomes in TLE patients by PET imaging of synaptic vesicle glycoprotein 2A (SV2A). We enrolled 16 TLE patients and 10 cognitively normal controls. All participants underwent SV2A PET imaging using [18F]SynVesT-1 and cognitive assessment. Lithium chloride-pilocarpine-induced rats with status epilepticus (n = 20) and controls (n = 6) rats received levetiracetam (LEV, specifically binds to SV2A), valproic acid (VPA), or saline for 14 days. Then, synaptic density was quantified by [18F]SynVesT-1 micro-PET/CT. The novel object recognition and Morris water maze tests evaluated TLE-related cognitive function. SV2A expression was examined and confirmed by immunohistochemistry. Temporal lobe epilepsy patients showed significantly reduced synaptic density in hippocampus, which was associated with cognitive performance. In the rat model of TLE, the expression of SV2A and synaptic density decreased consistently in a wider range of brain regions, including the entorhinal cortex, insula, hippocampus, amygdala, thalamus, and cortex. We treated TLE animal models with LEV or VPA to explore whether synaptic loss contributes to cognitive deficits. It was found that LEV significantly exerted protective effects against brain synaptic deficits and cognitive impairment. This is the first study to link synaptic loss to cognitive deficits in TLE, suggesting [18F]SynVesT-1 PET could be a promising biomarker for monitoring synaptic loss and cognitive dysfunction. LEV might help reverse synaptic deficits and ameliorate learning and memory impairments in TLE patients.

Antidepressant-like Effects of Chinese Quince (Chaenomeles sinensis) Fruit Based on In Vivo and Molecular Docking Studies

In this study, we examined the potential antidepressant-like effects of Chinese quince fruit extract (Chaenomeles sinensis fruit extract, CSFE) in an in vivo model induced by repeated injection of corticosterone (CORT)-induced depression. HPLC analysis determined that chlorogenic acid (CGA), neo-chlorogenic acid (neo-CGA), and rutin (RT) compounds were major constituents in CSFE. Male ICR mice (5 weeks old) were orally administered various doses (30, 100, and 300 mg/kg) of CSFE and selegiline (10 mg/kg), a monoamine oxidase B (MAO-B) inhibitor, as a positive control following daily intraperitoneal injections of CORT (40 mg/kg) for 21 days. In our results, mice treated with CSFE exhibited significant improvements in depressive-like behaviors induced by CORT. This was evidenced by reduced immobility times in the tail suspension test and forced swim test, as well as increased step-through latency times in the passive avoidance test. Indeed, mice treated with CSFE also exhibited a significant decrease in anxiety-like behaviors as measured by the elevated plus maze test. Moreover, molecular docking analysis indicated that CGA and neo-CGA from CSFE had stronger binding to the active site of MAO-B. Our results indicate that CSFE has potential antidepressant effects in a mouse model of repeated injections of CORT-induced depression.

Explorations about the correlation between biological changes of meninges in periodontitis mice and cognitive impairment via single-cell RNA sequencing

Objective: To clarify the potential correlation between biological changes of meninges in periodontitis mice and cognitive impairment by analyzing the biological changes of meninges in periodontitis mice using single-cell RNA sequencing. Methods: Thirty C57BL/6 mice were divided into two groups by using random number table method (15 mice in each group). Mice in the control group were locally administered 2% carboxyl methyl cellulose (CMC) without Porphyromonas gingivalis (Pg) on both buccal sides. A mixture of Pg and 2% CMC was applied on both buccal sides in the experimental group mice three times a week, lasting for 16 weeks in total. The absorption of alveolar bone, locomotor activity and cognitive function, the activation of microglia and astrocytes in the cortex were observed and assessed. The mRNA expression levels of Occludin in meninges and brain were detected in two groups. Single-cell RNA sequencing data of meninges were processed by uniform manifold approximation and projection (UMAP). Differential genes expressions of endothelial cells were processed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. In addition, real-time fluorescence quantitative PCR (RT-qPCR) was used to verify the expressions of Atf3 and Apold1. Results: Methylene blue staining found the distances of buccal and palatal cement-enamel junction-alveolar bone crest (CEJ-ABC) in experimental mice [(185.60±17.60), (206.90±13.37) μm] increased significantly compared with the control group [(135.33±9.57), (163.05±14.98) μm] (t=5.02, P=0.002; t=4.37, P=0.005). Open field experiment showed the total distance and average speed of mice in the experimental group [(971.88±164.57) cm; (3.25±0.55) cm/s] were not statistically significant compared with the control group [(914.24±278.81) cm; (3.05±0.93) cm/s] (t=0.65, P=0.525; t=0.65, P=0.520). The recognition index of the experimental group [(48.02±16.92) %] was lower than the control group [(66.27±17.90) %] (t=2.40, P=0.027) by novel object recognition tests. Compared with the control group [(63.56±11.88) %], the alternation of experimental group [(50.99±14.17) %] was significantly decreased in Y maze tests (t=2.33, P=0.030). Immunohistochemistry results showed microglia and astrocytes were activated in the cortex of experimental mice. Compared with the control group (1.02±0.25, 1.04±0.31), the relative mRNA expressions of Occludin decreased significantly in the meninges and brain of periodontitis mice, respectively (0.61±0.10, 0.64±0.20) (t=3.47, P=0.010; t=2.66, P=0.024). By single-cell RNA sequencing, meninges cells were divided into 11 types, such as endothelial cells, fibroblasts, immune cells and so on. Endothelial cells were the main cell types in meninges [the control group: 26.47% (1 589/6 004), the experimental group: 26.26% (807/3 073)]. Compared with the control group [5.56% (334/6 004)], the percentage of granulocytes increased in the periodontitis mice [11.65% (358/3 073)]. Using clustering analysis to further focus on endothelial cells, GO enrichment analysis revealed differential genes were mainly related to angiogenesis, cell adhesion, apoptosis and so on. KEGG enrichment analysis revealed that differential genes were related to signaling pathways of interleukin-17, relaxin and so on. The relative mRNA expressions of Atf3 and Apold1 in meninges of periodontitis mice (0.42±0.24, 0.54±0.27) were significantly lower than the control group (1.03±0.26, 1.02±0.23) (t=3.88, P=0.005; t=3.02, P=0.017). Conclusions: The mice chronically infected with W83 occurred memory impairment, neuroinflammation and changes of barrier function. In the meninges of periodontitis mice, there were infiltration of immune cells and down-regulation expressions of Atf3 and Apold1 by single-cell RNA sequencing. Meningeal immunity and changes of barrier function may play an important role in the cognitive impairment caused by periodontitis.

Omega-3 fatty acids supplementation prevents learning and memory impairment induced by chronic ethanol consumption in adolescent male rats through restoration of inflammatory and oxidative responses.

Ethanol (Eth) intake is known to cause numerous detrimental effects on the structure and function of the brain, and it is commonly used as a psychostimulant drug by adolescents. Conversely, omega-3 (O3) can reduce the risk of cognitive decline and promote the maintenance of neurophysiological functions. In this study, we investigated the protective effects of O3 on behavioral alterations, oxidative stress, and interleukin-6 (IL-6) levels induced by chronic Eth intake during adolescence in rats. Adolescent male rats (21 days old) were divided as follows: (1) Vehicle, (2) Eth (Eth in drinking water [20%]), (3-5) Eth + O3 (50/100/150 mg/kg), and (6) O3 (150 mg/kg). After 5weeks, Morris water maze (MWM) and passive avoidance (PA) tests were performed, and the hippocampal and cortical levels of oxidative stress markers and inflammatory indices were measured. Adolescent Eth intake impairs learning and memory function in MWM and PA tests (groups × day, p< 0.05 and p< 0.001, respectively). It was shown that Eth induced oxidative stress and neuroinflammation. O3 improved learning and impairment induced by Eth by reducing the adverse effects of Eth on the oxidant/antioxidant balance in the hippocampi (for malondialdehyde [MDA]/thiol: p< 0.01, p< 0.001, respectively) and for superoxide dismutase (SOD)/catalase (CAT): p< 0.01 and p< 0.05, respectively). Furthermore, we found that O3 prevented the Eth-induced increase of hippocampal IL-6 (p< 0.001). O3 supplementation acts as an effective approach to prevent learning and memory impairments induced by chronic Eth consumption during adolescence. In this respect, the antioxidant and anti-inflammatory properties of O3 seem to be the main underlying mechanisms of neuroprotection.

Mechanisms of Peitu Yimu acupuncture in repairing intestinal mucosal barrier by regulating CRF/CRFR1 pathway in diarrhea-predominant irritable bowel syndrome rats.

To investigate the effect of Peitu Yimu(strengthening spleen and soothing liver) acupuncture on intestinal mucosal barrier function and corticotropin-releasing factor (CRF)/CRF receptor 1 (CRFR1) pathway in rats with diarrhea-predominant irritable bowel syndrome (IBS-D), so as to explore its underlying mechanism in alleviating IBS-D. Forty female SD rats were randomly divided into blank, model, electroacupuncture (EA), and agonist groups, with 10 rats in each group. Except for the blank group, rats in the other groups were given folium sennae infusion by gavage combined with chronic unpredictable mild stress to establish IBS-D model. Rats in the EA group received acupuncture at "Tianshu"(ST25) and EA at "Zusanli"(ST36) and "Taichong"(LR3) (2 Hz/15 Hz) on one side for 20 min, with the side chosen alternately every other day, for 14 days after modeling. Rats in the agonist group received acupuncture 30 min after intravenous injection of CRFR1 agonist urocortin, with the same manipulation method and time as the EA group. Before and after intervention, visceral pain threshold and stool Bristol scores were measured. Elevated plus maze test and open field test were used to detect anxiety and depression like behavior of rats. ELISA was used to detect the contents of CRF and CRFR1 in rats serum. Immunohistochemistry was used to detect the positive expressions of CRF, CRFR1, zonula occludens protein 1(ZO-1), occlusal protein(Occludin), and closure protein 1 (Claudin-1) in colon tissue. Compared with the blank group, the visceral pain threshold, open arm time percentage (OT%), total distance of movement in the open field test, and positive expression of ZO-1, Occludin, and Claudin-1 in colon were decreased (P<0.01, P<0.05), while Bristol stool scores, serum CRF and CRFR1 contents, and positive expressions of CRF and CRFR1 in colon were increased (P<0.01) in the model group. After intervention and compared with the model group, the visceral pain threshold, OT%, total distance of movement in the open field test, and positive expressions of ZO-1, Occludin, and Claudin-1 in colon were increased (P<0.05, P<0.01), while Bristol stool scores, serum CRF and CRFR1 contents, and positive expressions of CRF and CRFR1 in colon were decreased (P<0.01) in the EA group；the Bristol stool scores, serum CRF content, and CRF positive expression in colon were significantly decreased in the agonist group (P<0.01). Peitu Yimu acupuncture can significantly improve visceral hypersensitivity and anxiety-depression state in IBS-D rats. Its mechanism may be related to the inhibition of CRF/CRFR1 pathway and restoration of intestinal tight junction protein expressions.

Efficacy of melatonin in alleviating disorders arising from repeated exposure to sevoflurane in males and females of the Wistar rats during preadolescence

Pediatricians use sevoflurane due to its fast action and short recovery time. However, studies have shown that repeated exposure to anesthesia can affect learning and memory. Melatonin, an indole-type neuroendocrine hormone, has significant anti-inflammatory, and neuroprotective properties. Melatonin’s impact on cognitive behavior in sevoflurane-anesthetized males and females of the Wistar rats during preadolescence was examined in this research. The cognitive function was evaluated by shuttle box and morris water maze tests, while interleukin-10, Catalase (CAT), Malondialdehyde (MDA), and Tumor Necrosis Factor-α (TNF-α) were evaluated using ELISA kits. The expression levels of the apoptosis-linked proteins, Bax, Bcl-2, and caspase-3, were determined using the western blotting technique. The learning and memory latencies of the rats were more significant in the sevoflurane groups than in the control group; however, the latencies were significantly shorter in the sevoflurane and melatonin groups than in the control group. The levels of MDA, TNF-α, Bax, and caspase-3 were significantly higher in the sevoflurane groups than in the control group. We also found that the levels of CAT and Bcl-2 were significantly reduced in the sevoflurane groups compared to the control group. Increasing levels of CAT, Bcl-2, and decreasing levels of MDA, TNF-α, Bax, and caspase-3 in response to melatonin indicate a possible contribution to the recovery from the sevoflurane impairment. Melatonin shows neuroprotective effects in male and female rats with sevoflurane-induced cognitive impairment. This suggests melatonin could be a valuable treatment for learning and memory deficits resulting from repeated exposure to sevoflurane, possibly by controlling apoptosis, oxidative stress, and inflammation.

Gut Microbiome-Mediated Mechanisms in Alleviating Opioid Addiction with Aqueous Extract of Anacyclus pyrethrum

The escalating rates of morbidity and mortality associated with opioid use disorder (OUD) have spurred a critical need for improved treatment outcomes. This study aimed to investigate the impact of prolonged exposure to Fentanyl, a potent opioid, on behavior, biochemical markers, oxidative stress, and the composition of the gut microbiome. Additionally, we sought to explore the therapeutic potential of Anacyclus pyrethrum in mitigating the adverse effects of Fentanyl withdrawal. The study unveiled that chronic Fentanyl administration induced a withdrawal syndrome characterized by elevated cortisol levels (12.09 mg/mL, compared to 6.3 mg/mL for the control group). This was accompanied by heightened anxiety, indicated by a reduction in time spent and entries made into the open arm in the Elevated Plus Maze Test, as well as depressive-like behaviors, manifested through increased immobility time in the Forced Swim Test. Additionally, Fentanyl exposure correlated with decreased gut microbiome density and diversity, coupled with heightened oxidative stress levels, evidenced by elevated malondialdehyde (MDA) and reduced levels of catalase (CAT) and superoxide dismutase (SOD). However, both post- and co-administration of A. pyrethrum exhibited substantial improvements in these adverse effects, effectively alleviating symptoms associated with OUD withdrawal syndrome and eliciting positive influences on gut microbiota. In conclusion, this research underscores the therapeutic potential of A. pyrethrum in managing Fentanyl withdrawal symptoms. The findings indicate promising effects in alleviating behavioral impairments, reducing stress, restoring gut microbiota, and mitigating oxidative stress, offering valuable insights for addressing the challenges of OUD treatment.

Increasing Ambient GABA Levels in the Hippocampus to Improve Cognition in a Mouse Model of Schizophrenia: A Research Protocol

Introduction: Schizophrenia is a complex psychiatric disorder characterized by cognitive, positive, and negative symptoms, with cognitive impairments significantly affecting learning, memory, and executive functions. The hippocampus, particularly the CA1 region, is a critical area of interest due to its role in learning and memory and its dysfunction in schizophrenia. This protocol explores the effects of increasing ambient Gamma-Aminobutyric Acid (GABA) levels in the CA1 region on cognitive functions in a Methylazoxymethanol Acetate (MAM) model of schizophrenia. Methods: Utilizing a two-by-two factorial design, male Sprague-Dawley rats undergo either a sham or MAM treatment, followed by a control or GABA modulation intervention. The study will employ GABA transporter inhibitor Tiagabine to increase ambient GABA levels and assess its impact on neuronal excitability and cognitive function. Behavioural assessments will include the Morris water maze and the Attentional set-shifting test to evaluate spatial memory and cognitive flexibility. Histological examinations and electrophysiological measurements will provide insights into structural and functional changes in the hippocampus. Results: The results are expected to demonstrate neurodevelopmental disruptions in MAM-treated offspring and improvements in cognitive performance following GABA modulation. Enhanced spatial memory and cognitive flexibility are anticipated in MAM-treated rats with GABA modulation, as evidenced by performance in the Morris water maze and Attentional set-shifting test. Electrophysiological recordings are likely to show increased tonic inhibition in the CA1 region. Discussion: This study aims to extend the understanding of tonic inhibition in schizophrenia treatment. By focusing on ambient GABA modulation, the research could offer novel insights into therapeutic strategies for schizophrenia, especially in enhancing cognitive functions. However, the translational applicability of intracerebral administration of uptake inhibitors like Tiagabine poses a significant challenge, highlighting the need for future research in more clinically viable methods of GABA modulation. Conclusion: This study was designed to contribute to schizophrenia research, particularly in understanding cognitive impairments and developing potential therapeutic strategies targeting the GABAergic system. The proposed findings could pave the way for novel treatments, improving the quality of life for individuals with schizophrenia.

Cornuside ameliorates cognitive impairments via RAGE/TXNIP/NF-κB signaling in Aβ1-42 induced Alzheimer's disease mice.

Cornuside has been discovered to improve learning and memory in AD mice, however, its underlying mechanism was not fully understood. In the present study, we established an AD mice model by intracerebroventricular injection of Aβ1-42, which were treated with cornuside (3, 10, 30mg/kg) for 2weeks. Cornuside significantly ameliorated cognitive function of AD mice in series of behavioral tests, including Morris water maze test, nest building test, novel object recognition test and step-down test. Additionally, cornuside could attenuate neuronal injury, and promote cholinergic synaptic transmission by restoring the level of acetylcholine (ACh) via inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as facilitating choline acetyltransferase (ChAT). Furthermore, cornuside inhibited oxidative stress levels amplified as decreased malondialdehyde (MDA), by inhibiting TXNIP expression, improving total anti-oxidative capacity (TAOC), raising activities of superoxide dismutase (SOD) and catalase (CAT). Cornuside also reduced the activation of microglia and astrocytes, decreased the level of proinflammatory factors TNF-α, IL-6, IL-1β, iNOS and COX2 via interfering RAGE-mediated IKK-IκB-NF-κB phosphorylation. Similar anti-oxidative and anti-inflammatory effects were also found in LPS-stimulated BV2 cells via hampering RAGE-mediated TXNIP activation and NF-κB nuclear translocation. Virtual docking revealed that cornuside could interact with the active pocket of RAGE V domain directly. In conclusion, cornuside could bind to the RAGE directly impeding the interaction of Aβ and RAGE, and cut down the expression of TXNIP inhibiting ROS production and oxidative stress, as well as hamper NF-κB p65 mediated the inflammation.

Safeguarding Neuronal Integrity: Unveiling Possible Role of NFκB in the Neuroprotective Efficacy of Andrographolide Contrary to Aluminium Chloride-induced Neurotoxicity and Associated Spatial Memory Impairments in Rats.

The current study was structured to evaluate the neuroprotective properties of andrographolide in the context of aluminum chloride (AlCl3)-induced neurotoxicity, along with its concurrent impact on spatial memory impairment in Wistar rats. The present investigation elucidated the biochemical and neurobehavioral outcomes of andrographolide treatment in rats, emphasizing the areas of the brain associated with memory, i.e., the cortex and the hippocampus. Prolonged dosing of AlCl3 (7 mg/kg) intraperitoneally for 10 days exhibited a substantial enhancement in the values of oxidative stress markers associated with a reduction in the concentrations of antioxidant enzymes within the brain. The selection of andrographolide doses (1, 2, and 3 mg/kg) was grounded in precedent safety and toxicity investigations, with subsequent oral administration. The evaluation of behavioral parameters, specifically spatial memory, was conducted through the utilization of the Radial Eight Arm Maze (RAM) test. On the concluding day of the experiment, the assessment encompassed biochemical parameter analysis and histological scrutiny of the brain tissue. The oral dosing of andrographolide at 1, 2, and 3 mg/kg, in conjunction with AlCl3, effectively mitigated the behavioral deficits induced by aluminum exposure. Notably, a significant suppression of NFκB was uncovered in the rats treated with andrographolide. Furthermore, histopathological examinations of the cortex and hippocampus of rat brains provided corroborative evidence, demonstrating that andrographolide substantially alleviated the toxic impact of AlCl3, thereby maintaining the typical histoarchitectural arrangement of these regions. These findings collectively suggest that andrographolide holds the potential to counteract memory impairment instigated by aluminum toxicity, accomplished through the modulation of NFκB activity and the amelioration of the adverse consequences of AlCl3 exposure.

Effect of Noisy Galvanic Vestibular Stimulation on Spatial Learning and Memory of Rats

Background and Aim: Previous studies have shown promising findings on effectiveness of noisy Galvanic Vestibular Stimulation (nGVS) in various cognitive disorders. The connections of the vestibular system with the hippocampus has been proven. Here we investigated the effect of vestibular galvanic stimulation on the improvement of spatial learning and memory of rats. Methods: Twelve Wistar rats were randomly divided into control and nGVS groups. The nGVS group underwent 30-minute sessions of stimulation at sub-threshold levels for a duration of fourteen days. Following the intervention, both groups underwent assessments of cognitive indices through the Morris water maze task, hippocampal neuronal spike rate by Single-Unit Recording (SUR) and the concentrations of c-fos protein in the hippocampus were measured using ELISA device. Results: The nGVS group exhibited a significant difference compared to the control group in both the time taken to reach the target platform and the percentage of time spent in the goal quarter during the Morris water maze test. The nGVS treatment significantly enhanced spike rate of hippocampal dentate gyrus (p&lt;0.01) compared to the control group. Additionally, c-fos protein concentrations were increased in the nGVS (5.833) than the control group (4.126), (p&lt;0.001). Conclusion: According to the obtained results, nGVS plays a role in improving spatial memory, and a longer duration of intervention is suggested to achieve more obvious improvement results. Keywords: Galvanic vestibular stimulation; spatial cognition; single-unit recording; hippocampus; rat

Experimental colitis in young Tg2576 mice accelerates the onset of an Alzheimer’s-like clinical phenotype

Systemic inflammation and neuroinflammation affect the natural course of the sporadic form of Alzheimer’s disease (AD), as supported by epidemiological and preclinical data, and several epidemiological studies indicate a higher prevalence of AD in patients with inflammatory bowel disease. In this study, we explored whether colitis induced by dextran sulfate sodium (DSS) in young, presymptomatic/preplaque mice worsens and/or anticipates age-dependent cognitive impairment in Tg2576, a widely used mouse model of AD. We demonstrated that DSS colitis induced in young Tg2576 mice anticipates the onset age of learning and memory deficit in the Morris water maze test. To explore potential mechanisms behind the acceleration of cognitive decline in Tg2576 mice by DSS colitis, we focused on gut microbiota, systemic inflammation and neuroinflammation markers. We observed a Firmicutes/Bacteroidetes ratio change in Tg2576 DSS animals comparable to that of elderly Tg2576 mice, suggesting accelerated microbiota aging in Tg2576 DSS mice, a change not observed in C57BL6 DSS mice. We also observed substantial differences between Tg2576 and WT mice in several inflammation and neuroinflammation-related parameters as early as 3 months of age, well before plaque deposition, a picture which evolved rapidly (between 3 and 5.5 months of age) in contrast to Tg2576 and WT littermates not treated with DSS. In detail, following induction of DSS colitis, WT and Tg2576 mice exhibited contrasting features in the expression level of inflammation-evoked astrocyte-associated genes in the hippocampus. No changes in microglial features occurred in the hippocampus between the experimental groups, whereas a reduced glial fibrillary acidic protein immunoreactivity was observed in Tg2576 vs. WT mice. This finding may reflect an atrophic, “loss-of-function” profile, further exacerbated by DSS where a decreased of GFAP mRNA expression level was detected. In conclusion, we suggest that as-yet unidentified peripheral mediators evoked by DSS colitis and involving the gut-brain axis emphasize an astrocyte “loss-of-function” profile present in young Tg2576 mice, leading to impaired synaptic morphological and functional integrity as a very early sign of AD.

CSF amino acid profiles in ICV-streptozotocin-induced sporadic Alzheimer's disease in male Wistar rat: a metabolomics and systems biology perspective.

Alzheimer's disease (AD) is an increasingly important public health concern due to the increasing proportion of older individuals within the general population. The impairment of processes responsible for adequate brain energy supply primarily determines the early features of the aging process. Restricting brain energy supply results in brain hypometabolism prior to clinical symptoms and is anatomically and functionally associated with cognitive impairment. The present study investigated changes in metabolic profiles induced by intracerebroventricular-streptozotocin (ICV-STZ) in an AD-like animal model. To this end, male Wistar rats received a single injection of STZ (3 mg·kg-1) by ICV (2.5 μL into each ventricle for 5 min on each side). In the second week after receiving ICV-STZ, rats were tested for cognitive performance using the Morris Water Maze test and subsequently prepared for positron emission tomography (PET) to confirm AD-like symptoms. Tandem Mass Spectrometry (MS/MS) analysis was used to detect amino acid changes in cerebrospinal fluid (CFS) samples. Our metabolomics study revealed a reduction in the concentrations of various amino acids (alanine, arginine, aspartic acid, glutamic acid, glycine, isoleucine, methionine, phenylalanine, proline, serine, threonine, tryptophane, tyrosine, and valine) in CSF of ICV-STZ-treated animals as compared to controls rats. The results of the current study indicate amino acid levels could potentially be considered targets of nutritional and/or pharmacological interventions to interfere with AD progression.

The chronic cerebral hypoperfusion model induces proinflammatory cascades in Alzheimer's disease

Cerebral neuroinflammation has emerged as a significant pathway contributing to the progression of Alzheimer's disease (AD) pathology. Research implicates the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome complex, initiating caspase 1-mediated maturation of interleukin-1 β (IL-1β) and interleukin-18 (IL-18). This study investigates whether chronic cerebral hypoperfusion (CCH), induced via permanent bilateral occlusion of the common carotid arteries (PBOCCA), leads to cognitive dysfunction and NLRP3 inflammasome activation. Twenty male Sprague Dawley (SD) rats underwent PBOCCA to induce CCH. Two weeks post-surgery, locomotor and Morris water maze (MWM) tests were conducted to examine motor functions, spatial learning, and memory, respectively. The gene expression levels of cathepsin B, NLRP3, an apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1 were analysed using real-time PCR, while the expression levels of the inflammatory cytokines were estimated using the ELISA method. Structural damage to the hippocampus was assessed using hematoxylin and eosin (HE) staining. Escape latencies and time spent in specific quadrants in PBOCCA significantly increased compared to sham-operated animals. There was no notable difference in locomotor activity between the PBOCCA and sham-operated groups. The number of pyknotic neurons with cytoplasmic shrinkage increased in the hippocampus. Gene expression of cathepsin B, NLRP3, ASC, and caspase-1 was upregulated in the PBOCCA group. The expression levels of IL-1β, IL-18, interleukin-6 (IL-6), and amyloid-β 1-42 (Aβ 1-42) were elevated in the PBOCCA group relative to sham. The findings confirm NLRP3 inflammasome induction, cognitive dysfunction, and inflammatory cytokines associated with AD and cerebral ischemia. The PBOCCA model provides a valuable tool for studying neurodegenerative including AD.

Oral administration of coenzyme Q10 ameliorates memory impairment induced by nicotine-ethanol abstinence through restoration of biochemical changes in male rat hippocampal tissues

Substance abuse among adolescents has become a growing issue throughout the world. The significance of research on this life period is based on the occurrence of neurobiological changes in adolescent brain which makes the individual more susceptible for risk-taking and impulsive behaviors. Alcohol and nicotine are among the most available drugs of abuse in adolescents. Prolonged consumption of nicotine and alcohol leads to drug dependence and withdrawal which induce various dysfunctions such as memory loss. Coenzyme Q10 (CoQ10) is known to improve learning and memory deficits induced by various pathological conditions such as Diabetes mellitus and Alzheimer's disease. In the present study we investigated whether CoQ10 treatment ameliorates memory loss following a nicotine-ethanol abstinence. Morris water maze and novel object recognition tests were done in male Wistar rats undergone nicotine-ethanol abstinence and the effect of CoQ10 was assessed on at behavioral and biochemical levels. Results indicated that nicotine-ethanol abstinence induces memory dysfunction which is associated with increased oxidative and inflammatory response, reduced cholinergic and neurotrophic function plus elevated Amyloid-B levels in hippocampi. CoQ10 treatment prevented memory deficits and biochemical alterations. Interestingly, this ameliorative effect of CoQ10 was found to be dose-dependent in most experiments and almost equipotential to that of bupropion and naloxone co-administration. CoQ10 treatment could effectively improve memory defects induced by nicotine-ethanol consumption through attenuation of oxidative damage, inflammation, amyloid-B level and enhancement of cholinergic and neurotrophic drive. Further studies are required to assess the unknown side effects and high dose tolerability of the drug in human subjects.

Alleviation of migraine related pain and anxiety by inhibiting calcium-stimulating AC1-dependent CGRP in the insula of adult rats.

Recent animal and clinical findings consistently highlight the critical role of calcitonin gene-related peptide (CGRP) in chronic migraine (CM) and related emotional responses. CGRP antibodies and receptor antagonists have been approved for CM treatment. However, the underlying CGRP-related signaling pathways in the pain-related cortex remain poorly understood. The SD rats were used to establish the CM model by dural infusions of inflammatory soup. Periorbital mechanical thresholds were assessed using von-Frey filaments, and anxiety-like behaviors were observed via open field and elevated plus maze tests. Expression of c-Fos, CGRP and NMDA GluN2B receptors was detected using immunofluorescence and western blotting analyses. The excitatory synaptic transmission was detected by whole-cell patch-clamp recording. A human-used adenylate cyclase 1 (AC1) inhibitor, hNB001, was applied via insula stereotaxic and intraperitoneal injections in CM rats. The insular cortex (IC) was activated in the migraine model rats. Glutamate-mediated excitatory transmission and NMDA GluN2B receptors in the IC were potentiated. CGRP levels in the IC significantly increased during nociceptive and anxiety-like activities. Locally applied hNB001 in the IC or intraperitoneally alleviated periorbital mechanical thresholds and anxiety behaviors in migraine rats. Furthermore, CGRP expression in the IC decreased after the hNB001 application. Our study indicated that AC1-dependent IC plasticity contributes to migraine and AC1 may be a promising target for treating migraine in the future.

Quercetin Inhibits Neuronal Pyroptosis and Ferroptosis by Modulating Microglial M1/M2 Polarization in Atherosclerosis.

Atherosclerosis (AS) with iron and lipid overload and systemic inflammation is a risk factor for Alzheimer's disease. M1 macrophage/microglia participate in neuronal pyroptosis and recently have been reported to be the ferroptosis-resistant phenotype. Quercetin plays a prominent role in preventing and treating neuroinflammation, but the protective mechanism against neurodegeneration caused by iron deposition is poorly understood. ApoE-/- mice were fed a high-fat diet with or without quercetin treatment. The Morris water maze and novel object recognition tests were conducted to assess spatial learning and memory, and nonspatial recognition memory, respectively. Prussian blue and immunofluorescence staining were performed to assess the iron levels in the whole brain and in microglia, microglia polarization, and the degree of microglia/neuron ferroptosis. In vitro, we further explored the molecular biological alterations associated with microglial polarization, neuronal pyroptosis, and ferroptosis via Western blot, flow cytometry, CCK8, LDH, propidium iodide, and coculture system. We found that quercetin improved brain lesions and spatial learning and memory in AS mice. Iron deposition in the whole brain or microglia was reversed by the quercetin treatment. In the AS group, the colocalization of iNOS with Iba1 was increased, which was reversed by quercetin. However, the colocalization of iNOS with PTGS2/TfR was not increased in the AS group, suggesting a character resisting ferroptosis. Quercetin induced the expression of Arg-1 and decreased the colocalizations of Arg-1 with PTGS2/TfR. In vitro, ox-LDL combined with ferric ammonium citrate treatment (OF) significantly shifted the microglial M1/M2 phenotype balance and increased the levels of free iron, ROS, and lipid peroxides, which was reversed by quercetin. M1 phenotype induced by OF caused neuronal pyroptosis and was promoted to ferroptosis by L-NIL treatment, which contributed to neuronal ferroptosis as well. However, quercetin induced the M1 to M2 phenotype and inhibited M2 macrophages/microglia and neuron pyroptosis or ferroptosis. In summary, quercetin alleviated neuroinflammation by inducing the M1 to M2 phenotype to inhibit neuronal pyroptosis and protected neurons from ferroptosis, which may provide a new idea for neuroinflammation prevention and treatment.

Novel combination of Olesoxime/Resveratrol-encapsulated exosomes to improve cognitive function by targeting amyloid β-induced Alzheimer's disease: investigation on in vitro and in vivo model.

Alzheimer's disease (AD) is a fatal neurological illness that worsens with time. Preventing the aggregate formation of amyloid beta protein is a promising approach to treat Alzheimer's disease. This article describes an amiable procedure for the synthesis of Olesoxime-Resveratrol (OLX-RSV) encapsulated in exosomes. By suppressing Aβ1-42 aggregation and crossing the blood-brain barrier also known as BBB after intravenous treatment without resulting in any discernible damage, the nanocomposite demonstrated good biocompatibility. A variety of characterization technique including particle size, TEM, and in vitro drug release experiments, were used to characterize the exosomes. Human Neuroblastoma (SHSY5Y) cells were used to test the cytotoxicity and viability of cells of the formulation using the Cell Counting Kit-8 assay. The prepared OLX-RSV-loaded exosomes were tested for their ability to suppress Aβ1-42 in SHSY5Y Cells by analyzing the amyloid samples using CD spectra. The effects of apoptosis on Human neuroblastoma cells were studied using cytofluorometry. The parameters of SOD, caspase-3 and the ability to scavenge reactive oxygen species (ROS) were also evaluated. The behavioral outcomes of Morris water maze test demonstrated that OLX-RSV-loaded exosomes significantly enhanced the APP/PS1 mice's capacity to learn and remember spatial cues. Therefore, we hypothesized that OLX-RSV-loaded exosomes could be a useful and efficient method in the treatment of AD.

Antidepressant effects of activation of infralimbic cortex via upregulation of BDNF and β-catenin in an estradiol withdrawal model.

Clinical and preclinical studies have demonstrated that estradiol withdrawal after delivery is one of important factors involved in the pathogenesis of postpartum depression (PPD). The infralimbic cortex (IL) is related to anxiety and mood disorders. Whether IL neurons mediate PPD is still unclear. This study was to observe the antidepressant effect and expression of BDNF and β-catenin in IL by allopregnanolone (ALLO) treatment or the selective activation or inhibition of IL neurons using a chemogenetic approach in a pseudopregnancy model of PPD. Administration of estradiol combined with progesterone and the abrupt withdrawal of estradiol simulated the pregnancy and early postpartum periods to induce depression in ovariectomized rats. The relative expression levels of β-catenin and BDNF were observed by western blotting. Immobility time was significantly increased in the forced swim test and open-arm movement was reduced in the elevated plus maze test in the estradiol-withdrawn rats. After ALLO treatment, the immobility time were lower and open-arm traveling times higher than those of the estradiol-withdrawn rats. Meanwhile, the expression level of BDNF or β-catenin in the IL was reduced significantly in estradiol-withdrawn rats, which was prevented by treatment with ALLO. The hM3Dq chemogenetic activation of pyramidal neurons in the IL reversed the immobility and open-arm travel time trends in the estradiol-withdrawal rat model, but chemogenetic inhibition of IL neurons failed to affect this. Upregulated BDNF and β-catenin expression and increased c-Fos in the basolateral amygdala were found following IL neuron excitation in model rats. Our results demonstrated that pseudopregnancy and estradiol withdrawal produced depressive-like behavior and anxiety. ALLO treatment or specific excitement of IL pyramidal neurons relieved abnormal behaviors and upregulated BDNF and β-catenin expression in the IL in the PPD model, suggesting that hypofunction of IL neurons may be involved in the pathogenesis of PPD.