Doxycycline cotherapy with albendazole relieves neural function damage in C57BL/6 and BALB/c mice infected with Angiostrongylus cantonensis.

BACKGROUND: We investigated the effects of combination therapy albendazole and doxycycline in Angiostrongylus cantonensis-infected mice during early and late treatment. MATERIALS AND METHODS: C57BL/6 and BALB/c mice were divided into five groups: (i) uninfected, (ii) infected with A. cantonensis, (iii) infected + 10 mg/kg albendazole, (iv) infected + 25mg/kg doxycycline, and (v) infected + 10 mg/kg albendazole + 25 mg/kg doxycycline. We administered drugs in both early treatments started at 7-day post infections (dpi) and late treatments (14 dpi) to A. cantonensis-infected C57BL/6 and BALB/c mice. To assess the impact of these treatments, we employed the Morris water maze test to evaluate spatial learning and memory abilities, and the rotarod test to measure motor coordination and balance in C57BL/6 mice. Additionally, we monitored the expression of the cytokine IL-33 and GFAP in the brain of these mice using western blot analysis. RESULTS: In this study, A. cantonensis infection was observed to cause extensive cerebral angiostrongyliasis in C57BL/6 mice. This condition significantly affected their spatial learning and memory abilities, as assessed by the Morris water maze test, as well as their motor coordination, which was evaluated using the rotarod test. Early treatment with albendazole led to favorable recovery outcomes. Both C57BL/6 and BALB/c mice express IL-33 and GFAP after co-therapy. The differences of levels and patterns of IL-33 and GFAP expression in mice may be influenced by the balance between pro-inflammatory and anti-inflammatory signals within the immune system. CONCLUSIONS: Combination therapy with anthelmintics and antibiotics in the early stage of A. cantonensis infection, in C57BL/6 and BALB/c mice resulted in the death of parasites in the brain and reduced the subsequent neural function damage and slowed brain damage and neurobehavior impairment. This study suggests a more effective and novel treatment, and drug delivery method for brain lesions that can decrease the neurological damage of angiostrongyliasis patients.

Telomere length and micronuclei trajectories in APP/PS1 mouse model of Alzheimer's disease: Correlating with cognitive impairment and brain amyloidosis in a sexually dimorphic manner.

Although studies have demonstrated that genome instability is accumulated in patients with Alzheimer's disease (AD), the specific types of genome instability linked to AD pathogenesis remain poorly understood. Here, we report the first characterization of the age- and sex-related trajectories of telomere length (TL) and micronuclei in APP/PS1 mice model and wild-type (WT) controls (C57BL/6). TL was measured in brain (prefrontal cortex, cerebellum, pituitary gland, and hippocampus), colon and skin, and MN was measured in bone marrow in 6- to 14-month-old mice. Variation in TL was attributable to tissue type, age, genotype and, to a lesser extent, sex. Compared to WT, APP/PS1 had a significantly shorter baseline TL across all examined tissues. TL was inversely associated with age in both genotypes and TL shortening was accelerated in brain of APP/PS1. Age-related increase of micronuclei was observed in both genotypes but was accelerated in APP/PS1. We integrated TL and micronuclei data with data on cognition performance and brain amyloidosis. TL and micronuclei were linearly correlated with cognition performance or Aß40 and Aß42 levels in both genotypes but to a greater extent in APP/PS1. These associations in APP/PS1 mice were dominantly driven by females. Together, our findings provide foundational knowledge to infer the TL and micronuclei trajectories in APP/PS1 mice during disease progression, and strongly support that TL attrition and micronucleation are tightly associated with AD pathogenesis in a female-biased manner.

Electronic Cigarette Vape Exposure Exacerbates Post-Ischemic Outcomes in Female but Not in Male Rats.

BACKGROUND: Nicotine-containing electronic cigarette (EC) vaping has become popular worldwide, and our understanding of the effects of vaping on stroke outcomes is elusive. Using a rat model of transient middle cerebral artery occlusion, the current exploratory study aims to evaluate the sex-dependent effects of EC exposure on brain energy metabolism and stroke outcomes. METHODS: Adult Sprague-Dawley rats of both sexes were randomly assigned to air/EC vapor (5% nicotine Juul pods) exposure for 16 nights, followed by randomization into 3 cohorts. The first cohort underwent exposure to air/EC preceding randomization to transient middle cerebral artery occlusion (90 minutes) or sham surgery, followed by survival for 21 days. During the survival period, rats underwent sensorimotor and Morris water maze testing. Subsequently, brains were collected for histopathology. A second cohort was exposed to air/EC after which brains were collected for unbiased metabolomics analysis. The third cohort of animals was exposed to air/EC and received transient middle cerebral artery occlusion/sham surgery, and brain tissue was collected 24 hours later for biochemical analysis. RESULTS: In females, EC significantly increased (P<0.05) infarct volumes by 94% as compared with air-exposed rats, 165±50 mm3 in EC-exposed rats, and 85±29 mm3 in air-exposed rats, respectively, while in males such a difference was not apparent. Morris water maze data showed significant deficits in spatial learning and working memory in the EC sham or transient middle cerebral artery occlusion groups compared with the respective air groups in rats of both sexes (P<0.05). Thirty-two metabolites of carbohydrate, glycolysis, tricarboxylic acid cycle, and lipid metabolism were significantly altered (P≤0.05) due to EC, 23 of which were specific for females. Steady-state protein levels of hexokinase significantly decreased (P<0.05) in EC-exposed females; however, these changes were not seen in males. CONCLUSIONS: Even brief EC exposure over 2 weeks impacts brain energy metabolism, exacerbates infarction, and worsens poststroke cognitive deficits in working memory more in female than male rats.

Influence of environmental enrichment on sexual behavior and the process of learning and memory in a rat model of autism with valproic acid.

Autism spectrum disorder (ASD) is a psychiatric disorder with severe behavioral consequences and no specific therapy. Its etiology is multifactorial, as it is caused by a complex interaction of genetic and environmental factors. In rats, prenatal exposure to the antiepileptic drug valproic acid (VPA) has been associated with an increased risk of autistic-like behaviors in offspring, including social behavior deficits, increased repetitive behaviors, and cognitive impairments. In addition, VPA-treated rats have shown altered sociosexual behaviors. However, the mechanisms underlying these alterations in reproductive processes in VPA-treated rats are not fully understood. Interestingly some abnormal behaviors in VPA autism models are improved by an enriched environment (EE). In the present study, we examined the effects of EE on memory performance and sexual behavior in male rats. We found that on postnatal day 90, EE reduced the time it took for both control and VPA-treated groups to find a hidden platform in the Morris water maze. On PND 100, prenatal exposure to VPA reduced total exploring time in object recognition tests. On PND 110, EE reduced mount and intromission latency and increased ejaculatory frequency in VPA-treated male rats. These results suggest that environmental stimuli significantly influence the onset of sexual behavior in VPA-treated male rats and that EE may be a potential tool for improving a variety of behavioral deficiencies in rodent models of autism.

Chronic Kidney Disease Induces Cognitive Impairment in the Early Stage.

OBJECTIVE: Previous research indicates a link between cognitive impairment and chronic kidney disease (CKD), but the underlying factors are not fully understood. This study aimed to investigate the progression of CKD-induced cognitive impairment and the involvement of cognition-related proteins by developing early- and late-stage CKD models in Sprague-Dawley rats. METHODS: The Morris water maze test and the step-down passive avoidance task were performed to evaluate the cognitive abilities of the rats at 24 weeks after surgery. Histopathologic examinations were conducted to examine renal and hippocampal damage. Real-time PCR, Western blotting analysis, and immunohistochemical staining were carried out to determine the hippocampal expression of brain-derived neurotrophic factor (BDNF), choline acetyltransferase (ChAT), and synaptophysin (SYP). RESULTS: Compared with the control rats, the rats with early-stage CKD exhibited mild renal damage, while those with late-stage CKD showed significantly increased serum creatinine levels as well as apparent renal and brain damage. The rats with early-stage CKD also demonstrated significantly impaired learning abilities and memory compared with the control rats, with further deterioration observed in the rats with late-stage CKD. Additionally, we observed a significant downregulation of cognition-related proteins in the hippocampus of rats with early-stage CKD, which was further exacerbated with declining renal function as well as worsening brain and renal damage in rats with late-stage CKD. CONCLUSION: These results suggest the importance of early screening to identify CKD-induced cognitive dysfunction promptly. In addition, the downregulation of cognition-related proteins may play a role in the progression of cognitive dysfunction.

Effects of hydroalcoholic, methanolic, and hexane extracts of brown algae Sargassum angustifolium on scopolamine-induced memory impairment and learning deficit in rodents.

Background and purpose: Properties of Alzheimer's disease, can be caused by several reasons and there is no definite treatment for it. We aimed to study the effect of the hydroalcoholic extract, methanolic and n-hexane fractions of brown algae Sargassum angustifolium on memory impairment in mice and rats. Experimental approach: Hydroalcoholic extract (25, 50, 100, 200 mg/kg), methanolic (20 and 40 mg/kg) and n-hexane (40 and 60 mg/kg) fractions of S. angustifolium were administered for 21 days intraperitoneally before scopolamine injection (2 mg/kg) on day 21. Rivastigmine was administered for 3 weeks intraperitoneally as well. Then, cognitive function was evaluated by three behavioral tests: passive avoidance, object recognition, and the Morris Water Maze test. Findings/Results: Scopolamine induced memory impairment and rivastigmine significantly reversed the memory dysfunction in all three tests. Hydroalcoholic extract and methanolic fraction significantly reversed scopolamine-induced memory impairment in passive avoidance by 64% and 55% and enhanced the recognition index in the object recognition test. In the Morris water maze test probe trial and training session, on days 3 and 4, the hydroalcoholic extract showed a significant decrease in time spent in the target quadrant and path length, respectively. Also, hydroalcoholic extract and methanolic fraction decreased escape latency time in training sessions on days 3 and 4, by 50% and 31% in comparison to scopolamine. N-hexane fractions had no significant effect on scopolamine-induced cognitive impairment. Conclusion and implications: Although the n-hexane fraction wasn't effective, the administration of hydroalcoholic extract and the methanolic fraction of S. angustifolium enhanced scopolamine-induced memory impairment.

Automating behavioral analysis in neuroscience: Development of an open-source python software for more consistent and reliable results.

BACKGROUND: The application of automated analyses in neuroscience has become a practical approach. With automation, the algorithms and tools employed perform fast and accurate data analysis. It minimizes the inherent errors of manual analysis performed by a human experimenter. It also reduces the time required to analyze a large amount of data and the need for human and financial resources. METHODS: In this work, we describe a protocol for the automated analysis of the Morris Water Maze (MWM) and the Open Field (OF) test using the OpenCV library in Python. This simple protocol tracks mice navigation with high accuracy. RESULTS: In the MWM, both automated and manual analysis revealed similar results regarding the time the mice stayed in the target quadrant (p = 0.109). In the OF test, both automated and manual analysis revealed similar results regarding the time the mice stayed in the center (p = 0.520) and in the border (p = 0.503) of the field. CONCLUSIONS: The automated analysis protocol has several advantages over manual analysis. It saves time, reduces human errors, can be customized, and provides more consistent information about animal behavior during tests. We conclude that the automated protocol described here is reliable and provides consistent behavioral analysis in mice. This automated protocol could lead to deeper insight into behavioral neuroscience.

Design, synthesis and biological evaluation of new multi-target scutellarein hybrids for treatment of Alzheimer's disease.

Scutellarein hybrids were designed, synthesized and evaluated as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). Compounds 11a-i, containing a 2-hydroxymethyl-3,5,6-trimethylpyrazine fragment at the 7-position of scutellarein, were found to have balanced and effective multi-target potencies against AD. Among them, compound 11e exhibited the most potent inhibition of electric eel and human acetylcholinesterase enzymes with IC50 values of 6.72 ± 0.09 and 8.91 ± 0.08 µM, respectively. In addition, compound 11e displayed not only excellent inhibition of self- and Cu2+-induced Aß1-42 aggregation (91.85% and 85.62%, respectively) but also induced disassembly of self- and Cu2+-induced Aß fibrils (84.54% and 83.49% disaggregation, respectively). Moreover, 11e significantly reduced tau protein hyperphosphorylation induced by Aß25-35, and also exhibited good inhibition of platelet aggregation. A neuroprotective assay demonstrated that pre-treatment of PC12 cells with 11e significantly decreased lactate dehydrogenase levels, increased cell viability, enhanced expression of relevant apoptotic proteins (Bcl-2, Bax and caspase-3) and inhibited RSL3-induced PC12 cell ferroptosis. Furthermore, hCMEC/D3 and hPepT1-MDCK cell line permeability assays indicated that 11e would have optimal blood-brain barrier and intestinal absorption characteristics. In addition, in vivo studies revealed that compound 11e significantly attenuated learning and memory impairment in an AD mice model. Toxicity experiments with the compound did not reveal any safety concerns. Notably, 11e significantly reduced ß-amyloid precursor protein (APP) and ß-site APP cleaving enzyme-1 (BACE-1) protein expression in brain tissue of scopolamine-treated mice. Taken together, these outstanding properties qualified compound 11e as a promising multi-target candidate for AD therapy, worthy of further studies.

Effects of S-Adenosylmethionine on Cognition in Animals and Humans: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: There is increasing evidence that supplementation of S-adenosylmethionine (SAM) can improve cognitive function in animals and humans, although the outcomes are not always inconsistent. OBJECTIVE: We conducted a systematic review and meta-analysis to evaluate the correlation between SAM supplementation and improved cognitive function. METHODS: We searched studies in the PubMed, Cochrane Library, Embase, Web of Science, and Clinical Trials databases from January 1, 2002 to January 1, 2022. Risk of bias was assessed using the Cochrane risk of bias 2.0 (human studies) and the Systematic Review Center for Laboratory Animal Experimentation risk of bias (animal studies) tools; and evidence quality was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation. STATA software was employed to perform meta-analysis, and the random-effects models was used to evaluate the standardized mean difference with 95% confidence intervals. RESULTS: Out of the 2,375 studies screened, 30 studies met the inclusion criteria. Meta-analyses of animal (p = 0.213) and human (p = 0.047) studies showed that there were no significant differences between the SAM supplementation and control groups. The results of the subgroup analyses showed that the animals aged ≤8 weeks (p = 0.027) and the intervention duration >8 weeks (p = 0.009) were significantly different compared to the controls. Additionally, the Morris water maze test (p = 0.005) used to assess the cognitive level of the animals revealed that SAM could enhance spatial learning and memory in animals. CONCLUSION: SAM supplementation showed no significant improvement in cognition. Therefore, further studies are needed to assess the effectiveness of SAM supplementation.

Preventive impacts of vitamin C on memory damage caused by unpredictable chronic mild stress in relation to biochemical parameters in the hippocampus of male rats.

The present study focused on examining the impact of vitamin C (Vit C) administration on the function of memory and the status of oxidative stress (OS) in the hippocampal area of the brain using an unpredictable chronic mild stress (UCMS) model in rats. To this end, 50 male Wistar rats (11-12 weeks of age at the start of the study) were assigned to five groups of six animals, including control, UCMS, UCMS + Vit C 50 mg/Kg, UCMS + Vit C 100 mg/Kg, and UCMS + Vit C 400 mg/Kg. The animals received daily intraperitoneal injections of Vit C at a certain time (9 am) before the initiation of a stressor. UCMS, including a progression of typical stressors, was applied for four weeks. Subsequently, using the passive avoidance (PA) and Morris water maze (MWM) tests were performed to investigate learning and memory. Eventually, hippocampal tissues were evaluated in terms of OS criteria. The results revealed that the latency to enter the dark chamber (P < 0. 01 and P < 0.05, PA test) and the time spent in the target quadrant (P < 0.0001, MWM test) were shorter in the UCMS group, while latency to discover the platform was longer (P < 0.05 and P < 0.001, MWM test) compared to the control group. However, UCMS decreased the content of thiol (P < 0.0001), as well as the activities of catalase (P < 0.0001) and superoxide dismutase (P < 0.0001), whereas the concentration of malondialdehyde (P < 0.01) increased in the hippocampal region of the brain in comparison to the control group. Interestingly, Vit C treatment reversed the mentioned effects of UCMS. Therefore, the latency to enter the dark chamber (P < 0. 05 and P < 0.01,1 and 24 h after the shock, PA test, UCMS + Vit C 400) and the time spent in the target quadrant (P < 0. 01 and P < 0.05, MWM test, UCMS + Vit C 400 and UCMS + Vit C 100, respectively) were longer in the UCMS + Vit C groups. Moreover, Vit C increased the content of thiol (P < 0.05, UCMS + Vit C 400), as well as the activity of catalase (P < 0.001, UCMS + Vit C 400) and superoxide dismutase (P < 0.0001, UCMS + Vit C 400, UCMS + Vit C 100), whereas the concentration of malondialdehyde (P < 0. 05 and P < 0.01, UCMS + Vit C 100, UCMS + Vit C 400) decreased in the hippocampal region of the brain in comparison to the UCMS group. Overall, these results suggest that Vit C could reverse UCMS-induced learning and memory impairment possibly through the modulation of brain OS.Key points Memory and learning impairments were induced by unpredictable chronic mild stress (UCMS)Vitamin C could prevent cognitive impairments caused by UCMS in rats by attenuation of oxidative stress in the brain.

The correlation between the severity of hypoxic-ischemic brain damage in neonatal rats and subsequent abnormal neurobehavior / 中国新生儿科杂志

Objective:To assess the severity of hypoxic-ischemic brain damage (HIBD) in neonatal rats and predict the occurrence of subsequent neurobehavioral abnormalities after brain injury by scoring and magnetic resonance imaging (MRI).Methods:7-day-old of 60 Sprague-Dawley (SD) rats were randomly divided into control group (14 rats), sham operation group (14 rats) and HIBD model group (32 rats). HIBD model was established by right common carotid artery dissection with Rice-Vannucci method and hypoxia. Within 24 h after modeling, the rats in the model group were evaluated by general condition score and Longa score, and the surviving rats with moderate and severe HIBD were selected for the experiment. 24 h after modeling, 5 rats of the model group were randomly selected for 2,3,5-triphenyltetrazole chloride staining to verify cerebral infarction. 1 week after modeling, 6 rats from each group were randomly selected for hematoxylin-eosin staining to observe HIBD brain injury. 4 weeks after modeling, 4 rats were randomly selected from the control group and the sham operation group, and 8 rats from the remaining model group were used to evaluate the volume of brain damage by MRI. 5-6 weeks after modeling, the remaining 8 rats from each group were subjected to the Cylinder test, and at 13 weeks, they underwent the Morris water maze test to evaluate their neurobehavior.Results:In HIBD model group, 19 rats with moderate to severe HIBD were selected from 32 rats. 24 h after modeling, cerebral infarction was verified in all rats, indicating moderate to severe HIBD. Brain tissue pathology observed 1 week after modeling revealed predominantly gray matter brain damage. MRI showed that 7 out of 8 rats had moderate to severe HIBD. Compared to the control and sham operation groups, the model group exhibited a significant decrease in the usage rate of the left forelimb in the Cylinder test at 5-6 weeks after modeling ( P<0.05), and the latency period in Morris water maze test was significantly prolonged at 13 weeks after modeling ( P<0.05), and the times of crossing platform quadrant were significantly reduced ( P<0.05). There was no significant difference in the right brain injury volume between 24 h and 4 weeks model group ( P>0.05). The brain injury volume in model group was negatively correlated with the usage rate of left forelimb in cylinder test at 5-6 weeks and the times of crossing platform quadrant in Morris water maze test at 13 weeks ( P<0.05), and positively correlated with latency period in Morris water maze test at 13 weeks ( P<0.05). Conclusions:Within 24 h of HIBD modeling, the severity of brain injury can be preliminarily predicted by general condition score and Longa score. 4 weeks after modeling, in the chronic phase of brain injury, MRI was proved to be an excellent predictor for mid-term and long-term neurobehavioral abnormalities in HIBD rats.

Correlation between in-vivo mercury exposure from Cinnabaris and memory disorders in juvenile rat / 中国药科大学学报

@#Cinnabaris(α-HgS) is a mineral traditional Chinese material medica, as a tranquilizer and sedative, which is widely used in combination with herbs for the treatment of children high fever and convulsion.However, a large amount of mercury in Cinnabaris poses a potential risk to the immature central nervous system of children and probably causes severe memory disorders.Inthisstudy,three groups of juvenile rats were given low, medium, and high doses of Cinnabaris by oral gavage once a day for 14 continuous weeks, respectively.The blood mercury concentrations of the rats at different growth phases were monitored by atomic fluorescence spectrometry.The brain structural and functional changes related to the memory functions were investigated through HE staining and Morris water-maze test. Correlation analysis was conducted to clarify the dose- mercury exposure-toxic effect relationship of Cinnabaris and memory disorders.It was found thatthe blood mercury levels increased in both time- and dose-dependent manner.After the 14-week continuous administration of Cinnabaris, the pathological lesions in hippocampal neurons of rats in the high dose group were observed including pyknosis and disordered cell arrangement.In the Morris water-maze test, compared with the control group, rats in the high dose group exhibited the significantly prolonged latency to find the platform and the target quadrant, and the time spent in the target quadrant was obviously shortened. Thus, the significant correlations were established between Cinnabaris dose and mercury exposure,mercury exposure and memory disorders, respectively. In conclusion, the long-term and overdose administration of Cinnabaris in juvenile rats can increase the in-vivo mercury level, destroy the normal hippocampal morphological structure, and lead to memory disorders. This study provided scientific references for the potential mercury poisoning risks pharmacovigilance of Cinnabaris-containing paediatric formulations.

Comparison of the effect of postweaning social isolation, enriched environment, and exercise training on learning and memory functions in rats.

Background/aim: To assess the effects of postweaning social isolation, an enriched environment, and exercise training on learning and memory functions in rats, as well as their relation with the brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) concentrations in the hippocampus. Materials and methods: Randomly assigned into 4 groups were 35 female postweaning rats (25 day old), as the control (C), social isolation (SI), enriched environment (EE), and exercise training (E) groups. The SI and the EE groups were housed under their specific conditions and the E and the C groups were housed under standard conditions for 6 weeks. The rats in the E group swam for 60 min/day, 5 days a week, for 6 weeks. After 6 weeks, the rats were evaluated in the Morris water maze (MWM). Following MWM assessment, hippocampal tissue and blood samples were taken to measure the BDNF and NGF. Results: According to the results of the MWM probe trial session, the thigmotaxis behavior was higher in the SI group compared to the C group (p < 0,05). Furthermore, the time spent in the target quadrant (quadrant with an escape platform) was lower in the SI group compared to the EE group (p < 0.05). The BDNF and NGF levels in the hippocampus and plasma were not different between the groups (p < 0.05). Conclusion: Postweaning social isolation may increase thigmotaxis behaviors. Postweaning social isolation, enriched environment, and exercise training did not affect the spatial learning, memory function, hippocampal BDNF or NGF levels in female rats.

Chronically administered Agave americana var. marginata extract ameliorates diabetes mellitus, associated behavioral comorbidities and biochemical parameters in alloxan-induced diabetic rats.

Introduction: Diabetes mellitus causes hyperglycemia and associated complications to the brain. In current study, the traditionally reported remedial claims of Agave americana var. marginata has been scientifically investigated in diabetic rats. Methodology: The methanolic extract of leaves of Agave americana var. marginata (Aa.Cr) was characterized for total phenols, flavonoids, and antioxidant potential through in-vitro testing. The rats chronically pre-treated with Aa.Cr (400 and 600 mg/kg) for 45 days were challenged with alloxan-induced hyperglycemia. The dose-dependent effects of Aa.Cr on blood glucose levels and body weights were compared with diabetic rats using glibenclamide (0.6 mg/kg) as a standard. The animals were tested for diabetes-associated neurological comorbidities through behavioral and biochemical evaluation. Results: The phenols and flavonoids enriched Aa.Cr caused a significant dose-dependent hypoglycemic effect. Aa.Cr showed protection from comorbid anxiety, depression and cognitive impairment as compared to diabetic rats. The alanine aminotransferase, total cholesterol, triglycerides and low-density lipoprotein were prominently reduced, and high-density lipoprotein was increased in rats treated with Aa.Cr. Moreover, the oxidative stress in isolated brains was reduced by Aa.Cr. Conclusion: These findings suggest that Aa.Cr is enriched with antioxidant and anti-inflammatory phytoconstituents valuable for diabetes and related neurological complications.

The effects of bilateral prostriata lesions on spatial learning and memory in the rat.

Area prostriata is the primary limbic structure for rapid response to the visual stimuli in the far peripheral visual field. Recent studies have revealed that the prostriata receives inputs not only from the visual and auditory cortices but also from many structures critical for spatial processing and navigation. To gain insight into the functions of the prostriata in spatial learning and memory the present study examines the effects of bilateral lesions of the prostriata on motor ability, exploratory interest and spatial learning and memory using the open field, elevated plus-maze and Morris water maze tests. Our results show that the spatial learning and memory abilities of the rats with bilateral prostriata lesions are significantly reduced compared to the control and sham groups. In addition, the lesion rats are found to be less interested in space exploration and more anxious while the exercise capacity of the rats is not affected based on the first two behavioral tests. These findings suggest that the prostriata plays important roles in spatial learning and memory and may be involved in anxiety as well.

Knockdown of CLC-3 may improve cognitive impairment caused by diabetic encephalopathy.

BACKGROUND: Diabetic encephalopathy(DE) is a neurological complication of diabetes, and its pathogenesis is unclear. Current studies indicate that insulin receptors and downstream signaling pathways play a key role in the occurrence and development of DE. Additionally, CLC-3, a member of the CLC family of anion channels and transporters, is closely related to the secretion and processing of insulin. Here, we investigated the changes and putative roles of CLC-3 in diabetic encephalopathy. RESULTS: To this aim, we combined lentivirus and adeno-associated virus gene transfer to change the expression level of CLC-3 in the HT-22 hippocampal cell line and hippocampal CA1. We studied the role of CLC-3 in DE through the Morris water maze test.CLC-3 expression increased significantly in HT-22 cells cultured with high glucose and STZ-induced DE model hippocampus. Moreover, Insulin receptor(IR) and downstream PI3K/AKT/GSK3ß signaling pathways were also dysfunctional. After knocking down CLC-3, impaired cell proliferation, apoptosis, IR and the downstream PI3K/AKT/GSK3ß signaling pathways were significantly improved. However, when CLC-3 was overexpressed, the neurotoxicity induced by high glucose was further aggravated. Rescue experiments found that through the use of inhibitors such as GSK3ß, the PI3K/AKT/GSK3ß signaling pathways pathway changes with the use of inhibition, and the expression of related downstream signaling molecules such as Tau and p-Tau also changes accordingly. Using adeno-associated virus gene transfer to knock down CLC-3 in the hippocampal CA1 of the DE model, the IR caused by DE and the dysfunction of the downstream PI3K/AKT/GSK3ß signaling pathway were significantly improved. In addition, the impaired spatial recognition of DE was partially restored. CONCLUSION: Our study proposes that CLC-3, as a key molecule, may regulate insulin receptor signaling and downstream PI3K/AKT/GSK3ß signaling pathways and affect the pathogenesis of diabetic encephalopathy.

Improvements of cognitive functions in mice heavily infected by Angiostrongylus cantonensis after treatment with albendazole, dexamethasone, or co-therapy.

Angiostrongylus cantonensis, the causative agent of human eosinophilic meningitis and eosinophilic meningoencepalitis, has been reported to cause cognitive impairments in the host. To determine whether drug treatment improves the cognitive functions, BALB/c mice infected with 50 third-stage larvae were treated with albendazole, dexamethasone, or co-therapy since day 7 or 14 post-infection for one or two weeks. Abilities of spatial memory and learning of these animals were assessed with the Morris water maze. Our results showed that body weight was significant higher then infected group in the albendazole and combined therapy groups. Significantly lower worm recovery rates were found in mice treated with the same groups. The mice treated with dexamethasone since day 7 for 14 day had significant longer time in the remaining groups were found in forced swimming test. The animals treated with albendazole and combined therapy since day 7 for 14 days was demonstrated to have significantly shorter latencies to the platform in learning memory on day 3 and 4. Mice in these two groups were demonstrated to have significantly higher sores in spatial memory tests. These results indicate that treatment with albendazole or combined therapy may be more efficient in preventing brain damages and depression as well as preserving their capabilities in learning and memory. Therefore, administration of albendazole alone or combined with dexamethasone should have higher efficacies than dexamethasone alone in treatment of BALB/c mice infected with a heavy dose of 50 third-stage larvae of A. cantonensis.

Intranasal Cerium Oxide Nanoparticles Ameliorate Cognitive Function in Rats with Alzheimer's via Anti-Oxidative Pathway.

Cerium oxide nanoparticles (CNPs), owing to their antioxidant property, have recently emerged as therapeutic candidate for Alzheimer's disease (AD). However, intravenous CNPs are limited due to their poor physicochemical properties, rapid blood clearance and poor blood-brain penetration. Thus, we developed intranasal CNPs and evaluated its potential in experimental AD. CNPs were synthesized using homogenous precipitation method and optimized through Box-Behnken Design. The formation of CNPs was confirmed by UV spectroscopy and FTIR. The optimized CNP were spherical, small (134.0 ± 3.35 nm), uniform (PDI, 0.158 ± 0.0019) and stable (ZP, -21.8 ± 4.94 mV). The presence of Ce in CNPs was confirmed by energy-dispersive X-ray analysis. Further, the X-ray diffraction spectra revealed that the CNPs were nano-crystalline. The DPPH assay showed that at concentration of 50 µg/mL, the percentage radical scavenging was 95.40 ± 0.006%. Results of the in vivo behavioral studies in the scopolamine-induced Alzheimer rat model showed that intranasal CNPs dose dependently reversed cognitive ability. At dose of 6 mg/kg the morris water maze results (escape latency, path length and dwell time) and passive avoidance results (retention latency) were significantly different from untreated group but not significantly different from positive control group (rivastigmine patch, 13.3 mg/24 h). Further, biochemical estimation showed that intranasal CNP upregulated the levels of SOD and GSH in brain. In conclusion, intranasal CNPs, through its antioxidant effect, could be a prospective therapeutics for the treatment of cognitive impairment in AD.

Improvement of cognitive deficit of curcumin on scopolamine-induced Alzheimer's disease models.

BACKGROUND: It has been suggested that curcumin may be useful in diseases with cognitive dysfunction because it slows the progression and leads to the improvement of cognitive functions. In this study, the protective effects of curcumin on scopolamine-induced rat models of cognitive impairment were evaluated. METHODS: 21 male Wistar Albino rats, 1 year old, 200±25 grams, were included in the study. They were divided into three groups (n: 7 in each group); the untreated control group, scopolamine group, and the group treated with curcumin and then exposed to scopolamine. Animals were evaluated for behavioral tasks with the Morris Water Maze test. Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), total oxidative status (TOS), and total antioxidative status (TAS) were measured in hippocampal tissues. CRP levels were measured in serum specimens. RESULTS: We found that the length to reach the platform was the highest in the scopolamine group, and the lowest in the curcumin group (p<0.001). Time to reach the platform was the longest in the scopolamine group, and the shortest in the curcumin group (P=0.002). The length to reach the platform was the highest in the scopolamine group, and the lowest in the control group in the probe test (p<0.001). IL-6 levels were higher in the scopolamine group than the curcumin group (P=0.017) and the control group (P=0.005). CONCLUSION: We revealed that curcumin provides a protective effect on scopolamine-induced cognitive impairment mimicking Alzheimer's disease. The use of curcumin for the protection of cognition in individuals at risk of developing AD may be considered.

Nano-Honokiol ameliorates the cognitive deficits in TgCRND8 mice of Alzheimer's disease via inhibiting neuropathology and modulating gut microbiota.

Introduction: Honokiol (HO) exerts neuroprotective effects in several animal models of Alzheimer's disease (AD), but the poor dissolution hampers its bioavailability and therapeutic efficacy. Objectives: A novel honokiol nanoscale drug delivery system (Nano-HO) with smaller size and excellent stability was developed in this study to improve the solubility and bioavailability of HO. The anti-AD effects of Nano-HO was determined. Methods: Male TgCRND8 mice were daily orally administered Nano-HO or HO at the same dosage (20 mg/kg) for 17 consecutive weeks, followed by assessment of the spatial learning and memory functions using the Morris Water Maze test (MWMT). Results: Our pharmacokinetic study indicated that the oral bioavailability was greatly improved by Nano-HO. In addition, Nano-HO significantly improved cognitive deficits and inhibited neuroinflammation via suppressing the levels of TNF-α, IL-6 and IL-1ß in the brain, preventing the activation of microglia (IBA-1) and astrocyte (GFAP), and reducing ß-amyloid (Aß) deposition in the cortex and hippocampus of TgCRND8 mice. Moreover, Nano-HO was more effective than HO in modulating amyloid precursor protein (APP) processing via suppressing ß-secretase, as well as enhancing Aß-degrading enzymes like neprilysin (NEP). Furthermore, Nano-HO more markedly inhibited tau hyperphosphorylation via decreasing the ratio of p-Tau (Thr 205)/tau and regulating tau-related apoptosis proteins (caspase-3 and Bcl-2). In addition, Nano-HO more markedly attenuated the ratios of p-JNK/JNK and p-35/CDK5, while enhancing the ratio of p-GSK-3ß (Ser9)/GSK-3ß. Finally, Nano-HO prevented the gut microflora dysbiosis in TgCRND8 mice in a more potent manner than free HO. Conclusion: Nano-HO was more potent than free HO in improving cognitive impairments in TgCRND8 mice via inhibiting Aß deposition, tau hyperphosphorylation and neuroinflammation through suppressing the activation of JNK/CDK5/GSK-3ß signaling pathway. Nano-HO also more potently modulated the gut microbiota community to protect its stability than free HO. These results suggest that Nano-HO has good potential for further development into therapeutic agent for AD treatment.