Oral administration of encapsulated catechin in chitosan-alginate nanoparticles improves cognitive function and neurodegeneration in an aluminum chloride-induced rat model of Alzheimer's disease.

The present study aimed to investigate the effect of catechin-loaded Chitosan-Alginate nanoparticles (NPs) on cognitive function in an aluminum chloride (AlCl3)-induced rat model of Alzheimer's disease (AD). The Catechin-loaded Chitosan-Alginate nanocarriers were synthesized through ionotropic gelation (IG) method. Physio-chemical characterization was conducted with the Zetasizer Nano system, the scanning electron microscope, and the Fourier transform infrared spectroscopy. The experiments were performed over 21 days on six groups of male Wistar rats. The control group, AlCl3 treated group, Catechin group, nanocarrier group, treatment group 1 (AlCl3 + Catechin), and treatment group 2 (AlCl3 + nanocarrier). A behavioral study was done by the Morris water maze (MWM) test. In addition, the level of oxidative indices and acetylcholine esterase (AChE) activity was determined by standard procedures at the end of the study. AlCl3 induced a significant increase in AChE activity, along with a significant decrease in the level of Catalase (CAT) and total antioxidant capacity (TAC) in the hippocampus. Moreover, the significant effect of AlCl3 was observed on the behavioral parameters of the MWM test. Both forms of Catechin markedly improved AChE activity, oxidative biomarkers, spatial memory, and learning. The present study indicated that the administration of Catechin-loaded Chitosan-Alginate NPs is a beneficial therapeutic option against behavioral and chemical alteration of AD in male Wistar rats.

[Resveratrol attenuates neuroinflammation and alleviates emotional dysfunction in mice with sepsis-associated encephalopathy through promoting chaperone-mediated autophagy (CMA)].

Objective To elucidate the role of chaperone-mediated autophagy (CMA) in alleviating emotional dysfunction in mice with sepsis-associated encephalopathy (SAE). Methods The SAE mouse model was established by cecal ligation and perforation (CLP). The severity of sepsis was assessed using the sepsis severity score (MSS). Emotional function in SAE mice was assessed by the open-field test and elevated plus-maze. The expression levels of cognitive heat shock cognate protein 70 (HSC70), lysosomal-associated membrane protein 2A (LAMP2A) and high mobility group box 1 protein B1 (HMGB1) were detected using Western blotting. Co-localization of LAMP2A in the hippocampal neurons was observed by immunofluorescence. The release of inflammatory factors interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) was measured using ELISA. Following 12 hours post-CLP, mice were orally administered resveratrol at a dose of 30 mg/kg once daily until day 14. Results The mortality rate of CLP mice was 45.83% 24 days post CLP, and all surviving mice exhibited emotional disturbances. 24 hours after CLP, a significant decrease in HSC70 and LAMP2A expression in hippocampal neurons was observed, indicating impaired CMA activity. Meanwhile, HMGB1 and inflammatory cytokines (IL-6 and TNF-α) levels increased. After resveratrol treatment, an increase of HSC70 and LAMP2A expression, and a decrease of HMGB1 expression and inflammatory cytokine release were observed, suggesting enhanced CMA activity and reduced neuroinflammation. Behavioral tests showed that emotional dysfunction was improved in SAE mice after resveratrol treatment. Conclusion CMA activity of hippocampal neurons in SAE mice is significantly reduced, leading to emotional dysfunction. Resveratrol can alleviate neuroinflammation and emotional dysfunction in SAE mice by promoting CMA and inhibiting the expression of HMGB1 and the release of inflammatory factors.

SEP-363856 exerts neuroprotection through the PI3K/AKT/GSK-3ß signaling pathway in a dual-hit neurodevelopmental model of schizophrenia-like mice.

Schizophrenia (SZ) is a serious, destructive neurodevelopmental disorder. Antipsychotic medications are the primary therapy approach for this illness, but it's important to pay attention to the adverse effects as well. Clinical studies for SZ are currently in phase ΙΙΙ for SEP-363856 (SEP-856)-a new antipsychotic that doesn't work on dopamine D2 receptors. However, the underlying action mechanism of SEP-856 remains unknown. This study aimed to evaluate the impact and underlying mechanisms of SEP-856 on SZ-like behavior in a perinatal MK-801 treatment combined with social isolation from the weaning to adulthood model (MK-SI). First, we created an animal model that resembles SZ that combines the perinatal MK-801 with social isolation from weaning to adulthood. Then, different classical behavioral tests were used to evaluate the antipsychotic properties of SEP-856. The levels of proinflammatory cytokines (tumor necrosis factor-α, interleukin-6, and interleukin-1ß), apoptosis-related genes (Bax and Bcl-2), and synaptic plasticity-related genes (brain-derived neurotrophic factor [BDNF] and PSD-95) in the hippocampus were analyzed by quantitative real-time PCR. Hematoxylin and eosin staining were used to observe the morphology of neurons in the hippocampal DG subregions. Western blot was performed to detect the protein expression levels of BDNF, PSD-95, Bax, Bcl-2, PI3K, p-PI3K, AKT, p-AKT, GSK-3ß, p-GSK-3ß in the hippocampus. MK-SI neurodevelopmental disease model studies have shown that compared with sham group, MK-SI group exhibit higher levels of autonomic activity, stereotyped behaviors, withdrawal from social interactions, dysregulated sensorimotor gating, and impaired recognition and spatial memory. These findings imply that the MK-SI model can mimic symptoms similar to those of SZ. Compared with the MK-SI model, high doses of SEP-856 all significantly reduced increased activity, improved social interaction, reduced stereotyping behavior, reversed sensorimotor gating dysregulation, and improved recognition memory and spatial memory impairment in MK-SI mice. In addition, SEP-856 can reduce the release of proinflammatory factors in the MK-SI model, promote the expression of BDNF and PSD-95 in the hippocampus, correct the Bax/Bcl-2 imbalance, turn on the PI3K/AKT/GSK-3ß signaling pathway, and ultimately help the MK-SI mice's behavioral abnormalities. SEP-856 may play an antipsychotic role in MK-SI "dual-hit" model-induced SZ-like behavior mice by promoting synaptic plasticity recovery, decreasing death of hippocampal neurons, lowering the production of pro-inflammatory substances in the hippocampal region, and subsequently initiating the PI3K/AKT/GSK-3ß signaling cascade.

Curcumin as a Potential Therapeutic Agent for Mitigating Carbon Monoxide Poisoning: Evidence from an Experimental Rat Study.

BACKGROUND Carbon monoxide (CO) is a poisonous gas and causes tissue damage through oxidative stress. We aimed to investigate the protective value of curcumin in CO poisoning. MATERIAL AND METHODS Twenty-four female Spraque Dawley rats were divided into 4 subgroups: controls (n=6), curcumin group (n=6), CO group (n=6), and curcumin+CO group (n=6). The experimental group was exposed to 3 L/min of CO gas at 3000 ppm. Curcumin was administered intraperitoneally at a dosage of 50 mg/kg. Hippocampal tissues were removed and separated for biochemical and immunohistochemical analysis. Tissue malondialdehyde (MDA) levels, nitric oxide (NO) levels, and superoxide dismutase (SOD) and catalase (CAT) activities were assayed spectrophotometrically, and serum asymmetric dimethylarginine (ADMA) were measured using the ELISA technique. Tissue Bcl-2 levels were detected by the immunohistochemistry method. RESULTS Tissue CAT and SOD activities and NO levels were significantly lower, and MDA and serum ADMA levels were higher in the CO group than in the control group (P<0.001). The curcumin+CO group had higher CAT activities (P=0.007) and lower MDA than the CO group (P<0.001) and higher ADMA levels than the control group (P=0.023). However, there was no significant difference observed for tissue SOD activity or NO levels between these 2 groups. In the curcumin+CO group, the Bcl-2 level was higher than that in the CO group (P=0.017). CONCLUSIONS The positive effect of curcumin on CAT activities, together with suppression of MDA levels, has shown that curcumin may have a protective effect against CO poisoning.

Fullerenols Ameliorate Social Deficiency and Rescue Cognitive Dysfunction of BTBR T+Itpr3tf/J Autistic-Like Mice.

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects social interaction and communication and can cause stereotypic behavior. Fullerenols, a type of carbon nanomaterial known for its neuroprotective properties, have not yet been studied for their potential in treating ASD. We aimed to investigate its role in improving autistic behaviors in BTBR T+Itpr3tf/J (BTBR) mice and its underlying mechanism, which could provide reliable clues for future ASD treatments. Methods: Our research involved treating C57BL/6J (C57) and BTBR mice with either 0.9% NaCl or fullerenols (10 mg/kg) daily for one week at seven weeks of age. We then conducted ASD-related behavioral tests in the eighth week and used RNA-seq to screen for vital pathways in the mouse hippocampus. Additionally, we used real-time quantitative PCR (RT-qPCR) to verify related pathway genes and evaluated the number of stem cells in the hippocampal dentate gyrus (DG) by Immunofluorescence staining. Results: Our findings revealed that fullerenols treatment significantly improved the related ASD-like behaviors of BTBR mice, manifested by enhanced social ability and improved cognitive deficits. Immunofluorescence results showed that fullerenols treatment increased the number of DCX+ and SOX2+/GFAP+ cells in the DG region of BTBR mice, indicating an expanded neural progenitor cell (NPC) pool of BTBR mice. RNA-seq analysis of the mouse hippocampus showed that VEGFA was involved in the rescued hippocampal neurogenesis by fullerenols treatment. Conclusion: In conclusion, our findings suggest that fullerenols treatment improves ASD-like behavior in BTBR mice by upregulating VEGFA, making nanoparticle- fullerenols a promising drug for ASD treatment.

Protective effect of melatonin against metabolic disorders and neuropsychiatric injuries in type 2 diabetes mellitus mice.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by hyperglycemia and progressive cognitive dysfunction, and our clinical investigation revealed that the plasma concentration of melatonin (Mlt) decreased and was closely related to cognition in T2DM patients. However, although many studies have suggested that Mlt has a certain protective effect on glucose and lipid metabolism disorders and neuropsychiatric injury, the underlying mechanism of Mlt against T2DM-related metabolic and cognitive impairments remains unclear. PURPOSE: The aim of the present study was to investigate the therapeutic effect of Mlt on metabolic disorders and Alzheimer's disease (AD)-like neuropsychiatric injuries in T2DM mice and to explore the possible underlying molecular mechanism involved. METHODS: A T2DM mouse model was established by a combination of a high-fat diet (HFD) and streptozotocin (STZ, 100 mg/kg, i.p.), and Mlt (5, 10 or 20 mg/kg) was intragastrically administered for six consecutive weeks. The serum levels of glycolipid metabolism indicators were measured, behavioral performance was tested, and the protein expression of key molecules involved in the regulation of synaptic plasticity, circadian rhythms, and neuroinflammation in the hippocampus was detected. Moreover, the fluorescence intensities of glial fibrillary acidic protein (GFAP), ionized calcium binding adapter molecule 1 (IBA-1), amyloid ß-protein (Aß) and phosphorylated Tau (p-Tau) in the hippocampus were also observed. RESULTS: Treatment with Mlt not only improved T2DM-related metabolic disorders, as indicated by increased serum concentrations of fasting blood glucose (FBG), glycosylated hemoglobin (HbAlc), insulin (INS), total cholesterol (TC) and triglyceride (TG), improved glucose tolerance and liver and pancreas function but also alleviated AD-like neuropsychiatric injuries in a HFD/STZ-induced mouse model, as indicated by decreased immobility time in the tail suspension test (TST) and forced swimming test (FST), increased preference indices of novel objects or novel arms in the novel object recognition test (NOR) and Y-maze test (Y-maze), and improved platform positioning capability in the Morris water maze (MWM) test. Moreover, treatment with Mlt also improved the hyperactivation of astrocytes and microglia in the hippocampus of mice, accompanied by reduced expression of interleukin 1ß (IL-1ß), interleukin 6 (IL-6), tumor necrosis factor (TNF-α), Aß, and p-Tau and increased expression of brain-derived neurotrophic factor (BDNF), Synapsin I, Synaptotagmin I, melatonin receptor 1B (MT1B), brain muscle arnt-like protein 1 (Bmal1), circadian locomotor output cycles kaput (Clock), period 2 (Per2), and cryptochrome 2 (Cry2). CONCLUSION: Mlt alleviated T2DM-related metabolic disorders and AD-like neuropsychiatric injuries in a HFD/STZ-induced mouse model, possibly through a mechanism involving the regulation of glial activation and associated neuroinflammation and the balancing of synaptic plasticity and circadian rhythms in the hippocampus.

Reduction in Hippocampal Amyloid-ß Peptide (Aß) Content during Glycine-Proline-Glutamate (Gly-Pro-Glu) Co-Administration Is Associated with Changes in Inflammation and Insulin-like Growth Factor (IGF)-I Signaling.

Alzheimer's disease (AD) is characterized by the deposition in the brain of senile plaques composed of amyloid-ß peptides (Aßs) that increase inflammation. An endogenous peptide derived from the insulin-like growth factor (IGF)-I, glycine-proline-glutamate (GPE), has IGF-I-sensitizing and neuroprotective actions. Here, we examined the effects of GPE on Aß levels and hippocampal inflammation generated by the intracerebroventricular infusion of Aß25-35 for 2 weeks (300 pmol/day) in ovariectomized rats and the signaling-related pathways and levels of Aß-degrading enzymes associated with these GPE-related effects. GPE prevented the Aß-induced increase in the phosphorylation of p38 mitogen-activated protein kinase and the reduction in activation of signal transducer and activator of transcription 3, insulin receptor substrate-1, and Akt, as well as on interleukin (IL)-2 and IL-13 levels in the hippocampus. The functionality of somatostatin, measured as the percentage of inhibition of adenylate cyclase activity and the levels of insulin-degrading enzyme, was also preserved by GPE co-treatment. These findings indicate that GPE co-administration may protect from Aß insult by changing hippocampal cytokine content and somatostatin functionality through regulation of leptin- and IGF-I-signaling pathways that could influence the reduction in Aß levels through modulation of levels and/or activity of Aß proteases.

Antiepileptic and Neuroprotective Effects of Rheum tanguticum Root Extract on Trimethyltin-Induced Epilepsy and Neurodegeneration: In Vivo and in Silico Analyses.

BACKGROUND: Rheum tanguticum root, cataloged as "Daehwang" in the Korean Pharmacopeia, is rich in various anthraquinones known for their anti-inflammatory and antioxidant properties. Formulations containing Daehwang are traditionally employed for treating neurological conditions. This study aimed to substantiate the antiepileptic and neuroprotective efficacy of R. tanguticum root extract (RTE) against trimethyltin (TMT)-induced epileptic seizures and hippocampal neurodegeneration. METHODS: The constituents of RTE were identified by ultra-performance liquid chromatography (UPLC). Experimental animals were grouped into the following five categories: control, TMT, and three TMT+RTE groups with dosages of 10, 30, and 100 mg/kg. Seizure severity was assessed daily for comparison between the groups. Brain tissue samples were examined to determine the extent of neurodegeneration and neuroinflammation using histological and molecular biology techniques. Network pharmacology analysis involved extracting herbal targets for Daehwang and disease targets for epilepsy from multiple databases. A protein-protein interaction network was built using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and pivotal targets were determined by topological analysis. Enrichment analysis was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) tool to elucidate the underlying mechanisms. RESULTS: The RTE formulation was found to contain sennoside A, sennoside B, chrysophanol, emodin, physcion, (+)-catechin, and quercetin-3-O-glucuronoid. RTE effectively inhibited TMT-induced seizures at 10, 30, and 100 mg/kg dosages and attenuated hippocampal neuronal decay and neuroinflammation at 30 and 100 mg/kg dosages. Furthermore, RTE significantly reduced mRNA levels of tumor necrosis factor (TNF-α), glial fibrillary acidic protein (GFAP), and c-fos in hippocampal tissues. Network analysis revealed TNF, Interleukin-1 beta (IL-1ß), Interleukin-6 (IL-6), Protein c-fos (FOS), RAC-alpha serine/threonine-protein kinase (AKT1), and Mammalian target of rapamycin (mTOR) as the core targets. Enrichment analysis demonstrated significant involvement of R. tanguticum components in neurodegeneration (p = 4.35 × 10-5) and TNF signaling pathway (p = 9.94 × 10-5). CONCLUSIONS: The in vivo and in silico analyses performed in this study suggests that RTE can potentially modulate TMT-induced epileptic seizures and neurodegeneration. Therefore, R. tanguticum root is a promising herbal treatment option for antiepileptic and neuroprotective applications.

Red Pine Bark Extract Alleviates Akt/GSK-3ß Signaling Disruption in the Hippocampus of Streptozotocin-Induced Diabetic Sprague-Dawley Rats.

This study investigates whether red pine (Pinus densiflora Sieb. et Zucc.) bark extract (PBE) can alleviate diabetes and abnormal apoptosis signaling pathways in the hippocampus of streptozotocin (STZ)-induced diabetic Sprague-Dawley (SD) rats. Two dosages of PBE (15 and 30 mg/kg of body weight/day) were administered orally to STZ-induced diabetic SD rats for 20 days. Blood glucose level and body weight were measured once per week. After 20 days of oral administration of PBE, the rat hippocampus was collected, and the production of Akt, p-Akt, GSK-3ß, p-GSK-3ß, tau, p-tau, Bax, and Bcl-2 proteins were determined by western blot analysis. A decrease in blood glucose level and recovery of body weight were observed in PBE-treated diabetic rats. In the Akt/GSK-3ß/tau signaling pathway, PBE inhibited diabetes-induced Akt inactivation, GSK-3ß inactivation, and tau hyperphosphorylation. The protein production ratio of Bax/Bcl-2 was restored to the control group level. These results suggest that PBE, rich in phenolic compounds, can be used as a functional food ingredient to ameliorate neuronal apoptosis in diabetes mellitus.

Ameliorated Effects of Fucoidan on Dextran Sulfate Sodium-Induced Ulcerative Colitis and Accompanying Anxiety and Depressive Behaviors in Aged C57BL/6 Mice.

Fucoidan has shown better effects on the improvement of acute ulcerative colitis (UC). However, the specific mechanisms by which fucoidan improves UC-related behavioral disorders in aged mice, especially its effect on the gut-brain axis, remain to be further explored. C57BL/6 male mice aged 8 months were gavaged with 400 or 100 mg/kg bw day fucoidan for five consecutive weeks, with UC being induced by ad libitum to dextran sulfate sodium (DSS) solution in the fifth week. The results showed that fucoidan ameliorated UC and accompanying anxiety- and depressive-like behaviors with downregulated expressions of (NOD)-like receptor family and pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), cysteine aspartate-specific protease-1 (Caspase-1) and interlekin-1ß (IL-1ß), and elevated mRNA levels of brain-derived neurotrophic factor (Bdnf) and postsynaptic-density protein 95 (Psd-95) in cortex and hippocampus. Furthermore, fucoidan improved the permeability of intestinal barrier and blood-brain barrier and restored the abnormal structure of the gut microbiota with a significantly decreased ratio of Firmicutes to Bacteroidota (F/B) and obviously increased abundance of Akkermansia. As a diet-derived bioactive ingredient, fucoidan might be a better alternative for the prevention of UC and accompanying anxiety- and depressive-like behaviors.

Subsequent maternal sleep deprivation aggravates cognitive impairment by modulating hippocampal neuroinflammatory responses and synaptic function in maternal isoflurane-exposed offspring mice.

INTRODUCTION: Pregnant women may need to undergo non-obstetric surgery under general anesthesia owing to medical needs, and pregnant women frequently experience sleep disturbances during late gestation. Preclinical studies demonstrated that maternal isoflurane exposure (MISO) or maternal sleep deprivation (MSD) contributed to cognitive impairments in offspring. Research studies in mice have revealed that SD can aggravate isoflurane-induced cognitive deficits. However, it remains unclear whether MSD aggravates MISO-induced cognitive deficits in offspring. The purpose of this research was to explore the combined effects of MSD and MISO on offspring cognitive function and the role of neuroinflammation and synaptic function in the process of MSD + MISO. METHODS: Pregnant mice were exposed to 1.4% isoflurane by inhalation for 4 h on gestational day (GD) 14. Dams were then subjected to SD for 6 h (12:00-18:00 h) during GD15-21. At 3 months of age, the offspring mice were subjected to the Morris water maze test to assess cognitive function. Then the levels of inflammatory and anti-inflammatory markers and synaptic function-related proteins were assessed using molecular biology methods. RESULTS: The results of this study demonstrated that MISO led to cognitive dysfunction, an effect that was aggravated by MSD. In addition, MSD exacerbated the maternal isoflurane inhalation, leading to an enhancement in the expression levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha and a reduction in the hippocampal levels of IL-10, synaptophysin, post-synaptic density-95, growth-associated protein-43, and brain-derived neurotrophic factor. CONCLUSION: Our findings revealed that MSD aggravated the cognitive deficits induced by MISO in male offspring mice, and these results were associated with neuroinflammation and alternations in synaptic function.

Auraptene-ameliorating depressive-like behaviors induced by lipopolysaccharide combined with chronic unpredictable mild stress in mice mitigate hippocampal neuroinflammation mediated by microglia.

An inflammatory response is one of the pathogeneses of depression. The anti-inflammatory and neuroprotective effects of auraptene have previously been confirmed. We established an inflammatory depression model by lipopolysaccharide (LPS) injection combined with unpredictable chronic mild stress (uCMS), aiming to explore the effects of auraptene on depressive-like behaviors in adult mice. Mice were divided into a control group, vehicle group, fluoxetine group, celecoxib group, and auraptene group. Then, behavioral tests were conducted to evaluate the effectiveness of auraptene in ameliorating depressive-like behavior. Cyclooxygenase-2 (COX-2), C-reactive protein (CRP), tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) were examined by ELISA. Interleukin-10 (IL-10), interleukin-4 (IL-4), and transforming growth factor-ß (TGF-ß) were examined by protein chip technology. The morphology of microglia was observed by the immunohistochemical method. The data showed that, compared with the control group, the vehicle group mice exhibited a depressive-like behavioral phenotype, accompanied by an imbalance in inflammatory cytokines and the activation of microglia in the hippocampus. The depressive behaviors of the auraptene group's mice were significantly alleviated, along with the decrease in pro-inflammatory factors and increase in anti-inflammatory factors, while the activation of microglia was inhibited in the hippocampus. Subsequently, we investigated the role of auraptene in vitro-cultured BV-2 cells treated with LPS. The analysis showed that auraptene downregulated the expression of IL-6, TNF-α, and NO, and diminished the ratio of CD86/CD206. The results showed that auraptene reduced the excessive phagocytosis and ROS production of LPS-induced BV2 cells. In conclusion, auraptene relieved depressive-like behaviors in mice probably via modulating hippocampal neuroinflammation mediated by microglia.

Rapidly reversible persistent long-term potentiation inhibition by patient-derived brain tau and amyloid ß proteins.

How the two pathognomonic proteins of Alzheimer's disease (AD); amyloid ß (Aß) and tau, cause synaptic failure remains enigmatic. Certain synthetic and recombinant forms of these proteins are known to act concurrently to acutely inhibit long-term potentiation (LTP). Here, we examined the effect of early amyloidosis on the acute disruptive action of synaptotoxic tau prepared from recombinant protein and tau in patient-derived aqueous brain extracts. We also explored the persistence of the inhibition of LTP by different synaptotoxic tau preparations. A single intracerebral injection of aggregates of recombinant human tau that had been prepared by either sonication of fibrils (SτAs) or disulfide bond formation (oTau) rapidly and persistently inhibited LTP in rat hippocampus. The threshold for the acute inhibitory effect of oTau was lowered in amyloid precursor protein (APP)-transgenic rats. A single injection of synaptotoxic tau-containing AD or Pick's disease brain extracts also inhibited LTP, for over two weeks. Remarkably, the persistent disruption of synaptic plasticity by patient-derived brain tau was rapidly reversed by a single intracerebral injection of different anti-tau monoclonal antibodies, including one directed to a specific human tau amino acid sequence. We conclude that patient-derived LTP-disrupting tau species persist in the brain for weeks, maintaining their neuroactivity often in concert with Aß. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Taurine Improved Autism-Like Behaviours and Defective Neurogenesis of the Hippocampus in BTBR Mice through the PTEN/mTOR/AKT Signalling Pathway.

Effective treatment of patients with autism spectrum disorder (ASD) is still absent so far. Taurine exhibits therapeutic effects towards the autism-like behaviour in ASD model animals. Here, we determined the mechanism of taurine effect on hippocampal neurogenesis in genetically inbred BTBR T+ tf/J (BTBR) mice, a proposed model of ASD. In this ASD mouse model, we explored the effect of oral taurine supplementation on ASD-like behaviours in an open field test, elevated plus maze, marble burying test, self-grooming test, and three-chamber test. The mice were divided into four groups of normal controls (WT) and models (BTBR), who did or did not receive 6-week taurine supplementation in water (WT, WT+ Taurine, BTBR, and BTBR+Taurine). Neurogenesis-related effects were determined by Ki67 immunofluorescence staining. Western blot analysis was performed to detect the expression of phosphatase and tensin homologue deleted from chromosome 10 (PTEN)/mTOR/AKT pathway-associated proteins. Our results showed that taurine improved the autism-like behaviour, increased the proliferation of hippocampal cells, promoted PTEN expression, and reduced phosphorylation of mTOR and AKT in hippocampal tissue of the BTBR mice. In conclusion, taurine reduced the autism-like behaviour in partially inherited autism model mice, which may be associa-ted with improving the defective neural precursor cell proliferation and enhancing the PTEN-associated pathway in hippocampal tissue.

A comprehensive study on the regulation of Compound Zaoren Granules on cAMP/CREB signaling pathway and metabolic disorder in CUMS-PCPA induced insomnia rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Zaoren Granules (CZG), an optimized herbal formulation based on the traditional Chinese medicine prescription Suanzaoren decoction, are designed specifically for insomnia treatment. However, the mechanisms underlying its efficacy in treating insomnia are not yet fully understood. AIM OF THE STUDY: The research investigated the mechanisms of CZG's improvement in insomnia by regulating cAMP/CREB signaling pathway and metabolic profiles. METHODS: The main components of CZG were characterized by liquid chromatography-mass spectrometry (LC-MS). Subsequently, these validated components were applied to network pharmacological analysis to predict signaling pathways associated with insomnia. We evaluated the effect of CZG on BV-2 cells in vitro. We also evaluated the behavioral indexes of CUMS combined with PCPA induced insomnia in rats. HE staining and Nissl staining were used to observe the pathological damage of hippocampus. ELISA was used to detect the levels of various neurotransmitters, orexins, HPA axis, and inflammatory factors in insomnia rats. Then we detected the expression of cAMP/CREB signaling pathway through ELISA, WB, and IHC. Finally, the metabolomics was further analyzed by using UHPLC-QTOF-MS/MS to investigate the changes in the hippocampus of insomnia rats and the possible metabolic pathways were also speculated. RESULTS: The results of CZG in vitro experiments showed that CZG has protective and anti-inflammatory effects on LPS induced BV-2 cells. A total of 161 chemical components were identified in CZG. After conducting network pharmacology analysis through these confirmed components, we select the cAMP/CREB signaling pathway for further investigate. The behavioral research results on insomnia rats showed that CZG significantly prolonged sleep time, mitigated brain tissue pathological damage, and exhibited liver protective properties. CZG treats insomnia by regulating the content of various neurotransmitters, reducing levels of orexin, HPA axis, and inflammatory factors. It can also treat insomnia by upregulating the expression of the cAMP/CREB signaling pathway. Hippocampus metabolomics analysis identified 69 differential metabolites associated with insomnia. The metabolic pathways related to these differential metabolites have also been predicted. CONCLUSION: These results indicate that CZG can significantly prolong sleep time. CZG is used to treat insomnia by regulating various neurotransmitters, HPA axis, inflammatory factors, cAMP/CREB signaling pathways, and metabolic disorders.

5,7-dihydroxy-3',4',5'-trimethoxyflavone mitigates lead induced neurotoxicity in rats via its chelating, antioxidant, anti-inflammatory and monoaminergic properties.

Chronic exposure to lead (Pb) induces neurodegenerative changes in animals and humans. Drugs with strong antioxidant properties are effective against Pb-mediated neurotoxicity. In a prior study, we identified 5,7-dihydroxy-3',4',5'-trimethoxyflavone (TMF) from Ocimum basilicum L. leaves as a potent antioxidant and neuroprotective compound. This research explores TMF's neuroprotective effects against Pb-induced brain toxicity in rats to establish it as a therapeutic agent. Rats received lead acetate (100 mg/kg, orally, once daily) for 30 days to induce brain injury, followed by TMF treatment (5 and 10 mg/kg, oral, once daily) 30 min later. Cognitive and motor functions were assessed using Morris Water Maze and horizontal bar tests. Lead, monoamine oxidase (MAO) A and B enzymes, reduced glutathione (GSH), thiobarbituric acid reactive species (TBARS), Tumor necrosis factor-alpha (TNF-α), and IL-6 levels were measured in the hippocampus and cerebellum. Pb exposure impaired cognitive and motor functions, increased Pb, TBARS, TNF-α, and IL-6 levels, and compromised MAO A & B and GSH levels. TMF reversed Pb-induced memory and motor deficits and normalized biochemical anomalies. TMF's neuroprotective effects against lead involve chelating, antioxidant, anti-inflammatory, and monoaminergic properties, suggesting its potential as a treatment for metal-induced brain injury.

The impact of Nrf2 knockout on the neuroprotective effects of dexmedetomidine in a mice model of cognitive impairment.

The nuclear factor erythroid 2-related factor 2 (Nrf2) signalling pathway represents a crucial intrinsic protective system against oxidative stress and inflammation and plays a significant role in various neurological disorders. However, the effect of Nrf2 signalling on the regulation of cognitive impairment remains unknown. Dexmedetomidine (DEX) has neuroprotective effects and can ameliorate lipopolysaccharide (LPS)-induced cognitive dysfunction. Our objective was to observe whether Nrf2 knockout influences the efficacy of DEX in improving cognitive impairment and to attempt to understand its underlying mechanisms. An LPS-induced cognitive dysfunction model in wild-type and Nrf2 knockout mice (Institute of Cancer Research background; male; 8-12 weeks) was used to observe the impact of DEX on cognitive dysfunction. LPS was intraperitoneally injected, followed by novel object recognition and morris water maze experiments 24 h later. Hippocampal tissues were collected for histopathological and molecular analyses. Our research findings suggest that DEX enhances the expression of NQO1, HO-1, PSD95, and SYP proteins in hippocampal tissue, inhibits microglial proliferation, reduces pro-inflammatory cytokines IL-1ß and TNF-ɑ, increases anti-inflammatory cytokine IL-10, and improves dendritic spine density, thereby alleviating cognitive dysfunction induced by LPS. However, the knockout of the Nrf2 gene negated the aforementioned effects of DEX. In conclusion, DEX alleviates cognitive deficits induced by LPS through mechanisms of anti-oxidative stress and anti-inflammation, as well as by increasing synaptic protein expression and dendritic spine density. However, the knockout of the Nrf2 gene reversed the effects of DEX. The Nrf2 signaling pathway plays a crucial role in the mitigation of LPS-induced cognitive impairment by DEX.

Antidepressant effect and mechanism of TMP269 on stress-induced depressive-like behavior in mice.

TMP269, a class IIA histone deacetylase inhibitor with selectivity, that has a protective effect on the central nervous system, yet its specific mechanism of action remains ambiguous. Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that histone deacetylase 5 plays a key role in the pathological process of depression and the fact that preclinical studies have shown HDAC5 to be a potential antidepressant target, the search for natural drugs or small molecule compounds that can target HDAC5 may be a potential therapeutic strategy for the treatment of depression. In addition, we examined the role of the Brain-derived neurotrophic factor (BDNF), an important neurotrophic factor for neuronal survival and growth, as a potential downstream target of HDAC5. We found downward revision of HDAC5 levels in the hippocampus ameliorated depressive-like behavior in LH (Learned helplessness) mice. Furthermore, injection of HDAC5 overexpressing adenoviral vectors in the hippocampal dentate gyrus of wild-type mice produced a somewhat depressive-like phenotype. Pharmacological, immunofluorescence and biochemical experiments showed that TMP269 could produce antidepressant effects by inhibiting mouse hippocampal HDAC5 and thus modulating its downstream BDNF. Over all, TMP269 mitigated LH-induced depressive-like behaviors and abnormalities in synapse formation and neurogenesis within the hippocampus. These findings suggest potential beneficial effects of TMP269 on depression.

Neurogenesis and pesticides: news of no new neurons.

New hippocampal neurons are continuously generated in the adult human brain. Several studies have demonstrated that the proliferation of hippocampal cells is strongly influenced by a variety of stimuli, including pesticides exposure. These effects are particularly important because neurogenesis dysregulation could be associated with the decline of neuronal and cognitive functions and the possible development of neuropsychiatric disorders.

Novos neurônios hipocampais são gerados continuamente no cérebro humano adulto. Vários estudos têm demonstrado que a proliferação de células do hipocampo é influenciada por uma variedade de estímulos, incluindo a exposição a pesticidas. Estes efeitos são particularmente importantes porque a desregulação da neurogênese pode estar associada ao declínio das funções neuronais e cognitivas e ao possível desenvolvimento de doenças neuropsiquiátricas.

Oral administration of liposome-encapsulated thymol could alleviate the inflammatory parameters in serum and hippocampus in a rat model of Alzheimer's disease.

BACKGROUND: Neuroinflammation is closely related to Alzheimer's Disease (AD) pathology, hence supplements with anti-inflammatory property could help attenuate the progression of AD. This study was conducted to evaluate the potential anti-inflammatory effects of liposome encapsulated thymol (LET), administered orally, in prevention of Alzheimer in a rat model by anti-inflammatory mechanisms. METHODS: The rats were grouped into six groups (n = 10 animals per group), including Control healthy (Con), Alzheimer's disease (AD) model, AD model treated with free thymol in 40 and 80 mg/kg body weight (TH40 and TH80), AD model treated with LET in 40 and 80 mg/kg of body weight (LET40 and LET80). The behavioral response of step through latency (Passive Avoidance Test), concentrations of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2) and brain-derived neurotrophic factor (BDNF) were assessed in serum and hippocampus. RESULTS: The results showed that significant increase in concentrations of IL-1ß (P = 0.001), IL-6 (P = 0.001), TNF-α (P = 0.001) and COX-2 (P = 0.001) in AD group compared with healthy control rats. AD induction significantly reduced step through latency and revealed deficits in passive avoidance performance. The results also showed the treatment with free thymol especially in higher concentrations and also LTE could decrease serum concentrations of IL-1ß (P < 0.05), IL-6 (P < 0.05), TNF-α (P < 0.05), and COX-2 (P < 0.05) and increase BDNF (P < 0.05) compared with control Alzheimer rats in hippocampus and serum. There were also significant correlations between serum and hippocampus concentrations of IL-1ß (r2 = 0.369, P = 0.001), IL-6 (r2 = 0.386, P = 0.001), TNF-α (r2 = 0.412, P = 0.001), and COX-2 (r2 = 0.357, P = 0.001). It means a closed and positive relation between serum and hippocampus concentrations of IL-1ß, IL-6, TNF-α, and COX-2. CONCLUSIONS: LET demonstrates its ability to attenuate neuroinflammatory reaction in AD model through suppression of IL-1ß, IL-6, and TNF-α and COX-2 indicators. Hence, it can ameliorate AD pathogenesis by declining inflammatory reaction.