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Background Sevoflurane is a superior agent for maintaining anesthesia during surgical procedures. However, the neurotoxic mechanisms of clinical concentration remain poorly understood. Sevoflurane can interfere with the normal function of neurons and synapses and impair cognitive function by acting on α5‐GABAAR. Methods Using MWM test, we evaluated cognitive abilities in mice following 1 h of anesthesia with 2.7%–3% sevoflurane. Based on hippocampal transcriptome analysis, we analyzed the differential genes and IL‐6 24 h post‐anesthesia. Western blot and RT‐PCR were performed to measure the levels of α5‐GABAAR, Radixin, P‐ERM, P‐Radixin, Gephyrin, IL‐6, and ROCK. The spatial distribution and expression of α5‐GABAAR on neuronal somata were analyzed using histological and three‐dimensional imaging techniques. Results MWM test indicated that partial long‐term learning and memory impairment. Combining molecular biology and histological analysis, our studies have demonstrated that sevoflurane induces immunosuppression, characterized by reduced IL‐6 expression levels, and that enhanced Radixin dephosphorylation undermines the microstructural stability of α5‐GABAAR, leading to its dissociation from synaptic exterior and resulting in a disordered distribution in α5‐GABAAR expression within neuronal cell bodies. On the synaptic cleft, the expression level of α5‐GABAAR remained unchanged, the spatial distribution became more compact, with an increased fluorescence intensity per voxel. On the extra‐synaptic space, the expression level of α5‐GABAAR decreased within unchanged spatial distribution, accompanied by an increased fluorescence intensity per voxel. Conclusion Dysregulated α5‐GABAAR expression and distribution contributes to sevoflurane‐induced partial long‐term learning and memory impairment, which lays the foundation for elucidating the underlying mechanisms in future studies. The increase in unphosphorylated Radixin causes the diffusion of α5‐GABAARs from the extra‐synaptic space to the synaptic cleft. α5‐GABAARs are localized to a smaller area at synaptic cleft but in unchanged confinement space at extra‐synaptic space, with reduced expression in the extra‐synaptic space but no change in the synaptic cleft, but all resulted in an increase in fluorescence intensity per voxel.

Periodontitis is one of the most common oral diseases and is a potential risk factor for systemic diseases. In this study, we aimed to investigate the association between periodontitis and learning and memory impairment. We established a periodontitis model by topical application of lipopolysaccharide ( -LPS) into the palatal gingival sulcus of the maxillary first molars of 10-week-old male rats for a 10-week period. We assessed alveolar bone resorption using micro-computed tomography analysis and learning and memory ability using the Morris water maze test. We determined the levels of cytokines [interleukin (IL)-1β, IL-6, IL-8, and IL-21] and LPS in the peripheral blood and cortex, as well as toll-like receptor 4 (TLR4)/NF-κB signaling pathway activation, using reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and western blot. We determined activation of microglia and astrocytes, expression of Aβ1-42, APP and Tau by immunohistochemistry. Finally, we measured the expression of amyloid precursor protein (APP) and its key secretases, as well as the Aβ1-40/1-42 ratio, by RT-PCR, western blot, and ELISA. We found that periodontitis induced learning and memory impairment in the rats. Further, we observed that it induced significant alveolar bone resorption. There was an increase in the levels of inflammatory cytokines and LPS. Moreover, we confirmed TLR4/NF-κB signaling pathway activation. We also observed activated microglia and astrocytes with enlarged cell bodies and irregular protrusions. Finally, we observed the promotion of β- and γ-secretases APP processing. Our findings indicated that periodontitis was associated with learning and memory impairment, probably induced by neuroinflammation via activating the TLR4/NF-κB signaling pathway. Furthermore, abnormal APP processing could be involved in this progress.

Learning and memory impairment is a common clinical symptom of aging and nervous system injuries, and seriously affects quality of life. Memory impairment is associated with increased oxidative stress (OS) and inflammatory response. β-hydroxybutyrate (BHBA) is a water-soluble endogenous small-molecule ketone body that easily crosses the blood-brain barrier and has shown neuroprotection activities. In this study, we investigated the effects and mechanisms of BHBA on D-galactose (D-gal)-induced memory impairment in mice by in vitro and in vivo experiments. BHBA was administered intragastrically to D-gal-injured C57BL/6 mice for 42 days. Water maze performance, the morphology of the hippocampus with Nissl staining, the ACh content, OS, and inflammation status were examined. To further investigate the mechanism, hippocampal neuronal cells (HT22) were treated with BHBA with or without the SIRT1 inhibitor or small interfering RNAs against sirt1 (si-SIRT1) before incubation with D-gal. BHBA significantly improved water maze performance; increased the ACh content, SOD activity, and SIRT1 expression; and decreased AChE and LDH activity, ROS, MDA, IL-1β, TNF-α contents, and NLRP3 expression. Further studies with the SIRT inhibitor or siRNAs against sirt1 reversed the above effects of BHBA. Collectively, BHBA inhibited hippocampal OS and the inflammation process to alleviate learning and memory impairment through activating the SIRT1 pathway in D-gal-injured mice, suggesting that BHBA could be a potential option for drug development of learning and memory impairment induced by nervous system injuries.

Dysregulated brain cholesterol metabolism is one of the characteristics of Alzheimer’s disease (AD). 27-Hydroxycholesterol (27-OHC) is a cholesterol metabolite that plays an essential role in regulating cholesterol metabolism and it is suggested that it contributes to AD-related cognitive deficits. However, the link between 27-OHC and cholesterol homeostasis, and how this relationship relates to AD pathogenesis, remain elusive. Here, 12-month-old ApoE ε4 transgenic mice were injected with saline, 27-OHC, 27-OHC synthetase inhibitor (anastrozole, ANS), and 27-OHC+ANS for 21 consecutive days. C57BL/6J mice injected with saline were used as wild-type controls. The indicators of cholesterol metabolism, synaptic structure, amyloid β 1-42 (Aβ1-42), and learning and memory abilities were measured. Compared with the wild-type mice, ApoE ε4 mice had poor memory and dysregulated cholesterol metabolism. Additionally, damaged brain tissue and synaptic structure, cognitive decline, and higher Aβ1-42 levels were observed in the 27-OHC group. Moreover, cholesterol transport proteins such as ATP-binding cassette transporter A1 (ABCA1), apolipoprotein E (ApoE), low-density lipoprotein receptor (LDLR), and low-density lipoprotein receptor-related protein1 (LRP1) were up-regulated in the cortex after the 27-OHC treatment. The levels of cholesterol metabolism-related indicators in the hippocampus were not consistent with those in the cortex. Additionally, higher serum apolipoprotein A1 (ApoA1) levels and lower serum ApoE levels were observed in the 27-OHC group. Notably, ANS partially reversed the effects of 27-OHC. In conclusion, the altered cholesterol metabolism induced by 27-OHC was involved in Aβ1-42 deposition and abnormalities in both the brain tissue and synaptic structure, ultimately leading to memory loss in the ApoE ε4 transgenic mice.

Accumulating clinical and epidemiological studies indicate that learning and memory impairment is more prevalent among people with diabetes mellitus (DM). PTP1B is a member of protein tyrosine phosphatase family and participates in a variety of pathophysiological effects including inflammatory, insulin signaling pathway, and learning and memory. This study was aimed to investigate the effects of CA, a specific inhibitor of PTP1B, on spatial learning and memory impairment in diabetic mice caused by high-fat diet and injection of streptozotocin. We found that the protein expressions of PTP1B increased in hippocampal CA1, CA3, and PFC regions of diabetic mice. Network pharmacology results showed that PTP1B might be one of the key targets between diabetes and cognitive dysfunction, and CA might alleviate DM-induced cognitive dysfunction. Animal experiments showed that CA ameliorated DM-induced spatial learning and memory impairment, and improved glucose and lipid metabolic disorders. Moreover, administration of CA alleviated hippocampal structure damage and enhanced the expressions of synaptic proteins, including PSD-95, SYN-1, and SYP in diabetic mice. Furthermore, CA treatment not only significantly down-regulated the expressions of PTP1B and NLRP3 inflammatory related proteins (NLRP3, ASC, Caspase-1, COX-2, IL-1β, and TNF-α), but also significantly up-regulated the expressions of insulin signaling pathway–related proteins (p-IRS1, p-PI3K, p-AKT, and p-GSK-3β) in diabetic mice. Taken together, these results suggested that PTP1B might be a targeted strategy to rescue learning and memory deficits in DM, possibly through inhibition of NLRP3 inflammasome and regulation of insulin signaling pathway.

Microwave (MW) and electromagnetic pulse (EMP) are considered environmental pollutants, both of which can induce learning and memory impairments. However, the bioeffects of combined exposure to MW and EMP have never been explored. This paper aimed to investigate the effects of combined exposure to MW and EMP on the learning and memory of rats as well as its association with ferroptosis in the hippocampus. In this study, rats were exposed to EMP, MW, or EMP and MW combined radiation. After exposure, impairment of learning and memory, alterations in brain electrophysiological activity, and damage to hippocampal neurons were observed in rats. Moreover, we also found alterations in ferroptosis hallmarks, including increased levels of iron, lipid peroxidation, and prostaglandin-endoperoxide synthase 2 (PTGS2) mRNA, as well as downregulation of glutathione peroxidase 4 (GPX4) protein in the rat hippocampus after exposure. Our results suggested that either single or combined exposure to MW and EMP radiation could impair learning and memory and damage hippocampal neurons in rats. Moreover, the adverse effects caused by the combined exposure were more severe than the single exposures, which might be due to cumulative effects rather than synergistic effects. Furthermore, ferroptosis in the hippocampus might be a common underlying mechanism of learning and memory impairment induced by both single and combined MW and EMP exposure.

Severe traumatic brain injuries (TBIs) are an important health issue worldwide, which are associated with harmful side effects. This meta-analysis investigates the cognitive and functional outcomes in severe brain trauma cases. It assesses the impact on memory, verbal and visual abilities, attention, learning, and the presence of depression. The study provides a comprehensive overview of the consequences of severe brain trauma injury on cognitive and functional domains. The main objective of the current comprehensive meta-analysis study is to assess and analyze the impact of severe TBI on functional and cognitive outcomes, including verbal, visual, attention, learning, memory, and emotional stability. We collected data from three online databases, including PubMed, Cochrane Library, and Embase. Case-control trials related to severe TBI association with cognitive and functional outcomes were included. Verbal strength, visual functions, learning abilities, attention, memory, and depression were considered primary outcomes. We have included 13 case-control studies with 1,442 subjects in this meta-analysis, which provide adequate data to determine the pooled effect size for targeted outcomes. The effect of severe TBI on the inducement of depression and impairment of memory, verbal, visual, attention, and learning abilities compared to the control group showed statistically significant outcomes (  < 0.05). Severe TBI is strongly associated with impaired cognitive and functional abilities, including visual and verbal disabilities, impaired memory, depression inducement, attention deficits, and learning disabilities.

Glutamine (Gln) is an immunomodulatory protein that mediates oxidative stress, inflammation, and apoptosis, but has not been reported in the treatment of hyperoxia (Hyp)-induced brain injury. The aim of this study was to determine whether Gln could improve hyp-induced brain injury in neonatal rats to and later learning and memory dysfunction, and to explore its possible mechanisms. We prepared a model of neonatal rat brain injury caused by normobaric hyperoxia while administered with Gln for 7 days for evaluation. Learning memory function was assessed with the Morris water maze test. Histological analysis, protein expression analysis, oxidative stress and inflammation level analysis were performed using hippocampal tissue. Gln treatment significantly reduced brain tissue water content, oxidative stress levels, microglia activation and inflammatory factor expression, and attenuated tissue damage and apoptosis in the hippocampal region. Gln ameliorates hyp-induced learning, memory impairment in neonatal rats in water maze test. It also increased MKP-1 protein expression and decreased p-p38, p-ERK and p-JNK. Therefore, it is hypothesized that Gln may exert neuroprotective effects by increasing MKP-1 expression to negatively regulate MAPK signaling, with potential cognitive improvement in hyp-induced brain injury.

Background Acanthopanax senticosus (AS) is a medicinal and food plant with many physiological functions, especially nerve protection. Its extract has many functional components, including polysaccharides, flavonoids, saponins, and amino acids. Our previous study indicated that AS extract protected against nerve damage caused by radiation. However, little is known about the gut‐brain axis mechanism of AS and its impact on radiation‐induced learning and memory impairment. Method In 60Co‐γ ray‐irradiated mice, we investigated the changes in behavior, neurotransmitters and gut microbiota after different days of administration of AS extract as a dietary supplement. Results The AS extract improved learning and memory ability in mice, and the neurotransmitter levels in the hippocampus and colon started to change from the 7th day, which accompanied changes of the gut microbiota, a decreased abundance of Helicobacter on the 7th day and an increased abundance of Lactobacillus on the 28th day. Among the marker bacteria, Ruminococcus and Clostridiales were associated with 5‐HT synthesis, and Streptococcus were associated with 5‐HT and ACH synthesis. In addition, the AS extract increased the tight junction protein, inhibited inflammation levels in colon, and even increased the relative protein expression of BDNF and NF‐κB and decreased the relative protein expression of IκBα in the hippocampus of irradiated mice. Conclusion These results will lay the foundation for further study on the mechanism of the gut‐brain axis of AS in preventing radiation‐induced learning and memory impairment. Acanthopanax senticosus extract alleviates radiation‐induced learning and memory impairment based on neurotransmitter‐gut microbiota communication. By Figdraw (www.figdraw.com).

With the aging of the population and the increasing incidence of neurological diseases, amnestic mild cognitive impairment (aMCI) has attracted attention. Hyperbaric oxygen (HBO) has gradually shown the potential in the treatment of aMCI as an emerging treatment method in recent times. This study is to observe the effect of HBO on the long-term learning memory of aMCI rats, and investigate the associated mechanisms. Seventy-two male rats (4-month-old) were randomly divided into control (CON) group, aMCI group, HBO group, 24 rats in each group. Each group was randomly divided into CON , CON , CON ; aMCI , aMCI , aMCI ; HBO , HBO , HBO , 8 rats in each group. The aMCI model rats were established in aMCI and HBO groups. HBO group was treated with HBO for 7 days. The ethological and cytopathology which include Morris water maze (MWM) test, HE staining, TUNEL staining and the expression of Fas/FasL on neuron membrane were conducted to evaluate the effects of HBO on day 1, day 7 and day 28 after HBO treatment. MWM test showed that the spatial learning and memory ability of the rats decreased in aMCI group, and recovered in HBO group; Compared with aMCI group, the pathological damage of hippocampal nerve cells was alleviated, the number of apoptotic cells was significantly reduced (P < 0.05), and the expression of Fas/FasL on the surface of nerve cell membrane was significantly weakened in HBO group (P < 0.05). There were no significant changes in the spatial learning and memory ability, pathological damage of hippocampal neurons, the number of apoptotic cells, and the changes of Fas/FasL on the surface of hippocampal neurons in HBO , HBO , and HBO groups (P > 0.05). However, in aMCI aMCI , and aMCI groups gradually aggravated (P < 0.05). 1. HBO can improve the long-term learning and memory impairment by attenuating neuronal apoptosis in aMCI rats. 2. Fas/FasL mediated cell receptor death pathway is involved in the apoptosis of hippocampal neurons.