Water Maze Experiment Research Articles

Melatonin pretreatment alleviates blast-induced oxidative stress in the hypothalamic-pituitary-gonadal axis by activating the Nrf2/HO-1 signaling pathway

Although melatonin has been demonstrated to exert a potent antioxidant effect, the ability of melatonin to alleviate blast-induced oxidative stress in the hypothalamic-pituitary-gonadal (HPG) axis remains unclear. This study aimed to elucidate the effects and underlying mechanism of melatonin pretreatment on the HPG axis disrupted by blast injury. Sixty C57BL/6 mice were randomly divided into control, blast, and blast + melatonin groups for behavioral experiments. The elevated maze experiment, open field experiment, and Morris Water Maze experiment were carried out on the 7th, 14th and 28th day after the blast injury. Fifty Sprague Dawley rats were randomly divided into control, blast, blast + melatonin, and blast + melatonin + luzindole groups for hormone assays and molecular and pathological experiments. Blood samples were used for HPG axis hormone detection and ELISA assays, and tissue samples were used to detect oxidative stress, inflammation, apoptosis, and stress-related protein levels. The results showed that melatonin pretreatment alleviated blast-induced behavioral abnormalities in mice and maintained the HPG axis hormone homeostasis in rats. Additionally, melatonin significantly reduced MDA5 expression and increased the expression of Nrf2/HO-1. Moreover, melatonin significantly inhibited NF-κB expression and upregulated IL-10 expression, and it reversed the blast-induced high expression of caspase-3 and Bax and the low expression of Bcl-2. Furthermore, luzindole counteracted melatonin inhibition of NF-κB and upregulated Nrf2/HO-1. Melatonin significantly alleviated blast-induced HPG axis hormone dyshomeostasis, behavioral abnormalities, oxidative stress, inflammation, and apoptosis, which may be achieved by upregulating the Nrf2/HO-1 signaling pathway. Our study suggested that melatonin pretreatment is a potential treatment for blast-induced HPG axis hormonal and behavioral abnormalities.

Comparison effects of chronic sleep deprivation on juvenile and young adult mice.

Sleeplessness leads to a spectrum of neuropsychiatric disorders, affecting both juveniles and young adults. Studies have shown different sleep patterns at different stages of development. However, the molecular mechanisms underlying the effects of the same chronic sleep deprivation (CSD) on behaviours of juveniles and young adults remain elusive. Here, we aimed to evaluate the effects of CSD (6days, 19h per day) on anxiety-like behaviour, cognitive performance and molecular alterations in juvenile and young adult mice. Change in body weight suggested impaired physical development in CSD animals, specifically juveniles gaining weight at a lower rate and young adults losing weight. Behavioural performance indicated that CSD had little effect on spatial memory, but induced analogous anxiety-like phenotypes in both juveniles and young adults, as evidenced by no significant difference in the Y-maze experiment (Y-M) or the Morris water maze experiment (MWM), as well as the decreased open-arm distance percentage in the elevated plus maze experiment (EPM). In addition, CSD reduced the N-methyl-D-aspartic receptor subunit 2B (NR2B) and postsynaptic density protein 95 (PSD95) levels in juveniles, but these were increased in young adults. In conclusion, our results suggested that although CSD resulted in analogous anxiety-like behaviours in both juvenile and young adult mice, the underlying mechanisms might be different, which was indicated by the opposite change of synaptic proteins under CSD. These findings may help to better understand the important role of sleep and have constructive significance for human health.

Thioredoxin-1 Is a Target to Attenuate Alzheimer-Like Pathology in Diabetic Encephalopathy by Alleviating Endoplasmic Reticulum Stress and Oxidative Stress.

Varying degrees of central nervous system neuropathy induced by diabetes mellitus (DM) contribute to a cognitive disorder known as diabetic encephalopathy (DE), which is also one of the independent risk factors for Alzheimer’s disease (AD). Endoplasmic reticulum stress (ERS) plays a critical role in the occurrence and development of DE and AD. However, its molecular mechanism remains largely unknown. This study aims to investigate whether thioredoxin-1 (Trx-1) could alleviate DE and AD through ERS, oxidative stress (OS) and apoptosis signaling pathways. Mice were randomly divided into a wild-type group (WT-NC), a streptozotocin (STZ)-treated DM group (WT-DM), a Trx-1-TG group (TG-NC) and a Trx-1-TG DM group (TG-DM). Diabetic animals showed an increase in the time spent in the target quadrant and the number of platform crossings as well as AD-like behavior in the water maze experiment. The immunocontent of the AD-related protein Tau and the levels of cell apoptosis, β-amyloid (Aβ) plaque formation and neuronal degeneration in the hippocampus of the diabetic group were increased. Some key factors associated with ERS, such as protein disulfide isomerase (PDI), glucose-regulated protein 78 (GRP78), inositol-requiring enzyme 1α (IRE1α), tumor necrosis factor receptor-associated factor 2 (TRAF2), apoptosis signal-regulating kinase-1 (ASK1), c-Jun N-terminal kinase (JNK), protein kinase RNA (PKR)-like ER kinase (PERK), and C/EBP homologous protein (CHOP), were upregulated, and other factors related to anti-oxidant stress, such as nuclear factor erythroid 2-related factor (Nrf2), were downregulated in the DM group. Moreover, DM caused an increase in the immunocontents of caspase-3 and caspase-12. However, these changes were reversed in the Trx-1-tg DM group. Therefore, we conclude that Trx-1 might be a key factor in alleviating DE and AD by regulating ERS and oxidative stress response, thus preventing apoptosis.

Effects of B-GOS on cognitive behavior and depression of transgenic mice with Alzheimer's disease

Objective: To investigate the effects of novel BimunoGalactooligosaccharides (B-GOS) on cognitive behavior and depression of APP/PS1/tau Alzheimer's disease transgenic mice. Methods: Five-month-old male APP/PS1/tau AD transgenic mice and C57BL/6J control mice were divide into C57+Vehicle group, C57+B-GOS group, APP/PS1/tau+Vehicle group and APP/PS1/tau+B-GOS group, with 10 mice in each group. After continuous administration of B-GOS for 5 months, the cognitive behavior and depressive mood changes of mice in each group were detected by open field experiment, new object recognition experiment, Y maze experiment, Morris water maze experiment, tail suspension test, forced swimming test and conditioned fear experiment, respectively. Results: ①Open field experiment: the percentage of activity time in the central area of open field in APP/PS1/tau+Vehicle group mice was significantly lower than that in C57+Vehicle group mice (P＜0.01), and was remarkably increased after B-GOS intervention (P＜0.05). ② New object recognition experiment: the new object recognition index (NOI) of APP/PS1/tau+Vehicle group mice was significantly lower than that of C57+Vehicle group mice (P＜0.01), and was observably increased after B-GOS intervention (P＜0.05). ③ Y maze experiment: the spontaneous alternation correct rate of APP/PS1/tau+Vehicle group mice was notably lower than that in C57+Vehicle group (P＜0.01), and was distinctly increased after B-GOS intervention (P＜0.01). ④ Classical water maze experiment: the escape latency of APP/PS1/tau+Vehicle group mice on the 4th and 5th days was significantly longer than that of C57+Vehicle group mice (P＜0.01), which was markedly shortened after B-GOS intervention (P＜0.05). During the space exploration phase, the percentage of swimming time in the target quadrant and the times of crossing the platform in APP/PS1/tau+Vehicle group mice were significantly lower than those in C57+Vehicle group mice (P＜0.01), which were notably increased after B-GOS intervention (P＜0.01). ⑤ Tail suspension test and forced swimming test: the percentage of immobility time in APP/PS1/tau+Vehicle group mice was dramatically higher than that in C57+Vehicle group mice (P＜0.01), and was obviously reduced after B-GOS intervention (P＜ 0.01). ⑥ Conditioned fear experiment: before conditioned stimulus (CS), the freezing ratio of mice in each group had no statistical difference (P＞0.05). After CS, the freezing ratio of APP/PS1/tau+Vehicle group mice was significantly lower than that of C57+Vehicle group mice (P＜0.01), and was notably increased after B-GOS intervention (P＜0.01). Conclusion: B-GOS could reverse the cognitive behavioral impairment of APP/PS1/tau mice and alleviate their depression to a large extent.

Three-dimensional-arterial spin labeling perfusion correlation with diabetes-associated cognitive dysfunction and vascular endothelial growth factor in type 2 diabetes mellitus rat.

BACKGROUNDType 2 diabetes mellitus (T2DM) has been strongly associated with an increased risk of developing cognitive dysfunction and dementia. The mechanisms of diabetes-associated cognitive dysfunction (DACD) have not been fully elucidated to date. Some studies proved lower cerebral blood flow (CBF) in the hippocampus was associated with poor executive function and memory in T2DM. Increasing evidence showed that diabetes leads to abnormal vascular endothelial growth factor (VEGF) expression and CBF changes in humans and animal models. In this study, we hypothesized that DACD was correlated with CBF alteration as measured by three-dimensional (3D) arterial spin labeling (3D-ASL) and VEGF expression in the hippocampus.AIMTo assess the correlation between CBF (measured by 3D-ASL and VEGF expression) and DACD in a rat model of T2DM.METHODSForty Sprague-Dawley male rats were divided into control and T2DM groups. The T2DM group was established by feeding rats a high-fat diet and glucose to induce impaired glucose tolerance and then injecting them with streptozotocin to induce T2DM. Cognitive function was assessed using the Morris water maze experiment. The CBF changes were measured by 3D-ASL magnetic resonance imaging. VEGF expression was determined using immunofluorescence. RESULTSThe escape latency time significantly reduced 15 wk after streptozotocin injection in the T2DM group. The total distance traveled was longer in the T2DM group; also, the platform was crossed fewer times. The percentage of distance in the target zone significantly decreased. CBF decreased in the bilateral hippocampus in the T2DM group. No difference was found between the right CBF value and the left CBF value in the T2DM group. The VEGF expression level in the hippocampus was lower in the T2DM group and correlated with the CBF value. The escape latency negatively correlated with the CBF value. The number of rats crossing the platform positively correlated with the CBF value. CONCLUSIONLow CBF in the hippocampus and decreased VEGF expression might be crucial in DACD. CBF measured by 3D-ASL might serve as a noninvasive imaging biomarker for cognitive impairment associated with T2DM.

Exploring the regulatory mechanism of Nao Tai Fang on vascular Dementia's biological network based on cheminformatics and transcriptomics strategy

Ethnopharmacological relevanceNao Tai Fang (NTF) is modified from Buyang Huanwu Decoction. Modern pharmacological research showed that NTF has a good anti-cerebral ischemic effect and can improve the learning and memory ability of cerebrovascular disease. AimThe purpose of this study is to explore the regulation mechanism of NTF on the regulation mechanism of vascular dementia (VD)'s biological network based on chemoinformatics and transcriptomics strategies. MethodFirst, the bilateral common carotid artery ligation method was used to create a rat VD model. After NTF intervention for 30 days, the treatment effect was evaluated by HE staining and water maze experiment. Then, the Agilent mRNA expression profiling chip was used to obtain mRNA expression data of hippocampal tissues of VD model rats before and after NTF intervention, and microarray analysis was used to screen for genes with significant differential expression. The BATMAN database was utilized to obtain the potential targets of NTF and the Genecards and OMIM were utilized to collect the VD potential genes. The cytoscape was utilized to construct and analyze the networks. ResultThe animal experiments showed that NTF can improve VD. A total of 180 up-regulated proteins and 289 down-regulated proteins were identified. The top 20 up- and down-regulated differentially expressed genes were utilized to construct differentially expressed gene's protein-protein interaction (PPI) network. A total of 677 NTF potential targets and 550 VD genes were obtained and were utilized to construct NTF-VD PPI network. The cheminformatics analysis showed that NTF can regulate a lot of biological processes and signaling pathways (such as inflammation modules, vasodilation and contraction modules, hypoxia modules, angiogenesis, coagulation, neurovascular unit modules, Neuroactive ligand-receptor interaction, Calcium signaling pathway, Serotonergic synapse). ConclusionNTF may play a role in the treatment of VD through the targets, signaling pathways and biological processes discovered in this study.

MiR-96 Inhibits SV2C to Promote Depression-Like Behavior and Memory Disorders in Mice.

Accumulating evidence continues to emphasize the role of microRNAs as significant contributors to depression-like behavior and memory disorders. The current study aimed to investigate the mechanism by which miR-96 influences depression-like behavior and memory deficit in mice. A depression-like behavior and memory disorder mouse model was initially established by means of intraperitoneal injection with lipopolysaccharide. Memory deficits in the mice were evaluated using the Novel Object Recognition Test and Morris water maze experiments, whereas the Sucrose Preference Experiment and forced swimming experiments were performed to identify depression-like behavior in mice. The levels of tumor necrosis factor-α, malondialdehyde, superoxide dismutase, glutathione, and the monoamine transmitters 5-hydroxytryptamine and dopamine were subsequently detected in the serum. Reverse transcription-quantitative polymerase chain reaction and Western blot analysis evaluated the expression of miR-96 and SV2C expression in the CA1 hippocampal region of the mice. Finally, the relationship of miR-96 and SV2C was verified by dual-luciferase reporter gene assay. Our data indicated that the expression of miR-96 was increased, whereas that of SV2C was decreased in the CA1 region of mice exhibiting depression-like behavior and memory impairment. When miR-96 was downregulated or SV2C was overexpressed via intra-cerebroventricular injection with a miR-96 antagonist (miR-96 antagomir) or overexpression of SV2C vector, the Novel Object Recognition Test and sucrose preference index were increased, whereas the escape latency, the number of water maze platform crossings, and the immobility time of the mice were decreased. The serum levels of tumor necrosis factor-α, interleukin-1β, and malondialdehyde in the mouse CA1 region of mice were reduced, whereas the levels of superoxide dismutase and glutathione were elevated after the downregulation of miR-96 or overexpression of SV2C. Collectively, our study demonstrates that miR-96 negatively regulates the expression of SV2C, which consequently leads to depression-like behavior and memory impairment in mice. Our findings highlight the potential of miR-96-targeted therapeutics.

BMP4 overexpression induces the upregulation of APP/Tau and memory deficits in Alzheimer\u2019s disease

Alzheimer’s disease (AD) is a chronic progressive degenerative disease of the nervous system. Its pathogenesis is complex and is related to the abnormal expression of the amyloid β (Aβ), APP, and Tau proteins. Evidence has demonstrated that bone morphogenetic protein 4 (BMP4) is highly expressed in transgenic mouse models of AD and that endogenous levels of BMP4 mainly affect hippocampal function. To determine whether BMP4 participates in AD development, transgenic mice were constructed that overexpress BMP4 under the control of the neuron-specific enolase (NSE) promoter. We also performed MTT, FACS, transfection, TUNEL, and Western blotting assays to define the role of BMP4 in cells. We found that middle-aged BMP4 transgenic mice exhibited impaired memory via the Morris water maze experiment. Moreover, their hippocampal tissues exhibited high expression levels of AD-related proteins, including APP, Aβ, PSEN-1, Tau, P-Tau (Thr181), and P-Tau (Thr231). Furthermore, in multiple cell lines, the overexpression of BMP4 increased the expression of AD-related proteins, whereas the downregulation of BMP4 demonstrated opposing effects. Consistent with these results, BMP4 modulation affected cell apoptosis via the regulation of BAX and Bcl-2 expression in cells. Our findings indicate that BMP4 overexpression might be a potential factor to induce AD.

Oral Herb Medicine Paste Improves Learning and Memory Function in Elderly Spontaneous Hypertensive Rats

Background: Oral herb medicine paste (Gao-Zi-Yao) has long been a unique way for treating various diseases. The present study is to explore the effect of Gao-Zi-Yao on learning and memory function in elderly spontaneous hypertensive rats (SHR) and its possible mechanism. Methods: Male elderly SHR were received different doses of Gao-Zi-Yao for 4 weeks. Systolic blood pressure (SBP) and heart rate were monitored. Morris water maze was performed to test the learning and memory function of the rats. Number of neurons in hippocampus was counted by Nissl staining. Western blot was applied to detect the expressions of learning and memory function related proteins, N-methyl-d-aspartate receptor 2B (NMDAR 2B), glutamate receptor 1 (GluR1), phosphorylated-calmodulin-dependent protein kinase II (p-CaMK II), and phosphorylated-cAMP responsive element-binding protein (p-CREB) in rat hippocampus. Findings: Data showed that Gao-Zi-Yao reduced SBP in elderly SHR. The results of Morris water maze experiment showed that Gao-Zi-Yao dose-dependently improved learning and memory function. Number of neurons in the hippocampal dentate gyrus (DG) region of the elderly SHR was increased by Gao-Zi-Yao treatment. In addition, Gao-Zi-Yao elevated the protein expressions of NMDAR 2B, GluR1, p-CaMK II, and p-CREB in hippocampus. Interpretation: Gao-Zi-Yao decreases SBP and improves the learning and memory function of the elderly SHR by regulation of neuron number in hippocampal DG area and the expressions of learning and memory function related proteins. Funding Statement: This work was supported by the National Natural Science Foundation of China (81970422), Suzhou Municipal Science and Technology Bureau (SS201745, GSWS2019022, SYSD2020210), and 5th 333 Project of Jiangsu Province. Declaration of Interests: The authors stated 'not applicable.' Ethics Approval Statement: The experiments were performed in according with the National Institutes of Health Guidelines for the Use of Laboratory Animals (NIH, publication number 85-23, revised 1996.), which were approved by and performed according to guidelines for the care and use of animals established by Soochow University. All the herbs and other materials used in the preparation of Gao-Zi Yao were approved by National Health Commission of the People’s Republic of China.

Repeated exposure to propofol in the neonatal period impairs hippocampal synaptic plasticity and the recognition function of rats in adulthood

Anesthesia of neonates with propofol induces persistent behavioral abnormalities in adulthood. Although propofol-triggered apoptosis of neurons in the developing brain may contribute to the development of cognitive deficits, the mechanism of neurotoxicity induced by neonatal exposure to propofol remains unclear. In this study, the effects of neonatal propofol anesthesia on synaptic plasticity and neurocognitive function were investigated. Postnatal day 7 (PND-7) Sprague-Dawley rats were intraperitoneally injected with fat emulsion or 20, 40 or 60 mg/kg propofol for three consecutive days. The expression of brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB) and postsynaptic density protein 95 (PSD-95) in the rat hippocampus at PND-10 and PND-12 was measured by Western blotting. The number of dendritic branches, total dendritic length and dendritic spine density were observed by Golgi-Cox staining 24 h and 72 h after the last propofol administration. Long-term potentiation (LTP) was measured electrophysiologically in hippocampus of PND-60 rats to evaluate the synaptic function. The learning and memory abilities of rats were evaluated by Morris water maze (MWM) experiments, Novel object recognition test (NORT) and Object location test (OLT) at PND-60. Our results showed that neonatal exposure to propofol significantly inhibited the expression of BDNF, TrkB and PSD-95 in the rat hippocampus. The number of dendritic branches, total dendritic length and dendritic spine density of neurons in the rat hippocampus were markedly reduced after neonatal propofol anesthesia. LTP was significantly diminished in hippocampus of PND-60 rats after repeated exposure to propofol in the neonatal period. Morris water maze experiments showed that repeated neonatal exposure to propofol significantly prolonged the escape latency and decreased the time spent in the target quadrant and the number of platform crossings. NORT and OLT showed that repeated neonatal exposure to propofol markedly reduced the Investigation Time for novel object or location. All of the results above indicate that repeated exposure to propofol in the neonatal period can impair hippocampal synaptic plasticity and the recognition function of rats in adulthood.

Suppression of neuronal cholesterol biosynthesis impairs brain functions through insulin-like growth factor I-Akt signaling.

Some relationship between abnormal cholesterol content and impairment of insulin/insulin-like growth factor I (IGF-1) signaling has been reported in the pathogenesis of Alzheimer's disease (AD). However, the underlying mechanism of this correlation remains unclear. It is known that 3-β hydroxycholesterol Δ 24 reductase (DHCR24) catalyzes the last step of cholesterol biosynthesis. To explore the function of cholesterol in the pathogenesis of AD, we depleted cellular cholesterol by targeting DHCR24 with siRNA (siDHCR24) or U18666A, an inhibitor of DHCR24, and studied the effect of the loss of cholesterol on the IGF-1-Akt signaling pathway in vitro and in vivo. Treatment with U18666A reduced the cellular cholesterol level and blocked the anti-apoptotic function of IGF-1 by impairing the formation of caveolae and the localization of IGF-1 receptor in caveolae of the PC12 cells. Downregulation of the DHCR24 expression induced by siRNA against DHCR24 also yielded similar results. Furthermore, the phosphorylation levels of IGF-1 receptor, insulin receptor substrate (IRS), Akt, and Bad in response to IGF-1 were all found to decrease in the U18666A-treated cells. Rats treated with U18666A via intracerebral injection also exhibited a significant decrease in the cholesterol level and impaired activities of IGF-1-related signaling proteins in the hippocampus region. A significant accumulation of amyloid β and a decrease in the expression of neuron-specific enolase (NSE) was also observed in rats with U18666A. Finally, the Morris water maze experiment revealed that U18666A-treated rats showed a significant cognitive impairment. Our findings provide new evidence strongly supporting that a reduction in cholesterol level can result in neural apoptosis via the impairment of the IGF-1-Akt survival signaling in the brain.

Effects of Moringa flavone on cognitive function and neuropathological indexes in diabetic encephalopathy rats

To investigate the effect of Moringa flavone on cognitive impairment and neuropathological indexes in diabetic encephalopathy (DE) rats. Sixty male Sprague-Dawley (SD) rats were divided into control group, model group, positive drug group, Moringa low-dose and high-dose groups according to the random number table method, with 10 rats in each group. Diabetic rat model was established by intraperitoneal injection of 25 mg/kg streptozotocin (STZ) after continuous feeding of high fat and high sugar diet for one week. Blood was collected from the tail vein after 72 hours, the mean value of twice random blood glucose was ≥ 16.67 mmol/L, and the continuous positive urine glucose showed that the diabetes model was successfully prepared. The control group was fed with conventional feed. After successful model establishment, the rats in the Moringa low and high dose groups were given 4.0 g/kg and 8.0 g/kg Moringa extract (Moringa flavone) by gavage everyday, the rats in the positive drug group were given piracetam 0.48 g/kg, and the rats in the model group and control group were given the same amount of normal saline once a day for 30 days. Morris water maze was used to evaluate the cognitive impairment of the rats. The hippocampus of the rats was harvested 12 hours after the last administration, and the advanced glycation end product receptor (RAGE) and nuclear factor-κB (NF-κB) were detected by immunohistochemistry. The contents of acetylcholinesterase (AChE), advanced glycation end product (AGE) and choline acetyl transferase (ChAT) were detected by enzyme linked immunosorbent assay (ELISA). Compared with the control group, the escape latency and the exploration distance in model group were extended, target quadrant stay time was shortened, the levels of AChE and AGE in brain tissue were significantly increased, and ChAT level was significantly decreased. Morris water maze experiment showed that compared with the model group, in the Moringa low and high dose groups from the 3rd day, the escape latency (s: 35.07±7.21, 33.14±5.35 vs. 43.09±9.83, both P < 0.05) and the exploration distance (m: 8.32±4.23, 8.10±4.97 vs. 13.02±3.67) were significantly shortened (both P < 0.05). The target qauadrant stay time was extended (s: 35.12±3.12, 41.53±8.37 vs. 23.15±4.89, both P < 0.01). The results of ELISA showed that compared with the model group, the levels of AChE and AGE in brain tissue of the Moringa low and high dose groups were significantly decreased [AChE (U/L): 180.22±12.03, 142.67±20.56 vs. 205.27±25.14, AGE (μg/L): 439.10±25.19, 428.27±19.14 vs. 501.28±21.53, all P < 0.05], and the levels of ChAT were significantly increased (U/L: 51.95±5.27, 53.13±5.04 vs. 37.91±5.10, both P < 0.01). There were no significant differences in AChE, AGE or ChAT between the Moringa low and high dose groups. The results of immunohistochemistry showed that the number of RAGE and NF-κB positive cells in DG area of hippocampus increased significantly, and the average gray values of RAGE and NF-κB decreased significantly. Compared with the model group, the RAGE and NF-κB positive cells in the Moringa low and high dose groups were significantly reduced, and the average gray values of RAGE and NF-κB in hippocampus were significantly increased [RAGE (gray value): 110.46±10.04, 117.76±8.64 vs. 92.19±8.76, NF-κB (gray value): 109.40±8.93, 116.59±7.26 vs. 90.74±13.27, all P < 0.05]. There were no significant differences in the expressions of RAGE or NF-κB between the Moringa low and high dose groups. Moringa flavonoids could obviously improve the cognitive dysfunction and memory ability of DE model rats, improve the pathological changes of hippocampus, and have a certain protective effect on brain.

Knockdown of lncRNA TUG1 inhibits hippocampal neuronal apoptosis and participates in aerobic exercise-alleviated vascular cognitive impairment

ObjectivesOur previous study indicated that aerobic exercise relieves cognitive impairment in patients with vascular cognitive impairment (VCI) via regulating brain-derived neurotrophic factor (BDNF), but the mechanism is not yet clear. This study aimed to explore whether lncRNA taurine upregulated gene 1 (TUG1) participates in the process of VCI by regulating BDNF.MethodsThe expressions of TUG1 and BDNF in the serum of VCI patients were detected. The potential molecular mechanisms of TUG1 in regulating hippocampal neuronal apoptosis were explored in oxygen and glucose deprivation-induced (OGD-induced) hippocampal cell line HT22. The VCI mouse model was established, and TUG1 and BDNF were overexpressed via lentivirus injection. The cognitive impairment of mice was detected by the Morris water maze experiment after the aerobic exercise.ResultsThe level of TUG1 was elevated in the serum of VCI patients compared with the control group. The knockdown of TUG1 in OGD-induced HT22 cells increased BDNF level and decreased cell apoptosis, and the downregulation of BDNF restored the decreased cell apoptosis. RNA immunoprecipitation and RNA pull-down assays showed that TUG1 could bind to BDNF protein. The aerobic exercise alleviated cognitive impairment and inhibited hippocampal apoptosis in VCI mice. Meanwhile, the overexpression of TUG1 reversed the therapeutic effects of aerobic exercise on cognitive impairment.ConclusionsThe knockdown of TUG1 reduced hippocampal neuronal apoptosis and participates in the aerobic exercise-alleviated VCI, which was partly through regulating BDNF.

The effect of sevoflurane on the spatial recall ability and expression of apolipoprotein E and β amyloid in the hippocampus in rats

This study aimed to observe the recent spatial recall ability and the changes of expression of hippocampal apolipoprotein E (ApoE) and amyloid β protein (Aβ) in adult rats after inhaling sevoflurane anesthetic drugs, and to analyze the mechanism of action. For this purpose, a total of 54 adult SD clean-grade rats were selected in this study and were randomly divided into the sevoflurane anesthesia group, carrier gas group and control group, 18 rats in each group. The rats in the carrier gas group were inhaled with 1 L/min of oxygen O2+1 L/min air mixed carrier gas for 2 h, and the rats in the sevoflurane anesthesia group were given 3.2%sevoflurane for 2 hours based on the carrier gas group, the control rats were naturally reared. Before the model was copied, the Morris water maze experiment was performed before the material was taken. Some rat brain tissues were extracted on the first day (T1), the third day (T3), and the seventh day (T7) after model replication. The immunohistochemistry was used to measure the mean optical density (MOD) value of APOE and Aβ in hippocampal CA1, CA3 and DG regions. The indicators above at different time points of each group were compared and analyzed. Results showed that the number of crossing the original platform at each time point, the residence time of the original platform quadrant, the number of entering the original platform quadrant, and the percentage of the original platform quadrant residence time in the sevoflurane anesthesia group and the carrier gas group were compared, and there were no significant differences between two groups (P&gt;0.05). Compared with the carrier gas group, the MOD values of APOE in the hippocampus at T1 and T3 time points in the sevoflurane anesthesia group were decreased (P&lt;0.05), the MOD values of Aβ in the hippocampus at the T7 time point were increased (P&lt;0.05). It concluded that Inhalation of 3.2%sevoflurane has no obvious damage to the recent spatial recall ability of adult rats. Within 7 days after inhalation of 3.2% sevoflurane, it can inhibit hippocampus Aβ deposition through down-regulating APOE expression level. The critical time point for hippocampal Aβ increasing was 7 days after anesthesia.

Forsythoside B attenuates memory impairment and neuroinflammation via inhibition on NF-\u03baB signaling in Alzheimer\u2019s disease

BackgroundNeuroinflammation is a principal element in Alzheimer’s disease (AD) pathogenesis, so anti-inflammation may be a promising therapeutic strategy. Forsythoside B (FTS•B), a phenylethanoid glycoside isolated from Forsythiae fructus, has been reported to exert anti-inflammatory effects. However, no studies have reported whether the anti-inflammatory properties of FTS•B have a neuroprotective effect in AD. In the present study, these effects of FTS•B were investigated using amyloid precursor protein/presenilin 1 (APP/PS1) mice, BV-2 cells, and HT22 cells.MethodsAPP/PS1 mice were administered FTS•B intragastrically for 36 days. Behavioral tests were then carried out to examine cognitive functions, including the Morris water maze, Y maze, and open field experiment. Immunohistochemistry was used to analyze the deposition of amyloid-beta (Aβ), the phosphorylation of tau protein, and the levels of 4-hydroxynonenal, glial fibrillary acidic protein, and ionized calcium-binding adapter molecule 1 in the hippocampus. Proteins that showed marked changes in levels related to neuroinflammation were identified using proteomics and verified using enzyme-linked immunosorbent assay and western blot. BV-2 and HT22 cells were also used to confirm the anti-neuroinflammatory effects of FTS•B.ResultsIn APP/PS1 mice, FTS•B counteracted cognitive decline, ameliorated the deposition of Aβ and the phosphorylation of tau protein, and attenuated the activation of microglia and astrocytes in the cortex and hippocampus. FTS•B affected vital signaling, particularly by decreasing the activation of JNK-interacting protein 3/C-Jun NH2-terminal kinase and suppressing WD-repeat and FYVE-domain-containing protein 1/toll-like receptor 3 (WDFY1/TLR3), further suppressing the activation of nuclear factor-κB (NF-κB) signaling. In BV-2 and HT22 cells, FTS•B prevented lipopolysaccharide-induced neuroinflammation and reduced the microglia-mediated neurotoxicity.ConclusionsFTS•B effectively counteracted cognitive decline by regulating neuroinflammation via NF-κB signaling in APP/PS1 mice, providing preliminary experimental evidence that FTS•B is a promising therapeutic agent in AD treatment.

Langat virus infection affects hippocampal neuron morphology and function in mice without disease signs

BackgroundTick-borne encephalitis virus (TBEV) is an important human pathogen that can cause the serious illness tick-borne encephalitis (TBE). Patients with clinical symptoms can suffer from severe meningoencephalitis with sequelae that include cognitive disorders and paralysis. While less than 30% of patients with clinical symptoms develop meningoencephalitis, the number of seropositive individuals in some regions indicates a much higher prevalence of TBEV infections, either with no or subclinical symptoms. The functional relevance of these subclinical TBEV infections and their influence on brain functions, such as learning and memory, has not been investigated so far.MethodsTo compare the effect of low and high viral replication in the brain, wildtype and Irf-7−/− mice were infected with Langat virus (LGTV), which belongs to the TBEV-serogroup. The viral burden was analyzed in the olfactory bulb and the hippocampus. Open field, elevated plus maze, and Morris water maze experiments were performed to determine the impact on anxiety-like behavior, learning, and memory formation. Spine density of hippocampal neurons and activation of microglia and astrocytes were analyzed.ResultsIn contrast to susceptible Irf-7−/− mice, wildtype mice showed no disease signs upon LGTV infection. Detection of viral RNA in the olfactory bulb revealed CNS infections in wildtype and Irf-7−/− mice. Very low levels of viral replication were detectable in the hippocampus of wildtype mice. Although wildtype mice develop no disease signs, they showed reduced anxiety-like behavior and impaired memory formation, whereas Irf-7−/− mice were not affected. This impairment was associated with a significant decrease in spine density of neurons in the hippocampal CA1 region of wildtype mice. Microglia activation and astrogliosis were detected in the hippocampus.ConclusionIn this study, we demonstrate that subclinical infections by viruses from the TBEV-serogroup affected anxiety-like behavior. Virus replication in the olfactory bulb induced far-reaching effects on hippocampal neuron morphology and impaired hippocampus-dependent learning and memory formation.

Terpenoids of Ganoderma lucidum reverse cognitive impairment through attenuating neurodegeneration via suppression of PI3K/AKT/mTOR expression in vivo model

Abstract This study investigated effects of triterpenoids derived from Ganoderma lucidum (GLT) on the ability to attenuate cognitive impairment and reduce oxidative stress and inflammation induced by D-galactose using an aged rats model. The data revealed that dietary GLT intervention improved the memory of aged rats in a water maze experiment. A reduction in inflammation was also achieved as GLT decreased the levels of MDA, AGEs, NO, TNF-α and AChE activity, and increased the activity of T-AOC, GSH-Px, T-SOD, CAT and IL-2 level in serum. The GLT intervention revised hepatocyte cellular arrangement and binucleation of the liver status, and even hippocampal neurons morphology. GLT upregulated the expression of FOXO4, SIRT1, and downregulated the expression of GFAP, iNOS, PI3K, AKT, mTOR and IL-6 with activation of PI3K/AKT/mTOR pathway. The current study highlights a promising dietary approach for prevention or alleviation of oxidative stress, inflammation and cognitive impairment induced by age-related conditions.

The role of GLP-1/GIP receptor agonists in Alzheimer's disease.

New glucagon-like peptide-1 (GLP-1) analogues developed in recent years have a long half-life and offer further prospects for clinical application. At present, the neuroprotection of GLP-1 analogues in Alzheimer's disease (AD) has just begun to be explored. To investigate how glucagon-like peptide-1 (liraglutide) plays a protective role in AD by regulating tau activation and BACE1 expression. Human neuroblastoma cell line SH-SY5Y cells were cultured in vitro and pretreated with different concentrations of liraglutide, and then treated with different concentrations of okadaic acid (OA) in order to observe the apoptosis of the SH-SY5Y cells. After liraglutide treatment, the apoptosis of neurons in AD rats was detected using flow cytometry, and tau activation and β-site APP cleaving enzyme 1 (BACE1) expression were detected using western blot. Different concentrations of OA were able to induce apoptosis of SH-SY5Y cells in a dose-dependent manner. Different concentrations of liraglutide were used to pretreat SH-SY5Y cells, which were able to protect the SH-SY5Y cells from apoptosis induced by OA. Okadaic acid significantly increased tau activation and BACE1 expression in the SH-SY5Y cells, which was blocked with liraglutide pretreatment. The results of a water maze experiment showed that liraglutide had significant protective effects on memory and cognitive ability in AD rats induced with OA, inhibited apoptosis of neural cells in AD rats, and inhibited tau activation and BACE1 expression of neural cells in AD rats induced with OA. Liraglutide has a protective effect on AD in vivo and in vitro, which may be mediated by preventing neuronal apoptosis and inhibiting the activation of tau and the expression of BACE1.

Effects of acorus tatarinowii Schott and alpha asarone on free radicals and nNOS/NO in hippocampus of rats with fatigue movement

To study the effects of acorus tatarinowii Schott and its active ingredient-alpha-asarone on learning and memory, free radical metabolism and nNOS/NO signal in hippocampus of rats with fatigue movement. Eighty SD male rats were randomly divided into eight groups: control group(A), exercise group(B), exercise + alpha-asarone low, middle and high dose treatment group (C, D, E), exercise + acorus tatarinowii Schott low, middle and high dose treatment group (F, G, H),with ten rats in each group. The rats in group C, D and E were administered with alpha-asarone at the doses of 0.10, 0.50 and 1.00 mg.kg-1.WT-1 by ig. The rats in group F, G and H were administered with the extracts of Acorus tatarinowii Schott of at the doses of 0.12, 1.20 and 4.80 g.kg-1.WT-1 by ig. Learning and memory of rats were tested by the method of water maze experiment, and the activities of SOD and NOS, the contents of MDA were detected by the biochemical methods, and the expression levels of nNOS protein in hippocampus of rats were tested by the method of Western blot in at the end of the experiment. The escape latency and MDA content in hippocampus of rats in groups E and H were lower than those in groups B, C, D, F and G and the numbers of Plateau crossing, SOD and NOS activities and the expression levels of nNOS protein in hippocampus of rats were higher than those in groups B, C, D, F and G(P＜0.01). The activities of SOD in hippocampus of rats in groups A, E and H were A＞E＞H, whereas the contents of MDA were opposite (P＜0.01); the activities of NOS and the expression levels of nNOS protein in hippocampus of group E were lower than those of groups A and H (P＜0.01 or P＜0.05), but there was no significant difference between groups A and H (P＞0.05). There were no significant difference in escape latency and numbers of crossing platform among groups A, E and H (P＞0.05). Acorus tatarinowii Schott and alpha-asarone can significantly improve learning and memory of rats with fatigue movement. The mechanism is related to reclaiming the imbalance of free radical metabolism and up-regulating nNOS/NO signal in hippocampus of the rats.

Mechanism and effects of fructose diphosphate on anti-hypoxia fatigue and learning memory ability.

This study aims to investigate the mechanisms through which fructose diphosphate (FDP) causes anti-hypoxia and anti-fatigue effects and improves learning and memory. Mice were divided into three groups: low-dose FDP (FDP-L), high-dose FDP (FDP-H), and a control group. Acute toxic hypoxia induced by carbon monoxide, sodium nitrite, and potassium cyanide and acute cerebral ischemic hypoxia were used to investigate the anti-hypoxia ability of FDP. The tests of rod-rotating, mouse tail suspension, and swimming endurance were used to explore the anti-fatigue effects of FDP. The Morris water maze experiment was used to determine the impact of FDP on learning and memory ability. Poisoning-induced hypoxic tests showed that mouse survival time was significantly prolonged in the FDP-L and FDP-H groups compared with the control group (p < 0.05). In the exhaustive swimming test, FDP significantly shortened struggling time and prolonged the time of mass-loaded swimming; the rod-rotating test showed that endurance time was significantly prolonged by using FDP (p < 0.05). FDP significantly decreased lactate and urea nitrogen levels and increased hepatic and muscle glycogen and glucose transporter-4 and Na+-K+-ATPase (p < 0.05). To conclude, FDP enhances hypoxia tolerance and fatigue resistance and improves learning and memory ability through regulating glucose and energy metabolism.