scholarly journals Metformin attenuates sepsis-induced neuronal injury and cognitive impairment

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Zhenghui Qin ◽  
Chenliang Zhou ◽  
Xiaochan Xiao ◽  
Cuiping Guo
Keyword(s):  
Cognitive Impairment ◽  
Neuronal Injury ◽  
Long Term Potentiation ◽  
Synaptic Proteins ◽  
Male Rats ◽  
Inflammatory Factors ◽  
Morris Water Maze Test ◽  
Biological Technology ◽  
High Risk Factor ◽  
Underlying Mechanisms

Abstract Background Sepsis is considered to be a high-risk factor for cognitive impairment in the brain. The purpose of our study is to explore whether sepsis causes cognitive impairment and try to evaluate the underlying mechanisms and intervention measures. Methods Here, we used cecum ligation and puncture (CLP) to simulate sepsis. Open field, Novel Objective Recognition, and Morris Water Maze Test were used to detect cognitive function, long-term potentiation was used to assess of synaptic plasticity, and molecular biological technics were used to assess synaptic proteins, ELISA kits were used to detect inflammatory factors. Metformin was injected into the lateral ventricle of SD rats, and we evaluated whether metformin alleviated CLP-mediated cognitive impairment using behavioral, electrophysiological and molecular biological technology experiments. Results Here we report hippocampal-dependent cognitive deficits and synaptic dysfunction induced by the CLP, accompanied by a significant increase in inflammatory factors. At the same time, metformin was able to improve cognitive impairment induced by CLP in adult male rats. Conclusion These findings highlight a novel pathogenic mechanism of sepsis-related cognitive impairment through activation of inflammatory factors, and these are blocked by metformin to attenuate sepsis-induced neuronal injury and cognitive impairment.

scholarly journals Tripchlorolide May Improve Spatial Cognition Dysfunction and Synaptic Plasticity after Chronic Cerebral Hypoperfusion

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Zhao-Hui Yao ◽  
Xiao-li Yao ◽  
Shao-feng Zhang ◽  
Ji-chang Hu ◽  
Yong Zhang
Keyword(s):  
Cognitive Impairment ◽  
Synaptic Plasticity ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Long Term Potentiation ◽  
Chronic Cerebral Hypoperfusion ◽  
Synaptic Proteins ◽  
Cerebral Hypoperfusion ◽  
Spatial Learning And Memory ◽  
Pathophysiological Mechanism

Chronic cerebral hypoperfusion (CCH) is a common pathophysiological mechanism that underlies cognitive decline and degenerative processes in dementia and other neurodegenerative diseases. Low cerebral blood flow (CBF) during CCH leads to disturbances in the homeostasis of hemodynamics and energy metabolism, which in turn results in oxidative stress, astroglia overactivation, and synaptic protein downregulation. These events contribute to synaptic plasticity and cognitive dysfunction after CCH. Tripchlorolide (TRC) is an herbal compound with potent neuroprotective effects. The potential of TRC to improve CCH-induced cognitive impairment has not yet been determined. In the current study, we employed behavioral techniques, electrophysiology, Western blotting, immunofluorescence, and Golgi staining to investigate the effect of TRC on spatial learning and memory impairment and on synaptic plasticity changes in rats after CCH. Our findings showed that TRC could rescue CCH-induced spatial learning and memory dysfunction and improve long-term potentiation (LTP) disorders. We also found that TRC could prevent CCH-induced reductions in N-methyl-D-aspartic acid receptor 2B, synapsin I, and postsynaptic density protein 95 levels. Moreover, TRC upregulated cAMP-response element binding protein, which is an important transcription factor for synaptic proteins. TRC also prevented the reduction in dendritic spine density that is caused by CCH. However, sham rats treated with TRC did not show any improvement in cognition. Because CCH causes disturbances in brain energy homeostasis, TRC therapy may resolve this instability by correcting a variety of cognitive-related signaling pathways. However, for the normal brain, TRC treatment led to neither disturbance nor improvement in neural plasticity. Additionally, this treatment neither impaired nor further improved cognition. In conclusion, we found that TRC can improve spatial learning and memory, enhance synaptic plasticity, upregulate the expression of some synaptic proteins, and increase the density of dendritic spines. Our findings suggest that TRC may be beneficial in the treatment of cognitive impairment induced by CCH.

scholarly journals Inhibition of MicroRNA-96 Ameliorates Cognitive Impairment and Inactivation Autophagy Following Chronic Cerebral Hypoperfusion in the Rat

2018 ◽  
Vol 49 (1) ◽  
pp. 78-86 ◽  
Author(s):  
Peifang Liu ◽  
Peijia Liu ◽  
Zhiyong Wang ◽  
Shaohong Fang ◽  
Yuting Liu ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Critical Role ◽  
Beclin 1 ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Vessel Occlusion ◽  
Protein Levels ◽  
Culture Cells ◽  
High Risk Factor ◽  
Underlying Mechanisms

Background/Aims: Chronic cerebral hypoperfusion (CCH) is a high-risk factor for vascular dementia and Alzheimer’s disease. Autophagy plays a critical role in the initiation and progression of CCH. However, the underlying mechanisms remain unclear. In this study, we identified the effect of a microRNA (miR) on autophagy under CCH. Methods: A CCH rat model was established by two-vessel occlusion (2VO). Learning and memory abilities were assessed by the Morris water maze. The protein levels of LC3, beclin-1, and mTOR were detected by western blotting and immunofluorescence assays, miR-96 expression was assessed by real-time PCR, luciferase assays were used to determine the effect of miR-96 on the 3′ untranslated region (UTR) of mTOR, and the number of autophagosomes was examined by electron microscopy. Results: The level of miR-96 was significantly increased in 2VO rats, and inhibition of miR-96 ameliorated the cognitive impairment induced by 2VO. Furthermore, the number of LC3- and beclin-1-positive autophagosomes was increased in 2VO rats, and was decreased after miR-96 antagomir injection. However, the protein level of mTOR was reduced in 2VO rats, and it was down-regulated by miR-96 overexpression and up-regulated by miR-96 inhibition in 2VO rats and primary culture cells. Moreover, the luciferase activity of the 3′-UTR of mTOR was suppressed by miR-96, which was relieved by mutation of the miR-96 binding sites. Conclusion: Our study demonstrated that miR-96 may play a key role in autophagy under CCH by regulating mTOR; therefore, miR-96 may represent a potential therapeutic target for CCH.

scholarly journals Phosphodiesterase-4D Knockdown in the Prefrontal Cortex Alleviates Memory Deficits and Synaptic Failure in Mouse Model of Alzheimer’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Yongchuan Shi ◽  
Jinpeng Lv ◽  
Ling Chen ◽  
Guojun Luo ◽  
Mengjia Tao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Prefrontal Cortex ◽  
Mouse Model ◽  
Long Term Potentiation ◽  
Synaptic Proteins ◽  
Novel Object ◽  
Model Of Alzheimer’S Disease ◽  
Synaptic Failure

Phosphodiesterase 4 (PDE4)-dependent cAMP signaling plays a crucial role in cognitive impairment associated with Alzheimer’s disease (AD). However, whether inhibition of PDE4 subtypes or their splice variants in the prefrontal cortex positively regulates synaptic plasticity and antioxidative stress, and reverses β-amyloid 1–42 (Aβ1–42, Aβ42)-induced cognitive impairment still need to be clarified. The present study determined whether and how PDE4D knockdown by microinjection of lenti-PDE4D-miRNA into the prefrontal cortex reversed Aβ1–42-induced cognitive impairment in behavioral, neurochemical, and molecular biology assays. The results suggested that PDE4D knockdown increased time to explore the novel object and decreased latency to leave the platform in novel object recognition and step-down passive avoidance tests. Further study suggested that PDE4D knockdown decreased the number of working memory errors in the eight-arm maze test. These effects were prevented by PKA inhibitor H89. The subsequent experiment suggested that inhibition of PDE4D in the prefrontal cortex rescued the long-term potentiation (LTP) and synaptic proteins’ expression; it also increased antioxidant response by increasing superoxide dismutase (SOD) and decreasing malondialdehyde (MDA) levels. PDE4D knockdown also increased phosphorylated cAMP response element-binding protein (pCREB), brain-derived neurotrophic factor (BNDF), and anti-apoptotic proteins’ expression, i.e., the ratio of Bcl-2/Bax, and decreased caspase-3 level in the prefrontal cortex. These findings extend the previous findings and support the hypothesis that RNA interference-mediated PDE4D knockdown in the prefrontal cortex ameliorated memory loss associated with synaptic failure in an AD mouse model by its antioxidant, anti-apoptotic, and neuroprotective properties.

Enriched environment alleviates post-stroke cognitive impairment through enhancing α7-nAChR expression in rats

2020 ◽  
Vol 78 (10) ◽  
pp. 603-610
Author(s):  
Mei YUAN ◽  
Xin-Xin ZHANG ◽  
Xiao-Cui FU ◽  
Xia BI
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Function ◽  
Infarct Volume ◽  
Long Term Potentiation ◽  
Enriched Environment ◽  
Morris Water Maze Test ◽  
Control Group ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Post Stroke ◽  
Α7 Nachr

ABSTRACT Background: Enriched environment (EE) is a simple and effective intervention to improve cognitive function in post-stroke cognitive impairment (PSCI), partly due to the rebalancing of the cholinergic signaling pathway in the hippocampus. α7-nicotinic acetylcholine receptor (α7-nAChR) is a cholinergic receptor whose activation inhibits inflammation and promotes the recovery of neurological function in PSCI patients. However, it is still unclear whether EE can regulate α7-nAChR and activate the cholinergic anti-inflammatory pathway (CAP) in PSCI. Objective: To investigate the effects of EE on cognitive impairment, and the role of α7-nAChR in PSCI. Methods: A PSCI rat model was induced by middle cerebral artery occlusion and reperfusion (MCAO/R) and were reared in standard environment (SE) or EE for 28d, control group with sham surgery. Cognitive function was determined by Morris water maze test. The long-term potentiation (LTP) was assessed by Electrophysiology. Histopathological methods were used to determine infarct volume, α7-nAChR expression and the cytokines and cholinergic proteins expression. Results: Compared with SE group, rats in EE group had better cognitive function, higher expression of α7-nAChR positive neurons in hippocampal CA1 region. In addition, EE attenuated unfavorable changes induced by MCAO/R in cytokines and cholinergic proteins, and also enhanced LTP promoted by nicotine and attenuated by α-BGT; but showed no significantly difference in infarct volume. Conclusions: EE markedly improves cognitive impairment and enhances neuroplasticity in PSCI rats, which may be closely related to enhancement of α7-nAChR expression.

scholarly journals Asiatic Acid Prevents Cognitive Deficits by Inhibiting Calpain Activation and Preserving Synaptic and Mitochondrial Function in Rats with Kainic Acid-Induced Seizure

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 284
Author(s):  
Cheng-Wei Lu ◽  
Tzu-Yu Lin ◽  
Tai-Long Pan ◽  
Pei-Wen Wang ◽  
Kuan-Ming Chiu ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Kainic Acid ◽  
Cognitive Deficits ◽  
Mitochondrial Function ◽  
Neuronal Damage ◽  
Synaptic Proteins ◽  
Morris Water Maze Test ◽  
Mitochondrial Morphology ◽  
Asiatic Acid ◽  
Calpain Activation

Cognitive impairment is not only associated with seizures but also reported as an adverse effect of antiepileptic drugs. Thus, new molecules that can ameliorate seizures and maintain satisfactory cognitive function should be developed. The antiepileptic potential of asiatic acid, a triterpene derived from the medicinal herb Centella asiatica, has already been demonstrated; however, its role in epilepsy-related cognitive deficits is yet to be determined. In this study, we evaluated the effects of asiatic acid on cognitive deficits in rats with kainic acid (KA)-induced seizure and explored the potential mechanisms underlying these effects. Our results revealed that asiatic acid administrated intraperitoneally 30 min prior to KA (15 mg/kg) injection ameliorated seizures and significantly improved KA-induced memory deficits, as demonstrated by the results of the Morris water maze test. In addition, asiatic acid ameliorated neuronal damage, inhibited calpain activation, and increased protein kinase B (AKT) activation in the hippocampus of KA-treated rats. Asiatic acid also increased the levels of synaptic proteins and the number of synaptic vesicles as well as attenuated mitochondrial morphology damage in the hippocampus of KA-treated rats. Furthermore, proteomic and Western blot analyses of hippocampal synaptosomes revealed that asiatic acid reversed KA-induced changes in mitochondria function-associated proteins, including lipoamide dehydrogenase, glutamate dehydrogenase 1 (GLUD1), ATP synthase (ATP5A), and mitochondrial deacetylase sirtuin-3 (SIRT3). Our data suggest that asiatic acid can prevent seizures and improve cognitive impairment in KA-treated rats by reducing hippocampal neuronal damage through the inhibition of calpain activation and the elevation of activated AKT, coupled with an increase in synaptic and mitochondrial function.

scholarly journals Banhasasim-Tang Attenuates Lipopolysaccharide-Induced Cognitive Impairment by Suppressing Neuroinflammation in Mice

Nutrients ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 2019
Author(s):  
You-Chang Oh ◽  
Yun Hee Jeong ◽  
Malk Eun Pak ◽  
Younghoon Go
Keyword(s):  
Cognitive Impairment ◽  
Neuronal Damage ◽  
Inflammatory Diseases ◽  
Memory Loss ◽  
Cognitive Disorder ◽  
Inflammatory Factors ◽  
Morris Water Maze Test ◽  
Histopathological Analysis ◽  
Activation Markers ◽  
Upper Abdomen

Banhasasim-tang (BHS) is an herbal medicine that has been widely used in East Asia to treat various symptoms associated with upper abdomen swelling. BHS has not been studied previously for neuroinflammation or cognitive disorder. Here, we use a lipopolysaccharide (LPS) model to investigate the effects and mechanisms of BHS in neuroinflammation and cognitive impairment of mice. We used a mouse model of LPS-induced cognitive impairment and neuroinflammation and examined whether administration of BHS prevents these deficits via Morris water maze test, passive avoidance test, histopathological analysis, Western blotting, and real-time reverse transcription polymerase chain reaction (RT-qPCR). We found via behavioral tests that BHS treatment effectively prevented LPS-induced memory loss and neuronal damage in mice. Histopathological analysis of mouse brains revealed that BHS inhibited LPS-induced expression of microglial and astrocyte activation markers. Furthermore, BHS inhibits the production of markers related to neurodegeneration, amyloidogenesis, and inflammation, and mRNA expression of inflammatory mediators in mouse brain tissue. Additionally, BHS pretreatment effectively inhibited generation of inflammatory factors and pathways in BV2 microglial cells stimulated by LPS. These observations indicate that BHS is effective in preventing cognitive impairment caused by neuroinflammation and has strong potential as a candidate treatment for neuronal inflammatory diseases.

scholarly journals Effect of Ginkgo biloba Extract EGb761 on Hippocampal Neuronal Injury and Carbonyl Stress of D-show="" $132#?=""Gal-Induced Aging Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Juan Li ◽  
Yi-Chang Zhang ◽  
Gang Chen
Keyword(s):  
Ginkgo Biloba ◽  
Neuronal Damage ◽  
Neuronal Injury ◽  
Telomerase Activity ◽  
Male Rats ◽  
Morris Water Maze Test ◽  
Carbonyl Stress ◽  
Ultrastructural Observation ◽  
Aging Rats ◽  
Model Control

Background. Ginkgo biloba extract is widely studied for antiaging activities, but little is known about its antiaging mechanism of protein carbonylation. In order to verify carbonyl toxification (stress) hypothesis of aging, we have investigated the effects of EGb761 on hippocampal neuronal injury and carbonyl stress of aging rats. Methods. Seventy-two Wister male rats were randomly assigned into six groups (n = 12), normal control (NC), model control (MC), vitamin E (VE, 60 mg/kg) group, EGb761 low doses (GBEL, 8.75 mg/kg), EGb761 moderate doses (GBEM, 17.5 mg/kg), and EGb761 high doses (GBEH, 35 mg/kg). Except the NC, the other groups were subject to subcutaneous administration of 0.5% D-gal (10 ml/kg/day) for 6 weeks to induce aging model. The study detected cognitive impairment in rats by Morris water maze test and the contents of superoxidase dismutase (SOD), malondialdehyde (MDA), total antioxidant capacity (T-AOC) by the related kits. The level of 4-hydroxy-2-nonenal (4-HNE) protein adducts in rat brain was detected, and the ultrastructure of hippocampus was observed. Results. The EGb761 treatment groups significantly improved the spatial learning and memory of rats. Moreover, EGb761 treatment could reduce hippocampal neuronal damage based on histopathological and ultrastructural observation. Further studies have proved that these activities are remarkably related with the reducing level of MDA, protein carbonyl and lipofuscin, and 4-HNE protein expression, as well as the increasing of SOD and T-AOC content. Furthermore, EGb761 improves telomerase activity by detecting telomerase activity in the brain of aging rats. Conclusion. Our data indicate that EGb761 is an effective agent against D-gal-induced hippocampal neuronal loss owing to its antioxidative as well as carbonyl stress properties. Meanwhile, the carbonylation hypothesis is confirmed that the high level of 4-HNE may cause age-related neurodegenerative disorders.

Effects of aging on axon terminals in the dentate molecular layer

1987 ◽  
Vol 45 ◽  
pp. 928-929
Author(s):  
K. Cullen-Dockstader ◽  
E. Fifkova
Keyword(s):  
Granule Cells ◽  
Molecular Layer ◽  
Age Groups ◽  
Long Term Potentiation ◽  
Male Rats ◽  
Perforant Path ◽  
Axon Terminals ◽  
Fischer 344 ◽  
Spatial Memory Deficit ◽  
Effects Of Aging

Normal aging results in a pronounced spatial memory deficit associated with a rapid decay of long-term potentiation at the synapses between the perforant path and spines in the medial and distal thirds of the dentate molecular layer (DML), suggesting the alteration of synaptic transmission in the dentate fascia. While the number of dentate granule cells remains unchanged, and there are no obvious pathological changes in these cells associated with increasing age, the density of their axospinous contacts has been shown to decrease. There are indications that the presynaptic element is affected by senescence before the postsynaptic element, yet little attention has been given to the fine structure of the remaining axon terminals. Therefore, we studied the axon terminals of the perforant path in the DML across three age groups.5 Male rats (Fischer 344) of each age group (3, 24 and 30 months), were perfused through the aorta.

Resveratrol Rescues Tau-Induced Cognitive Deficits and Neuropathology in a Mouse Model of Tauopathy

2019 ◽  
Vol 16 (8) ◽  
pp. 710-722 ◽  
Author(s):  
Xiao-Ying Sun ◽  
Quan-Xiu Dong ◽  
Jie Zhu ◽  
Xun Sun ◽  
Li-Fan Zhang ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Synaptic Proteins ◽  
Morris Water Maze Test ◽  
Phosphorylated Tau ◽  
Tau Pathology ◽  
Maze Test ◽  
N2a Cells ◽  
Tau Aggregation

Background: Alzheimer’s Disease (AD) is characterized by the presence of extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles assembled by the microtubuleassociated protein tau. Increasing evidence demonstrated that tau pathology played an important role in AD progression. Resveratrol (RSV) has previously proved to exert neuroprotective effect against AD by inhibiting Aβ generation and Aβ-induced neurocytotoxicity, while its effect on tau pathology is still unknown. Method: The effect of RSV on tau aggregation was measured by Thioflavin T fluorescence and Transmission electron microscope imaging. The effect of RSV on tau oligomer-induced cytotoxicity was assessed by MTT assay and the uptake of extracellular tau by N2a cells was determined by immunocytochemistry. 6-month-old male PS19 mice were treated with RSV or vehicle by oral administration (gavage) once a day for 5 weeks. The cognitive performance was determined using Morris water maze test, object recognition test and Y-maze test. The levels of phosphorylated-tau, gliosis, proinflammatory cytokines such as TNF-α and IL-1β, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunoblotting, immunostaining and ELISA, respectively. Results: RSV significantly inhibited tau aggregation and tau oligomer-induced cytotoxicity, and blocked the uptake of extracellular tau oligomers by N2a cells. When applied to PS19 mice, RSV treatment effectively rescued cognitive deficits, reducing the levels of phosphorylated tau, neuroinflammation and synapse loss in the brains of mice. Conclusion: These findings suggest that RSV has promising therapeutic potential for AD and other tauopathies.

Berberine nanoencapsulation attenuates hallmarks of scoplomine induced Alzheimer's-like disease in rats

2020 ◽  
Vol 15 ◽  
Author(s):  
Samar R. Saleh ◽  
Mariam M. Abady ◽  
Mohammed Nofal ◽  
Nashwa W. Yassa ◽  
Mohamed S. Abdel-latif ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Histopathological Examination ◽  
Memory Function ◽  
Amyloid Β ◽  
Active Pharmaceutical Ingredient ◽  
Isoquinoline Alkaloid ◽  
Drug Uptake ◽  
Male Rats ◽  
Morris Water Maze Test ◽  
Neuroprotective Effects

Background: Berberine (BBR), an isoquinoline alkaloid, acts as a multipotent active pharmaceutical ingredient to counteract several types of dementia based on its numerous pharmacological actions including antioxidant, antiinflammatory, cholesterol-lowering effect, and inhibition of Aβ production and AChE. However, BBR suffers from poor absorption, bioavailability and brain drug uptake. The present study is directed for the formulation and characterization of Chitosan BBR-nanoparticles (BBR-NPs) as well as the estimation of its neuroprotective effects against scopolamine induced cognitive impairments. Methods: BBR-NPs were formulated using ionic gelation method and tripolyphosphate was chosen as a cross linker. Nanoparticles size, zeta potential, encapsulation efficiency and releasing profile were estimated. To investigate the neuroprotective effects, adult fifty six Wistar male rats were randomly distributed into: three control groups, received saline, polyethylene glycol or chitosan- NPs respectively; induced group, received scopolamine (2 mg/ kg, i.p.) and three treated groups were orally administrated BBR (50 mg/ kg), BBR- NP (7 mg/ kg) and donepezil (2.25 mg/ kg, as positive control) followed by scopolamine injection after 40 min, daily for 4 weeks. Morris water maze test, oxidative stress parameters, cholinergic and amyloid-β processing intermediates as well as neuroplasticity markers and histopathological examination were assessed. Results: Our results showed that BBR- NPs were better than BBR and donepezil as BBR- NPs were powerful inhibitory ligands toward AChE and Aβ42 formation and significantly down regulated Tau, iNOS and BACE gene expression in rats’ hippocampus. BBR-NPs administration, at 1/6 of BBR therapeutic recommended dose, significantly improved learning and memory function. This could be accredited to the diminution of oxidative stress and amyloid-β toxicity in addition to the improvement of the neuroplasticity markers. Conclusions: The enhancing effect of BBR- NPs could be related to the enhancing of its bioavailability, absorption and brain drug uptake which need more investigation in future work.

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