Activation of the α2A adrenoceptor in microglia promotes LPS-induced TNF-α production and cognitive impairment in mice

2020 ◽  
Author(s):  
Ming Fang ◽  
Wen-Liang Song ◽  
Xiao-Meng Dai ◽  
Rui-Jie Wang ◽  
Hui Xu ◽  
...  
Keyword(s):  
Western Blotting ◽  
Gene Knockout ◽  
Neurological Dysfunction ◽  
Morris Water Maze Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Motor Impairments ◽  
Knock Out ◽  
Pkc Inhibitor ◽  
Elevated Plus Maze Test ◽  
Maze Test

Abstract Background: a2A adrenoceptor receptor (a2A-AR) plays an important role in inflammatory response in Kupffer cells in sepsis. Blockage of a2A-AR inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor a (TNF-a) production and protects the target organ functions in sepsis animal models; however, its expression and function in microglia have remained obscure. This study aimed to determine whether a2A-AR was expressed in microglia and whether its activation would exacerbate microglial inflammation and sepsis-related neurological dysfunction. Methods: Western blotting and immunofluorescence were used to detect a2A-AR expression in BV-2 microglia. Enzyme-linked immunosorbent assay (ELISA) was used to assess the TNF-a production in the supernatant after LPS induced BV-2 cells were pretreated with a2A-AR agonist BHT933, and/or a2A-AR antagonist BRL44408, and also in the supernatants derived from BV-2 cells treated with BHT933 and/or PKC inhibitor. Signaling pathways including JNK，P38，ERK，IκBa, CREB and PCK were detected by western blotting. a2A-AR gene knock-out (KO) and wild type (WT) mice were prepared by intraperitoneal injection of LPS. Lectin /TNF-a labeled microglia and synaptophysin/NeuN expression in the hippocampus were localized by immunofluorescence. Morris water maze test, Rotating-stick test, Elevated plus maze test and Open-field test were conducted over 4 weeks.Results: a2A-AR was constitutively expressed in BV-2 microglia, which was enhanced by LPS. Pretreatment with BHT933 promoted LPS-induced IκB and JNK phosphorylation, and TNF-a secretion in BV-2 microglia which were abrogated by BRL44408. Activation of a2A-AR by BHT933 also increased PKC phosphorylation in LPS-treated BV-2 microglia. PKC inhibitor significantly reversed the promoting effects of BHT933 on IκB and JNK phosphorylation as well as TNF-a secretion in LPS-treated BV-2 microglia. Furthermore, LPS treatment significantly increased hippocampal microglia activation and TNF-a expression, decreased hippocampal synaptophysin expression, and impaired cognitive and motor functions in WT mice, all of which were markedly reversed by a2A-AR gene knockout. Conclusion: a2A-AR activation promotes LPS-induced IκB and JNK phosphorylation as well as TNF-a production in microglia through the PKC signaling pathway. Knockout of a2A-AR gene significantly improves LPS-induced cognitive and motor impairments in mice, indicating that a2A-AR is a potential therapeutic target for sepsis-associated encephalopathy.

scholarly journals Maternal Exposure to Sevoflurane Disrupts Oligodendrocyte Myelination of the Postnatal Hippocampus and Induces Cognitive and Motor Impairments in Offspring

2021 ◽  
Author(s):  
Ze Fan ◽  
Lirong Liang ◽  
Ruixue Ma ◽  
Rougang Xie ◽  
Youyi Zhao ◽  
...  
Keyword(s):  
Motor Coordination ◽  
Maternal Exposure ◽  
Morris Water Maze Test ◽  
The Novel ◽  
Motor Impairments ◽  
Object Recognition Test ◽  
Maze Test ◽  
Transmission Electron ◽  
Proliferation And Differentiation ◽  
Oligodendrocyte Precursor

Abstract Maternal exposure to sevoflurane can impose significant neurocognitive risks on the developing brain of infants. Several studies have indicated that oligodendrocytes may be involved in sevoflurane-induced neurotoxicity, but the concrete effects of sevoflurane on the development and myelination of oligodendrocytes remain unclear. In this study, we assessed fetal myelination and neural behavior after maternal exposure to sevoflurane. Pregnant C57BL/6J mice (gestational day 15.5) were exposed to sevoflurane (2.5%) for 6 h. The cognitive function and motor coordination of offspring (8 weeks of age) were determined via the novel object recognition test, the Morris water maze test and the accelerating rotarod test. Proliferation and differentiation of cultured oligodendrocyte precursor cells (OPCs) were detected via immunocytochemistry. Expression and ultrastructure of myelin in the fetal hippocampus were analyzed using immunohistochemistry and transmission electron microscopy (TEM). Myelin-associated genes and proteins were tested via qRT-PCR, immunofluorescence and western blotting. The functionality of myelin was evaluated by electrophysiology. The results showed that maternal exposure to sevoflurane induced cognitive and motor impairments in infants, accompanied by inhibitions of OPC proliferation and differentiation, and damages of myelin structure. Myelin-associated genes and proteins (including MBP, Olig1, PDNFRα, Sox10, etc.) were downregulated. The conduction velocity of axons also declined. These results suggested that maternal exposure to sevoflurane could induce detrimental effects on cognitive and motor functions in offspring, which might be associated with disrupted myelination of oligodendrocytes in the hippocampus.

Ellagic Acid Administration Negated the Development of Streptozotocin-Induced Memory Deficit in Rats

Drug Research ◽  
2017 ◽  
Vol 67 (07) ◽  
pp. 425-431 ◽  
Author(s):  
Nitin Bansal ◽  
Pushplata Yadav ◽  
Manish Kumar
Keyword(s):  
Morris Water Maze ◽  
Cognitive Deficits ◽  
Ellagic Acid ◽  
Water Maze ◽  
Elevated Plus Maze ◽  
Morris Water Maze Test ◽  
Elevated Plus Maze Test ◽  
Maze Test ◽  
Tnf Α ◽  
Plus Maze

AbstractRampant production of pro-oxidants and inadequate antioxidant availability in brain exert oxidative stress, which in synergism with impaired glucose metabolism and inflammation leads to neurodegeneration and cognitive deficits. Ellagic acid (EGA) is a phenolic compound present in various fruits and is reported to possess robust antioxidant and anti-inflammatory properties. The present study investigated the effect of EGA administration on streptozotocin (STZ) induced dementia in rats. Bilateral intracerebroventricle (ICV) injection of STZ (3 mg/kg) was given to Wistar rats (200 g) on day 1 and 3. EGA (17.5 and 35 mg/kg) was administered orally to rats for 28 days daily. The spatial memory of rats was quantified by using Morris water maze and elevated plus maze. Brain TBARS, GSH and TNF-α were also measured. Administration of EGA prevented the induction of STZ-ICV triggered cognitive deficits as evident by a significant (p<0.05) reduction in mean escape latency during acquisition trial and increased (p<0.05) time spent in target quadrant during retrieval trial in Morris water maze test, and reduction (p<0.05) in transfer latency in elevated plus maze test. Furthermore, both the doses of EGA attenuated STZ-ICV induced rise in brain TBARS as well as TNF-α and simultaneously enhanced the GSH content. Thus, EGA ameliorated STZ-induced dementia by probably restoring the balance between cellular pro-oxidants and anti-oxidants in brain of rats.

scholarly journals High Methionine Diet-Induced Alzheimer’s Disease like Symptoms Are Accompanied by 5-Methylcytosine Elevated Levels in the Brain

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Tingting Pi ◽  
Shenjiao Wei ◽  
Yongxuan Jiang ◽  
Jing-Shan Shi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Food Intake ◽  
Amyloid Β ◽  
The Body ◽  
Morris Water Maze Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Ability Test ◽  
Maze Test ◽  
Related Proteins

Background. Excessive or insufficient intake of methionine (Met) causes neuronal dysfunction, neurodegeneration, cerebrovascular dysfunction, vascular leakage, and short-term memory loss, which result in the occurrence of Alzheimer’s disease- (AD-) like symptoms. Objective. To determine the relationship between high methionine diets (HMD) induced AD-like symptoms and 5-methylcytosine (5-mC) level. Methods. C57BL/6J mice were randomly divided into two groups: the control group (Maintain diets) and the model group (2% HMD). Mice were fed with 2% HMD for 9 weeks. Animals were weighed and food intake was recorded weekly. Open field test, nesting ability test, Y maze test, new object recognition test, and Morris water maze test were used to detect the motor, learning, and memory ability. Hematoxylin-eosin (HE) staining was used to observe the damage of cells in hippocampus and cortex. Immunofluorescence (IF) staining was used to detect the expression and distribution of amyloid-β 1-40 (Aβ1-40), amyloid-β 1-42 (Aβ1-42), and 5-methylcytosine (5-mC) in hippocampus and cortex. Western blotting (WB) was used to determine the expression of Aβ and DNA methyltransferases- (DNMTs-) related proteins in the cortex. Enzyme-linked immunosorbent assay (ELISA) was performed to detect homocysteine (Hcy) level (ELISA). Results. Feeding of HMD decreased the body weight and food intake of mice. Behavioral testing revealed that HMD caused learning, memory, and motor ability impairment in the mice. HE staining results showed that HMD feeding caused damage of hippocampal and cortical neurons, along with disordered cell arrangement, and loss of neurons. Furthermore, HMD increased the contents of Aβ1-40, Aβ1-42, and 5-mC in the hippocampus and cortex. WB results showed that HMD increased the expression of Aβ production-related proteins, such as amyloid precursor protein (APP) and beta-secretase 1 (BACE1), and decreased the expression of Aβ metabolism-related protein in the cortex, including insulin-degrading enzyme (IDE) and neprilysin (NEP). Additionally, the decreased expression of DNA methyltransferase1 (DNMT1) was observed in HMD-treated mice, but there was no significant change of DNMT3a level. ELISA results showed that HMD increased the levels of Hcy in serum. Conclusion. Our result suggested that the HMD can cause neurotoxicity, leading to AD-like symptoms in mice, which may be related to 5-mC elevated.

scholarly journals Effects of Insulin against Aluminium Induced Neurotoxicity in Wistar Rats

2020 ◽  
Vol 5 (2) ◽  
Author(s):  
MD Amir Alam ◽  
Garima Bansal
Keyword(s):  
Morris Water Maze ◽  
Water Maze ◽  
Wistar Rats ◽  
Elevated Plus Maze ◽  
Aluminium Toxicity ◽  
Morris Water Maze Test ◽  
Rotarod Test ◽  
Elevated Plus Maze Test ◽  
Maze Test ◽  
Plus Maze

Aluminium toxicity is well known to cause neurotoxicity leading to Alzheimer disease with dementia. The aim of the present study is to evaluate the effects of Insulin in Aluminium induced neurotoxicity. Thirty male wistar rats randomized into three groups (group V, C, T) of ten each were used for the study after obtaining institutional animal ethics committee approval. Chronic aluminium neurotoxicity was induced in the rats and the neurobehavior was evaluated using Morris water maze test, elevated plus maze test and rotarod test using standard methodologies. Group C rats exhibited significant deviation in performance of behavioural test of the study during day 1 (Morris water maze test- 18.6±9.5, elevated plus maze test- 34.9±1.9, rotarod test- 118.6±15.2) and day 30 (Morris water maze test- 64.5±4.6, elevated plus maze test- 72.1±3.9, rotarod test- 110.7±9.3). Rats of group T showed decrease in behavioural changes induced by aluminium toxicity (P value: Morris water maze test-0.0002, elevated plus maze test- 0.0007 and rotarod test- 0.015). Insulin may play a role in neuroprotection against toxicity similar to that of aluminium induced neurotoxicity.

Ameliorating Alzheimer’s-like pathology by Minocycline via inhibiting Cdk5/p25 signaling

2021 ◽  
Vol 19 ◽  
Author(s):  
Yu Zhao ◽  
Chuanling Wang ◽  
Wenbo He ◽  
Zhiyou Cai
Keyword(s):  
Matrix Metalloproteinases ◽  
Cognitive Deficits ◽  
Inflammatory Cytokine ◽  
Underlying Mechanism ◽  
Brain Diseases ◽  
Morris Water Maze Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Total Tau ◽  
Maze Test ◽  
Improved Learning

Background: Minocycline has multiple neuroprotective roles in abundant brain diseases, including the prevention and treatment of Alzheimer’s disease (AD). Cdk5/p25 signaling plays an important role in the onset and development of Alzheimer’s-like pathology. The aim of the present work was to further explore the underlying mechanism which minocycline effects on Cdk5/p25 signaling related to the Alzheimer’s-like pathology. Methods: The cognitive function of animals was measured by the Morris water maze test. The levels of Aβ were determined by enzyme-linked immunosorbent assay. The levels of APP, β- and γ-secretases; and the biomarkers of tau (total tau and hyperphosphorylated tau), inflammatory cytokine and matrix metalloproteinases (MMP-2 and MMP-9), biomarkers of synapse and Cdk5/p25 signaling were detected by Western blotting. The biomarkers of synapse, inflammatory cytokine and matrix metalloproteinases (MMP-2 and MMP-9) were also determined by immunofluorescence. Results: Minocycline improved learning and memory in APP/PS1 mice. Minocycline limits the production of Aβ and hyperphosphorylation of tau in the hippocampus, and ameliorates synaptic deficit while minocycline inhibits the activation of Cdk5/p25 signaling, inflammation and activation of matrix metalloproteinases. Conclusion: Minocycline mitigates Alzheimer’s-like pathology via limiting the activation of Cdk5/p25 signaling pathway and improves cognitive deficits.

scholarly journals Danggui-Shaoyao-San, a Traditional Chinese Medicine, Relieved Depression and Cognitive Disorder Induced by Chronic Restraint Stress Involved in Regulating Dendritic Spines Remodeling

2017 ◽  
Author(s):  
Kecheng Zhou ◽  
Junbin Yin ◽  
Huanghui Wu ◽  
Wei Hu ◽  
Zhen Gao ◽  
...  
Keyword(s):  
Learning And Memory ◽  
Neural Plasticity ◽  
Restraint Stress ◽  
Cognitive Disorder ◽  
Morris Water Maze Test ◽  
Chronic Restraint Stress ◽  
Elevated Plus Maze Test ◽  
Maze Test ◽  
Treatment Dose ◽  
Mushroom Spines

Background: Clinical trails have revealed that patients with depression generally accompanied with learning and memory impairment, which critically impact on individual&rsquo;s health and development. Danggui-Shaoyao-San (DSS), a famous Chinese complex prescription, significantly overcame depression and relieved cognitive disorder based on previous research and publication. However, its effectsand potential mechanism against chronic restraint stress (CRS) remained unknown. Methods: CRS animal model was established and mice were divided to six groups while they were oral administrated with Danggui-Shaoyao-San at doses of 1.25, 2.5 and 5 g/kg for 14 days. Emotional and cognitive performances were detected by behavior tests, meanwhile neural plasticity and its molecular mechanism were examined by Dil staining, western blot and immunofluorescence. Results: DSS treatment dose-dependently improved locomotion ability in open filed test, overcame depression behavior in forced swimming test and elevated plus maze test, enhanced learning and memory ability in Morris water maze test. CRS decreased number of total spines and mushroom spines, while DSS treatment dose-dependently restored these by Dil staining. Expression of BDNF and GluR1 were significantly down-regulated in CRS group, which were significantly normalized by DSS. Conclusions: DSS treatment dose-dependently reversed CRS-induced cognitive impairments by inducing structural remodeling of neurons.

Berberine Alleviates Amyloid-beta Pathogenesis Via Activating LKB1/AMPK Signaling in the Brain of APP/PS1 Transgenic Mice

2019 ◽  
Vol 19 (5) ◽  
pp. 342-348 ◽  
Author(s):  
Zhi-You Cai ◽  
Chuan-Ling Wang ◽  
Tao-Tao Lu ◽  
Wen-Ming Yang
Keyword(s):  
Transgenic Mice ◽  
Western Blotting ◽  
Amyloid Β ◽  
Adenosine Monophosphate ◽  
Camp Response Element Binding ◽  
Enzyme Linked Immunosorbent Assay ◽  
Synaptic Density ◽  
Ampk Signaling ◽  
The Brain ◽  
Post Synaptic Density

Background:Liver kinase B1 (LKB1)/5’-adenosine monophosphate-activated protein kinase (AMPK) signaling, a metabolic checkpoint, plays a neuro-protective role in the pathogenesis of Alzheimer’s disease (AD). Amyloid-β (Aβ) acts as a classical biomarker of AD. The aim of the present study was to explore whether berberine (BBR) activates LKB1/AMPK signaling and ameliorates Aβ pathology.Methods:The Aβ levels were detected using enzyme-linked immunosorbent assay and immunohistochemistry. The following biomarkers were measured by Western blotting: phosphorylated (p-) LKB1 (Ser334 and Thr189), p-AMPK (AMPKα and AMPKβ1), synaptophysin, post-synaptic density protein 95 and p-cAMP-response element binding protein (p-CREB). The glial fibrillary acidic protein (GFAP) was determined using Western blotting and immunohistochemistry.Results:BBR inhibited Aβ expression in the brain of APP/PS1 mice. There was a strong up-regulation of both p-LKB1 (Ser334 and Thr189) and p-AMPK (AMPKα and AMPKβ1) in the brains of APP/PS1 transgenic mice after BBR-treatment (P<0.01). BBR promoted the expression of synaptophysin, post-synaptic density protein 95 and p-CREB(Ser133) in the AD brain, compared with the model mice.Conclusion:BBR alleviates Aβ pathogenesis and rescues synapse damage via activating LKB1/AMPK signaling in the brain of APP/PS1 transgenic mice.

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.

Anticonvulsant, Anxiolytic and Antidepressant Properties of the β-caryophyllene in Swiss Mice: Involvement of Benzodiazepine-GABAAergic, Serotonergic and Nitrergic Systems

2020 ◽  
Vol 14 (1) ◽  
pp. 36-51 ◽  
Author(s):  
George L. da Silva Oliveira ◽  
José C. Correia L. da Silva ◽  
Ana P. dos Santos C. L da Silva ◽  
Chistiane M. Feitosa ◽  
Fernanda R. de Castro Almeida
Keyword(s):  
Receptor Antagonist ◽  
Molecular Mechanisms ◽  
Elevated Plus Maze ◽  
Feeding Test ◽  
Swiss Mice ◽  
Elevated Plus Maze Test ◽  
Maze Test ◽  
Plus Maze ◽  
Gabaergic Receptors ◽  
Pre Treatment

Background: Central nervous system disorders such as anxiety, depression and epilepsy are characterized by sharing several molecular mechanisms in common and the involvement of the L-arginine/NO pathway in neurobehavioral studies with β-caryophyllene is still little discussed. Objectives: One of the objectives of the present study was to demonstrate the anxiolytic behavioral effect of β-caryophyllene (β-CBP) in female Swiss mice, as well as to investigate the molecular mechanisms underlying the results obtained. Methods: This study evaluated the neurobehavioral effects of β-CBP using the open field test, rota-rod test, elevated plus maze test, novelty suppressed feeding test, tail suspension test and forced swim test, as well as pilocarpine, pentylenetetrazole and isoniazid-induced epileptic seizure models. Results:: The results demonstrated that the neuropharmacological activities of β-CBP may involve benzodiazepine/GABAergic receptors, since the pre-treatment of β-CBP (200 mg/kg) associated with flumazenil (5 mg/kg, benzodiazepine receptor antagonist) and bicuculline (1 mg/kg, selective GABAA receptor antagonist) reestablished the anxiety parameters in the elevated plus-maze test, as well as the results of reduced latency to consume food in the novelty suppressed feeding test. In addition to benzodiazepine/GABAergic receptors, the neuropharmacological properties of β-CBP may be related to inhibition of nitric oxide synthesis, since pre-treatment with L-arginine (500- 750 mg/kg) reversed significantly the anxiolytic, antidepressant and anticonvulsant activities of β-CBP. Conclusion: The results obtained provide additional support in understanding the neuromolecular mechanisms underlying the anxiolytic, antidepressant and anticonvulsive properties of β-CBP in female Swiss mice.

Sign in / Sign up

Export Citation Format

Share Document