CREB Protects against Temporal Lobe Epilepsy Associated with Cognitive Impairment by Controlling Oxidative Neuronal Damage

2019 ◽  
Vol 19 (5-6) ◽  
pp. 225-237 ◽  
Author(s):  
Jihong Xing ◽  
Dongfeng Han ◽  
Dahai Xu ◽  
Xingliang Li ◽  
Lichao Sun
Keyword(s):  
Oxidative Stress ◽  
Cognitive Impairment ◽  
Temporal Lobe Epilepsy ◽  
Cognitive Dysfunction ◽  
Neuronal Apoptosis ◽  
Neuronal Damage ◽  
Primary Neurons ◽  
Mitochondrial Oxidative Stress ◽  
Memory Decline ◽  
Downstream Signaling

Background: Cognitive dysfunction as a common comorbidity of epilepsy often manifests as learning and memory impairments in patients with temporal lobe epilepsy (TLE). The pathogenetic molecular mechanisms underlying epilepsy-associated cognitive dysfunction are incompletely understood. We investigated the role of cAMP response element binding protein (CREB) and its downstream signaling pathways in the pathogenesis of cognitive impairment in mice with TLE. Methods: Plasmid vectors of CREB-specific short-hairpin RNAs and CREB cDNA were prepared and transfected into primary neurons. Neuronal apoptosis and mitochondrial oxidative stress were assessed by flow cytometry. For in vivo studies, TLE in mice was induced by pilocarpine injection, and TLE-associated memory decline was evaluated using the Morris water maze after treatment with the CREB inhibitor 666-15, with or without the mitochondria-specific antioxidant MitoQ. CREB and its downstream mediators were examined by Western blotting analysis and quantitative reverse transcription polymerase chain reaction. Results: CREB knockdown induced mitochondrial reactive oxygen species production and apoptosis in primary neurons whereas CREB overexpression brought the opposite effects. The TLE mice exhibited elevated oxidative stress and neuronal apoptosis with decreased expression of CREB and its downstream mediators including PKA, CaMKIV, arc, and c-fos. CREB inhibition exacerbated TLE-associated oxidative neuronal apoptosis and memory decline. MitoQ treatment restored the expression of CREB and its downstream mediators, and prevented TLE-associated oxidative neuronal damage and memory deficits aggravated by CREB inhibition. Conclusion: CREB plays a significant role in TLE-associated oxidative neuronal damage and memory impairment. This novel finding provides the evidence of the relationship between CREB and mitochondrial oxidative stress and cognitive dysfunction in epilepsy. Mitochondria-specific antioxidants such as MitoQ may alleviate TLE-associated cognitive dysfunction through activation of CREB and its downstream signaling pathways.

scholarly journals Effects of Lacosamide Treatment on Epileptogenesis, Neuronal Damage and Behavioral Comorbidities in a Rat Model of Temporal Lobe Epilepsy

2021 ◽  
Vol 22 (9) ◽  
pp. 4667
Author(s):  
Michaela Shishmanova-Doseva ◽  
Dimitrinka Atanasova ◽  
Yordanka Uzunova ◽  
Lyubka Yoanidu ◽  
Lyudmil Peychev ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Basolateral Amygdala ◽  
Neuronal Damage ◽  
Piriform Cortex ◽  
Preference Test ◽  
Neuroprotective Activity ◽  
Object Recognition Test ◽  
Beneficial Effects

Clinically, temporal lobe epilepsy (TLE) is the most prevalent type of partial epilepsy and often accompanied by various comorbidities. The present study aimed to evaluate the effects of chronic treatment with the antiepileptic drug (AED) lacosamide (LCM) on spontaneous motor seizures (SMS), behavioral comorbidities, oxidative stress, neuroinflammation, and neuronal damage in a model of TLE. Vehicle/LCM treatment (30 mg/kg, p.o.) was administered 3 h after the pilocarpine-induced status epilepticus (SE) and continued for up to 12 weeks in Wistar rats. Our study showed that LCM attenuated the number of SMS and corrected comorbid to epilepsy impaired motor activity, anxiety, memory, and alleviated depressive-like responses measured in the elevated plus maze, object recognition test, radial arm maze test, and sucrose preference test, respectively. This AED suppressed oxidative stress through increased superoxide dismutase activity and glutathione levels, and alleviated catalase activity and lipid peroxidation in the hippocampus. Lacosamide treatment after SE mitigated the increased levels of IL-1β and TNF-α in the hippocampus and exerted strong neuroprotection both in the dorsal and ventral hippocampus, basolateral amygdala, and partially in the piriform cortex. Our results suggest that the antioxidant, anti-inflammatory, and neuroprotective activity of LCM is an important prerequisite for its anticonvulsant and beneficial effects on SE-induced behavioral comorbidities.

Matrine Protects PC12 Cells Against Aβ25–35-Induced Cytotoxicity, Oxidative Stress, Inflammation, Neuronal Apoptosis and Cell Senescence

2021 ◽  
Vol 11 (9) ◽  
pp. 1691-1697
Author(s):  
Huanli Zhang ◽  
Zhen Zhang
Keyword(s):  
Oxidative Stress ◽  
Cell Viability ◽  
Pc12 Cells ◽  
Neuronal Apoptosis ◽  
Inflammatory Responses ◽  
Neuronal Damage ◽  
Cell Senescence ◽  
Tunel Staining ◽  
Elisa Assay ◽  
Amyloid A

Background and Objectives: Beta-amyloid (Aβ) has pivotal functions in the pathogenesis of Alzheimer’s Disease (AD). The main purpose of this study is to explore the protective role and possible mechanisms of matrine against Aβ25–35-induced neurotoxicity in PC12 cells. Materials and Methods: A vitro model that involved Aβ25–35-induced neuronal damage in PC12 cells was adopted in the present study. Cell viability and apoptosis of PC12 cells were determined by CCK-8 assay and TUNEL staining, respectively. Intracellular ROS levels were determined by DCFH-DA probe and levels of TNFα, IL-6 and IL-1β were assessed by ELISA assay. In addition, telomerase reverse transcriptase (TERT) levels were determined by ELISA assay and telomere lengths were examined by real-time quantitative PCR analysis to assess telomerase activities. Furthermore, vital proteins related to cell apoptosis and hallmarks of senescence were detected by western blot analysis. Results: Matrine (10, 20, 50 μg/ml) dose-dependently protected cell viability against Aβ25–35 cytotoxicity in PC12 cells. Meanwhile, matrine at 10, 20, 50 μg/ml markedly reduced ROS production and downregulated the levels of TNFα, IL-6 and IL-1β in Aβ25–35-injuried PC12 cells. The results also proved that matrine may restore telomerase activities and telomere lengths in Aβ25–35-injuried PC12 cells by inhibiting inflammatory responses and oxidative stress. Neuronal apoptosis induced by Aβ25–35 were reversed upon cotreatment with matrine. Moreover, matrine markedly mitigated Aβ25–35 induced cell senescence in a concentration-dependentmanner. Conclusion: Our findings demonstrated that matrine protected PC12 cells against Aβ25–35-induced cytotoxicity, oxidative stress, inflammation, neuronal apoptosis and cell senescence.

Abstract P116: Exercise Ameliorated Cognitive Impairment Through ER Stress Mitigation in Alcohol Treated Exercise Ameliorated Cognitive Impairment Through Er Stress Mitigation in Alcohol Treated C57bl/6 Male Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Akash George ◽  
Kennedy Richardson ◽  
Yuankun Zhai ◽  
Suresh C Tyagi ◽  
Neetu Tyagi
Keyword(s):  
Oxidative Stress ◽  
Cognitive Impairment ◽  
Alcohol Consumption ◽  
Er Stress ◽  
Neuronal Damage ◽  
Treated Group ◽  
Potent Inducer ◽  
Brain Functions ◽  
Y Maze ◽  
And Behavior

Alcohol consumption is a potent inducer of oxidative stress (OS). Oxidative stress cause disturbance of endoplasmic reticulum (ER) homeostasis, that triggers ER stress (ERS), cause neuronal damage in the brain. Our Previous data indicate that Alcohol consumption induces mitochondrial dysfunction and free radical production in mouse cerebral cortex. Exercise has been recommended by clinicians as a secondary protective therapy; however, its effect on brain functions through ER stress has not been fully explored. Therefore, we hypothesized that exercise improves Alcohol-induced neurodegeneration and decline in cognitive function through ER stress mitigation. To test this hypothesis, we selected 10-12 weeks old male wild-type mice (C57BL/6, WT), grouped as follows: 1) WT, 2) WT+ Alcohol, 3) WT+ Exercise, 4) WT+ Alcohol + Exercise. Mice were given an intraperitoneal injection of Alcohol (1.5g/kg BW) or saline solution every day for 8 weeks. The mice were exercised for 8 weeks on a treadmill with a controlled speed of 7 meters/min for the first week, the speed of 10 meters/min for the second week and 11 meters/min in the following weeks and a total of 330 meters every day. After each 110 meters mice were given rest of 10 minutes. Cognitive and behavior alterations were assessed by novel object recognition, Passive avoidance, and Y-maze tests. Our result showed there is a significantly impaired cognitive and behavior functions (600.00 ± 0.00 vs 480 ± 20.00, P<0.05) in Alcohol-treated group compared to WT control mice. However exercised significantly improved (0.37 ± 0.05 vs 0.63 ± 0.04 P<0.01) these functions as compared to Alcohol-treated group. Also, we observed an elevated blood pressure in the Alcohol-treated group (123.50 ± 1.17) and exercise brought that to the normal level (108.98 ± 4.47, P<0.01). In addition, the effect of exercise on neuronal survival in the Alcohol-treated mouse brain was confirmed by a decrease in by fluoro-jade C reactivity. Taken together, our results indicate a myriad of beneficiary effects of exercise over ER mitigation in Alcohol-treated mice. Furthermore, our findings suggest exercise alleviates neurodegeneration and cognitive dysfunction and thereby improving total brain function. This work was supported by NIH grant HL107640-NT

scholarly journals Pink1 protects cortical neurons from thapsigargin-induced oxidative stress and neuronal apoptosis

2015 ◽  
Vol 35 (1) ◽  
Author(s):  
Lin Li ◽  
Guo-ku Hu
Keyword(s):  
Oxidative Stress ◽  
Cortical Neurons ◽  
Neuronal Apoptosis ◽  
Physiological Role ◽  
Cultured Neurons ◽  
Mitochondrial Oxidative Stress

Pink1 (PTEN-induced kinase 1) have a physiological role in mitochondrial maintenance, suppressing mitochondrial oxidative stress, fission, and autophagy. Our findings indicated that thapsigargin induced oxidative stress and neuronal apoptosis in cultured neurons is at least partly mediated inactivation of Pink1.

scholarly journals Dexmedetomidine Alleviates Hypoxia-Induced Synaptic Loss and Cognitive Impairment via Inhibition of Microglial NOX2 Activation in the Hippocampus of Neonatal Rats

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Xiaohui Chen ◽  
Dongtai Chen ◽  
Qiang Li ◽  
Shuyan Wu ◽  
Jiahao Pan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cognitive Impairment ◽  
Hippocampal Neurons ◽  
Neuronal Damage ◽  
Neuroprotective Effect ◽  
Neurological Deficits ◽  
Neonatal Rats ◽  
Synaptic Loss ◽  
Neonatal Hypoxia ◽  
Bv2 Microglia

Background. Perinatal hypoxia is a universal cause of death and neurological deficits in neonates worldwide. Activation of microglial NADPH oxidase 2 (NOX2) leads to oxidative stress and neuroinflammation, which may contribute to hypoxic damage in the developing brain. Dexmedetomidine has been reported to exert potent neuroprotection in several neurological diseases, but the mechanism remains unclear. We investigated whether dexmedetomidine acts through microglial NOX2 to reduce neonatal hypoxic brain damage. Methods. The potential role of microglial NOX2 in dexmedetomidine-mediated alleviation of hypoxic damage was evaluated in cultured BV2 microglia and neonatal rats subjected to hypoxia. In vivo, neonatal rats received dexmedetomidine (25 μg/kg, i.p.) 30 min before or immediately after hypoxia (5% O2, 2 h). Apocynin-mediated NOX inhibition and lentivirus-mediated NOX2 overexpression were applied to further assess the involvement of microglial NOX2 activation. Results. Pre- or posttreatment with dexmedetomidine alleviated hypoxia-induced cognitive impairment, restored damaged synapses, and increased postsynaptic density-95 and synaptophysin protein expression following neonatal hypoxia. Importantly, dexmedetomidine treatment suppressed hypoxia-induced microglial NOX2 activation and subsequent oxidative stress and the neuroinflammatory response, as reflected by reduced 4-hydroxynonenal and ROS accumulation, and decreased nuclear NF-κB p65 and proinflammatory cytokine levels in cultured BV2 microglia and the developing hippocampus. In addition, treating primary hippocampal neurons with conditioned medium (CM) from hypoxia-activated BV2 microglia resulted in neuronal damage, which was alleviated by CM from dexmedetomidine-treated microglia. Moreover, the neuroprotective effect of dexmedetomidine was reversed in NOX2-overexpressing BV2 microglia and diminished in apocynin-pretreated neonatal rats. Conclusion. Dexmedetomidine targets microglial NOX2 to reduce oxidative stress and neuroinflammation and subsequently protects against hippocampal synaptic loss following neonatal hypoxia.

scholarly journals Roscovitine, a CDK5 Inhibitor, Alleviates Sevoflurane-Induced Cognitive Dysfunction via Regulation Tau/GSK3β and ERK/PPARγ/CREB Signaling

2017 ◽  
Vol 44 (2) ◽  
pp. 423-435 ◽  
Author(s):  
Jianhui Liu ◽  
Junjun Yang ◽  
Yinhua Xu ◽  
Gang Guo ◽  
Li Cai ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Dysfunction ◽  
Hippocampal Neurons ◽  
Glycogen Synthase ◽  
Neuronal Damage ◽  
Immunohistochemical Analysis ◽  
Peroxisome Proliferator ◽  
Neuroprotective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

Background/Aims: Multiple exposures to anesthesia in children may increase the risk of developing cognitive impairment. Sevoflurane is an anesthetic that is commonly used in children during surgery. Cyclin-dependent kinase (CDK) 5 is involved in the regulation of sevoflurane-induced cognitive dysfunction, but the mechanistic details remain unclear. The present study evaluated the mechanism by which CDK5 mediates sevoflurane-induced cognitive dysfunction in mice. Methods: Hippocampal neurons were isolated from postnatal day 0 C57BL/6 mouse pups. Six-day-old wild-type mice were exposed to sevoflurane and then treated with the CDK5 inhibitor roscovitine. The effects on cognitive function were evaluated with the Morris water maze and neuronal damage in the hippocampus was assessed by immunohistochemical analysis. Results: CDK5 activation increased neuronal damage by inducing Tau/glycogen synthase kinase (GSK) 3β and suppressing extracellular signal-regulated kinase (ERK)/peroxisome proliferator-activated receptor (PPAR)γ/cyclic AMP response element-binding protein (CREB) signaling following exposure to sevoflurane. CDK5 inhibition by roscovitine administration alleviated sevoflurane-induced neuronal damage and cognitive impairment. Conclusions: Inhibiting CDK5 with roscovitine has neuroprotective effects against neuronal injury and cognitive dysfunction caused by sevoflurane anesthesia that are exerted via modulation of Tau/GSK3β and ERK/PPARγ/CREB signaling.

scholarly journals Krill Oil Attenuates Cognitive Impairment by the Regulation of Oxidative Stress and Neuronal Apoptosis in an Amyloid β-Induced Alzheimer’s Disease Mouse Model

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 3942
Author(s):  
Ji Hyun Kim ◽  
Hui Wen Meng ◽  
Mei Tong He ◽  
Ji Myung Choi ◽  
Dongjun Lee ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mouse Model ◽  
Neuronal Apoptosis ◽  
Morris Water Maze Test ◽  
Krill Oil ◽  
Cognitive Improvement ◽  
The Brain

In the present study, we investigated the cognitive improvement effects and its mechanisms of krill oil (KO) in Aβ25–35-induced Alzheimer’s disease (AD) mouse model. The Aβ25–35-injected AD mouse showed memory and cognitive impairment in the behavior tests. However, the administration of KO improved novel object recognition ability and passive avoidance ability compared with Aβ25–35-injected control mice in behavior tests. In addition, KO-administered mice showed shorter latency to find the hidden platform in a Morris water maze test, indicating that KO improved learning and memory abilities. To evaluate the cognitive improvement mechanisms of KO, we measured the oxidative stress-related biomarkers and apoptosis-related protein expressions in the brain. The administration of KO inhibited oxidative stress-related biomarkers such as reactive oxygen species, malondialdehyde, and nitric oxide compared with AD control mice induced by Aβ25–35. In addition, KO-administered mice showed down-regulation of Bax/Bcl-2 ratio in the brain. Therefore, this study indicated that KO-administered mice improved cognitive function against Aβ25–35 by attenuations of neuronal oxidative stress and neuronal apoptosis. It suggests that KO might be a potential agent for prevention and treatment of AD.

Neuroprotective Effects of Salidroside Against Beta-Amyloid-Induced Cognitive Impairment in Alzheimer’s Disease Mice Through the PKC/p38MAPK Pathway

2020 ◽  
Vol 10 (2) ◽  
pp. 212-217
Author(s):  
Wei Li ◽  
Sixia Yang ◽  
Zeping Xie ◽  
Hui Lu ◽  
Junjun Ling ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Protein Expression ◽  
Cognitive Dysfunction ◽  
Neuronal Damage ◽  
Nissl Staining ◽  
Neuroprotective Effects ◽  
Neural Apoptosis ◽  
P38mapk Pathway

Alzheimer’s disease (AD) is a common neurodegenerative disease as well as the main cause of dementia. A progressive cognitive decline with age is considered as the major manifestation of AD. Amyloid beta-peptide (Aβ) is one of the primary causes leading to cognitive dysfunction in AD. Recent studies have suggested that the activation of PKC/p38MAPK pathway is related to the neurotoxicity induced by β-amyloid. Salidroside is the major active component of Rhodiola crenu-lata, has been reported with widely neuroprotective effects. The protective effects of salidroside against β-amyloid induced neural apoptosis via the MAPKs pathway has been confirmed in the vitro study. The present study aimed to investigate the neuroprotective effects of salidroside through the PKC/p38MAPK pathway in β-amyloid induced AD mice. The results by Y maze showed that salidroside improved Aβ-induced cognitive impairment. Nissl staining results showed that salidroside affected neuronal damage in hippocampus and cerebral cortex of AD mice. Western blot results revealed that salidroside enhanced protein expression of p-PKC, whereas it suppressed protein expression of p-p38MAPK, Bax and cleaved caspase-3. Thus, the present results demonstrated that salidroside ameliorated cognitive dysfunction in Aβ25–35 induced AD mice. And the effects on protein expression of p-PKC and p-p38MAPK contributed to the neuroprotective effects of salidroside against neural apoptosis in AD mice.

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