scholarly journals Tilianin Ameliorates Cognitive Dysfunction and Neuronal Damage in Rats with Vascular Dementia via p-CaMKII/ERK/CREB and ox-CaMKII-Dependent MAPK/NF-κB Pathways

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Hailun Jiang ◽  
Ghulam Md Ashraf ◽  
Mimin Liu ◽  
Kaiyue Zhao ◽  
Yu Wang ◽  
...  
Keyword(s):  
Vascular Dementia ◽  
Neuronal Damage ◽  
Neuroprotective Effect ◽  
Glucose Deprivation ◽  
Long Term Memory ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Vessel Occlusion ◽  
Neuronal Viability ◽  
Human Neurons

Vascular dementia (VaD) is a common cause of cognitive decline and dementia of vascular origin, but the precise pathological mechanisms are unknown, and so effective clinical treatments have not been established. Tilianin, the principal active compound of total flavonoid extract from Dracocephalum moldavica L., is a candidate therapy for cardio-cerebrovascular diseases in China. However, its potential in the treatment of VaD is unclear. The present study is aimed at investigating the protective effects of tilianin on VaD and exploring the underlying mechanism of the action. A model of VaD was established by permanent 2-vessel occlusion (2VO) in rats. Human neurons (hNCs) differentiated from human-induced pluripotent stem cells were used to establish an oxygen-glucose deprivation (OGD) model. The therapeutic effects and potential mechanisms of tilianin were identified using behavioral tests, histochemistry, and multiple molecular biology techniques such as Western blot analysis and gene silencing. The results demonstrated that tilianin modified spatial cognitive impairment, neurodegeneration, oxidation, and apoptosis in rats with VaD and protected hNCs against OGD by increasing cell viability and decreasing apoptosis rates. A study of the mechanism indicated that tilianin restored p-CaMKII/ERK1/2/CREB signaling in the hippocampus, maintaining hippocampus-independent memory. In addition, tilianin inhibited an ox-CaMKII/p38 MAPK/JNK/NF-κB associated inflammatory response caused by cerebral oxidative stress imbalance in rats with VaD. Furthermore, specific CaMKIIα siRNA action revealed that tilianin-exerted neuroprotection involved increase of neuronal viability, inhibition of apoptosis, and suppression of inflammation, which was dependent on CaMKIIα. In conclusion, the results suggested the neuroprotective effect of tilianin in VaD and the potential mechanism associated with dysfunction in the regulation of p-CaMKII-mediated long-term memory and oxidation and inflammation involved with ox-CaMKII, which may lay the foundation for clinical trials of tilianin for the treatment of VaD in the future.

scholarly journals Hwangryunhaedok-Tang Exerts Neuropreventive Effect on Memory Impairment by Reducing Cholinergic System Dysfunction and Inflammatory Response in a Vascular Dementia Rat Model

Molecules ◽  
2019 ◽  
Vol 24 (2) ◽  
pp. 343 ◽  
Author(s):  
Eunjin Sohn ◽  
Yu Kim ◽  
Hye-Sun Lim ◽  
Bu-Yeo Kim ◽  
Soo-Jin Jeong
Keyword(s):  
Vascular Dementia ◽  
Rat Model ◽  
Memory Impairment ◽  
Neuronal Damage ◽  
Inflammatory Diseases ◽  
Ethanol Extract ◽  
Mitogen Activated Protein Kinase ◽  
Therapeutic Effects ◽  
Sprague Dawley ◽  
Cholinergic Dysfunction

Hwangryunhaedok-tang (HRT) is a traditional oriental herbal formula used in Asian countries for treating inflammatory diseases and controlling fever. Our present study aimed to determine whether HRT has therapeutic effects for patients with vascular dementia (VaD) using a bilateral common carotid artery occlusion (BCCAO) rat model and assessing spatial memory impairment and activation of neuroinflammation. BCCAO was performed in male Sprague Dawley rats to induce VaD, and oral HRT was administered daily for 30 d. Our data showed that HRT ameliorated BCCAO-induced memory and cognitive impairment in behavioral tests. In addition, HRT reversed cholinergic dysfunction and neuronal damage in the hippocampus of BCCAO rats. Furthermore, HRT attenuated microglial activation and reduced the phosphorylation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase (JNK) induced by BCCAO. Simultaneous high-performance liquid chromatography analysis of HRT using index compounds from the herbal composition revealed that both HRT ethanol extract and commercial HRT granules primarily comprise geniposide, baicalin, and berberine. Our study showed that HRT administration resulted in the prevention of neuronal injury induced by BCCAO through improvement of cholinergic dysfunction and inhibition of neuroinflammatory responses, suggesting that HRT may have potential as a treatment for VaD.

scholarly journals STUDY ON THE SYNTHESIS OF PUERARIN DERIVATIVES AND THEIR ANTI-VASCULAR DEMENTIA ACTIVITY

2016 ◽  
Vol 8 (2) ◽  
pp. 11
Author(s):  
Pei Jiang
Keyword(s):  
Vascular Dementia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cyclooxygenase 2 ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
H Nmr ◽  
Cox 2 ◽  
Oxide Synthase

<p class="lead">In this study, puerarin derivatives were designed by adding an active acetonitrile group that inhibits cyclooxygenase-2 (COX-2) in order to enhance the anti-vascular dementia drug activity. The acetonitrile group was linked to puerarin at the 7/4 'positions by a phenolic hydroxyl to give 7-mono-and 7, 4' di-substituted derivatives of puerarin. These structures were confirmed by <sup>1</sup>H NMR spectroscopy and MS spectroscopy. We compared the affinity of puerarin derivatives and puerarin for cyclooxygenase-2 (COX-2) using molecular docking. In addition, the anti-vascular dementia activity of the developed puerarin derivatives was studied by water maze, novel object recognition, and the determination of inducible nitric oxide synthase (iNOS) enzyme activity at the cerebral cortex of mice. Experimental results showed that the puerarin derivatives have a good affinity for COX-2 with therapeutic effects against vascular dementia. The results of this study suggest that the protective effects of the puerarin derivatives against vascular dementia may be related to suppression of inflammation associated with ischemia-reperfusion injury through inhibition of COX-2.</p>

scholarly journals Resveratrol Promotes Mitochondrial Biogenesis and Protects against Seizure-Induced Neuronal Cell Damage in the Hippocampus Following Status Epilepticus by Activation of the PGC-1α Signaling Pathway

2019 ◽  
Vol 20 (4) ◽  
pp. 998 ◽  
Author(s):  
Yao-Chung Chuang ◽  
Shang-Der Chen ◽  
Chung-Yao Hsu ◽  
Shu-Fang Chen ◽  
Nai-Ching Chen ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Signaling Pathway ◽  
Mitochondrial Biogenesis ◽  
Neuronal Damage ◽  
Cell Damage ◽  
Neuroprotective Effect ◽  
Neuronal Cell ◽  
Protective Mechanism ◽  
Protective Effects ◽  
Prolonged Seizure

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is known to regulate mitochondrial biogenesis. Resveratrol is present in a variety of plants, including the skin of grapes, blueberries, raspberries, mulberries, and peanuts. It has been shown to offer protective effects against a number of cardiovascular and neurodegenerative diseases, stroke, and epilepsy. This study examined the neuroprotective effect of resveratrol on mitochondrial biogenesis in the hippocampus following experimental status epilepticus. Kainic acid was microinjected into left hippocampal CA3 in Sprague Dawley rats to induce bilateral prolonged seizure activity. PGC-1α expression and related mitochondrial biogenesis were investigated. Amounts of nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (Tfam), cytochrome c oxidase 1 (COX1), and mitochondrial DNA (mtDNA) were measured to evaluate the extent of mitochondrial biogenesis. Increased PGC-1α and mitochondrial biogenesis machinery after prolonged seizure were found in CA3. Resveratrol increased expression of PGC-1α, NRF1, and Tfam, NRF1 binding activity, COX1 level, and mtDNA amount. In addition, resveratrol reduced activated caspase-3 activity and attenuated neuronal cell damage in the hippocampus following status epilepticus. These results suggest that resveratrol plays a pivotal role in the mitochondrial biogenesis machinery that may provide a protective mechanism counteracting seizure-induced neuronal damage by activation of the PGC-1α signaling pathway.

scholarly journals DHEA Attenuates Microglial Activation via Induction of JMJD3 in Experimental Subarachnoid Haemorrhage

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Tao Tao ◽  
Guang-Jie Liu ◽  
Xuan Shi ◽  
Yan Zhou ◽  
Yue Lu ◽  
...  
Keyword(s):  
Subarachnoid Haemorrhage ◽  
Microglial Activation ◽  
Neuronal Damage ◽  
Neuroprotective Effect ◽  
Early Brain Injury ◽  
Protective Effects ◽  
In Vivo Models ◽  
The Brain

Abstract Background Microglia are resident immune cells in the central nervous system and central to the innate immune system. Excessive activation of microglia after subarachnoid haemorrhage (SAH) contributes greatly to early brain injury, which is responsible for poor outcomes. Dehydroepiandrosterone (DHEA), a steroid hormone enriched in the brain, has recently been found to regulate microglial activation. The purpose of this study was to address the role of DHEA in SAH. Methods We used in vivo models of endovascular perforation and in vitro models of haemoglobin exposure to illustrate the effects of DHEA on microglia in SAH. Results In experimental SAH mice, exogenous DHEA administration increased DHEA levels in the brain and modulated microglial activation. Ameliorated neuronal damage and improved neurological outcomes were also observed in the SAH mice pretreated with DHEA, suggesting neuronal protective effects of DHEA. In cultured microglia, DHEA elevated the mRNA and protein levels of Jumonji d3 (JMJD3, histone 3 demethylase) after haemoglobin exposure, downregulated the H3K27me3 level, and inhibited the transcription of proinflammatory genes. The devastating proinflammatory microglia-mediated effects on primary neurons were also attenuated by DHEA; however, specific inhibition of JMJD3 abolished the protective effects of DHEA. We next verified that DHEA-induced JMJD3 expression, at least in part, through the tropomyosin-related kinase A (TrkA)/Akt signalling pathway. Conclusions DHEA has a neuroprotective effect after SAH. Moreover, DHEA increases microglial JMJD3 expression to regulate proinflammatory/anti-inflammatory microglial activation after haemoglobin exposure, thereby suppressing inflammation.

scholarly journals Neuroprotective effects of adenosine deaminase in the striatum

2016 ◽  
Vol 36 (4) ◽  
pp. 709-720 ◽  
Author(s):  
Risa Tamura ◽  
Hiroyuki Ohta ◽  
Yasushi Satoh ◽  
Shigeaki Nonoyama ◽  
Yasuhiro Nishida ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Adenosine Deaminase ◽  
Neuronal Damage ◽  
Brain Slices ◽  
Field Potential ◽  
Glucose Deprivation ◽  
Oxygen Glucose Deprivation ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Negative Effect

Adenosine deaminase (ADA) is a ubiquitous enzyme that catabolizes adenosine and deoxyadenosine. During cerebral ischemia, extracellular adenosine levels increase acutely and adenosine deaminase catabolizes the increased levels of adenosine. Since adenosine is a known neuroprotective agent, adenosine deaminase was thought to have a negative effect during ischemia. In this study, however, we demonstrate that adenosine deaminase has substantial neuroprotective effects in the striatum, which is especially vulnerable during cerebral ischemia. We used temporary oxygen/glucose deprivation (OGD) to simulate ischemia in rat corticostriatal brain slices. We used field potentials as the primary measure of neuronal damage. For stable and efficient electrophysiological assessment, we used transgenic rats expressing channelrhodopsin-2, which depolarizes neurons in response to blue light. Time courses of electrically evoked striatal field potential (eFP) and optogenetically evoked striatal field potential (optFP) were recorded during and after oxygen/glucose deprivation. The levels of both eFP and optFP decreased after 10 min of oxygen/glucose deprivation. Bath-application of 10 µg/ml adenosine deaminase during oxygen/glucose deprivation significantly attenuated the oxygen/glucose deprivation-induced reduction in levels of eFP and optFP. The number of injured cells decreased significantly, and western blot analysis indicated a significant decrease of autophagic signaling in the adenosine deaminase-treated oxygen/glucose deprivation slices. These results indicate that adenosine deaminase has protective effects in the striatum.

scholarly journals Mitochondria damaged by Oxygen Glucose Deprivation can be Restored through Activation of the PI3K/Akt Pathway and Inhibition of Calcium Influx by Amlodipine Camsylate

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hyun-Hee Park ◽  
Myung-Hoon Han ◽  
Hojin Choi ◽  
Young Joo Lee ◽  
Jae Min Kim ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Calcium Influx ◽  
Neuroprotective Effect ◽  
Glucose Deprivation ◽  
Structure And Function ◽  
Oxygen Glucose Deprivation ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Mitochondrial Structure ◽  
And Function

Abstract Amlodipine, a L-type calcium channel blocker, has been reported to have a neuroprotective effect in brain ischemia. Mitochondrial calcium overload leads to apoptosis of cells in neurologic diseases. We evaluated the neuroprotective effects of amlodipine camsylate (AC) on neural stem cells (NSCs) injured by oxygen glucose deprivation (OGD) with a focus on mitochondrial structure and function. NSCs were isolated from rodent embryonic brains. Effects of AC on cell viability, proliferation, level of free radicals, and expression of intracellular signaling proteins were assessed in OGD-injured NSCs. We also investigated the effect of AC on mitochondrial structure in NSCs under OGD by transmission electron microscopy. AC increased the viability and proliferation of NSCs. This beneficial effect of AC was achieved by strong protection of mitochondria. AC markedly enhanced the expression of mitochondrial biogenesis-related proteins and mitochondrial anti-apoptosis proteins. Together, our results indicate that AC protects OGD-injured NSCs by protecting mitochondrial structure and function. The results of the present study provide insight into the mechanisms underlying the protective effects of AC on NSCs.

scholarly journals HDAC4 and HDAC5 form a complex with DREAM that epigenetically down-regulates NCX3 gene and its pharmacological inhibition reduces neuronal stroke damage

2019 ◽  
Vol 40 (10) ◽  
pp. 2081-2097 ◽  
Author(s):  
Luigi Formisano ◽  
Giusy Laudati ◽  
Natascia Guida ◽  
Luigi Mascolo ◽  
Angelo Serani ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Histone Deacetylases ◽  
Neuronal Damage ◽  
Neuroprotective Effect ◽  
Regulatory Element ◽  
Glucose Deprivation ◽  
Histone Deacetylation ◽  
Pharmacological Inhibition ◽  
Gene And Protein Expression ◽  
Class Iia Hdacs

The histone deacetylases (HDACs)-dependent mechanisms regulating gene transcription of the Na+/Ca+ exchanger isoform 3 ( ncx3) after stroke are still unknown. Overexpression or knocking-down of HDAC4/HDAC5 down-regulates or increases, respectively, NCX3 mRNA and protein. Likewise, MC1568 (class IIa HDACs inhibitor), but not MS-275 (class I HDACs inhibitor) increased NCX3 promoter activity, gene and protein expression. Furthermore, HDAC4 and HDAC5 physically interacted with the transcription factor downstream regulatory element antagonist modulator (DREAM). As MC1568, DREAM knocking-down prevented HDAC4 and HDAC5 recruitment to the ncx3 promoter. Importantly, DREAM, HDAC4, and HDAC5 recruitment to the ncx3 gene was increased in the temporoparietal cortex of rats subjected to transient middle cerebral artery occlusion (tMCAO), with a consequent histone-deacetylation of ncx3 promoter. Conversely, the tMCAO-induced NCX3 reduction was prevented by intracerebroventricular injection of siDREAM, siHDAC4, and siHDAC5. Notably, MC1568 prevented oxygen glucose deprivation plus reoxygenation and tMCAO-induced neuronal damage, whereas its neuroprotective effect was abolished by ncx3 knockdown. Collectively, we found that: (1) DREAM/HDAC4/HDAC5 complex epigenetically down-regulates ncx3 gene transcription after stroke, and (2) pharmacological inhibition of class IIa HDACs reduces stroke-induced neurodetrimental effects.

Abstract WP113: Induced Pluripotent Stem Cells Derived Neurons Ideally Serve as a Human Stroke Model of Neuronal Damage and Neuroprotective Intervention

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Mushfiquddin Khan ◽  
Tajinder S Dhammu ◽  
Mauhamad Baarine ◽  
Avtar K Singh ◽  
Inderjit Singh
Keyword(s):  
Nitric Oxide ◽  
Neuronal Damage ◽  
Glucose Deprivation ◽  
Therapeutic Interventions ◽  
Suitable Model ◽  
Expression Levels ◽  
Human Neurons ◽  
Human Stroke ◽  
Induced Pluripotent ◽  
Calpain System

Background: Basic science research on stroke is lagging. Results from both animal and animal-derived neural cell models are, more often than not, less valid for human stroke. To address this lack of models for human stroke mechanisms, we developed induced pluripotent stem cell (iPSC)-derived human neurons and subjected them to excitotoxicity and oxygen-glucose deprivation (OGD) conditions. These conditions produced a disturbed nitric oxide (NO) metabolome similar to human stroke. A therapeutic intervention, the NO-based neuroprotective agent S-nitrosoglutathione (GSNO), was investigated for neuroprotection against excitotoxicity as well as OGD-induced neuronal nitric oxide synthase (nNOS) activation and the deleterious nNOS/peroxynitrite/calpain neurodegenerative system. Methods: The iPSC were generated using skin fibroblasts from normal adult human subjects. Neural precursor cells (NPC) were prepared using embryonic body and NPC were differentiated into neurons. Results: The differentiated iPSC neurons were positive for NeuN and β-tubulin (neuronal markers), and they responded to glutamate/NMDA-induced Ca 2+ influx. The majority of iPSC neurons (~90%) were nNOS-positive, supporting them as a suitable model for NO metabolome studies. To examine this model’s nNOS/peroxynitrite/calpain system under stroke conditions, nNOS activation (pnNOS)-dependent toxicity in the iPSC-derived neurons was observed. High expression levels were found for pnNOS Ser 1412 , 3-NT, and p25 fragment in glutamate/NMDA- and OGD-treated cells. GSNO treatment reversibly blocked glutamate/NMDA- and OGD-induced pnNOS and 3-NT expression levels. Calpain activity was also blocked. Conclusions: This study of iPSC-derived human neurons is the first of its kind to investigate excitotoxicity or OGD-mediated neurodegeneration mechanisms and therapeutic interventions under stroke conditions. The data provide evidence that the deleterious nNOS/peroxynitrite/calpain system in iPSC neurons is similar to human stroke and that GSNO treatment down regulates this deleterious system. These observations support that iPSC human neurons are a suitable model for studies on stroke-associated neurodegenerative mechanisms as well as therapeutic interventions.

scholarly journals Protective Effects and Mechanism of Hyperoside in PC12 Cells Against Oxidative Stress Injury Induced by Hydrogen Peroxide

2021 ◽  
Vol 16 (5) ◽  
pp. 1934578X2110151
Author(s):  
Yan Feng ◽  
Dongxu Wang ◽  
Qi Wang ◽  
Zhifeng Li ◽  
Shi-Lin Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Neurodegenerative Diseases ◽  
Pc12 Cells ◽  
Neuronal Damage ◽  
Neuroprotective Effect ◽  
Natural Antioxidants ◽  
Protective Effects ◽  
Stress Injury ◽  
Stress Damage

As the aging phenomenon continues to increase, the incidence of neurodegenerative diseases continues to increase annually. As one of the significant contributive factors of neurodegenerative diseases, oxidative stress damage has received extensive attention in recent years. Oxidative stress plays an important role in neuronal damage through various apoptotic mechanisms related to neurodegenerative diseases. The use of natural antioxidants to combat oxidative stress may be a useful approach in delaying disease progression. In this study, we explored the neuroprotective effect of hyperoside on rat pheochromoma (PC12) cells. Specifically, the antioxidant effect and mechanism of hyperoside in hydrogen peroxide (H2O2)-induced cellular cytotoxicity were investigated. Our results showed that hyperoside could significantly increase the survival rate of rat PC12 cells when exposed to H2O2. In addition, hyperoside regulated the expression of genes and proteins in the corresponding pathways by up-regulating the phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt), and light chain 3β (LC3B) pathways and down-regulating the nuclear factor-ᴋ-gene binding (NF-κB), Bcl2-associated X (Bax), cysteinyl aspartate specific proteinase 3 (Caspase 3), and P62 pathways, thereby inhibiting cell apoptosis. Therefore, hyperoside can effectively inhibit H2O2-induced oxidative stress damage by regulating inflammation, autophagy, and apoptosis-related pathways.

scholarly journals Effects of imperatorin on apoptosis and synaptic plasticity in vascular dementia rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ying Huang ◽  
Xiangping Liao ◽  
Huaiwei Wang ◽  
Jianghong Luo ◽  
Shanquan Zhong ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Cognitive Function ◽  
Vascular Dementia ◽  
Molecular Mechanisms ◽  
Morphological Changes ◽  
Therapeutic Effects ◽  
Active Constituent ◽  
Vessel Occlusion ◽  
Synaptic Ultrastructure ◽  
Neuron Damage

AbstractIn view of the complicated pathophysiological process of vascular dementia (VD), drugs for the clinical treatment of VD mainly target related risk factors, while drugs with excellent efficacy in cognitive function are still relatively lacking. Imperatorin (IMP), an active constituent extracted from angelica dahuricae and notopterygium Notopterygii, which has anti-inflammatory, vasodilator, anticoagulant, block calcium channel, anticonvulsant, and anti oxygen free radical injury properties. Therefore,the present study examined its effects on VD rats and the underlying molecular mechanisms, in order to provide promising therapeutic methods. VD was established by modified ligation of perpetual two-vessel occlusion (2VO). After 2VO surgery, IMP (2.5, 5, and 10 mg/kg) was administered by intraperitoneal injection for 12 consecutive weeks to evaluate therapeutic effects. Cognitive function was verified by the Morris water maze. The neuronal morphological changes were examined via Hematoxylin–Eosin staining. Real-Time PCR and Western blot were used for detecting pro- and antiapoptotic biomarkers, and the hippocampus synaptic damage was examined by Transmission electron microscope. We revealed that 2VO-induced cognitive impairment, hippocampus CA1 neuron damage, apoptosis and synaptic damage. IMP-treatment significantly improved 2VO-induced cognitive deficits and hippocampus neuron damage. Molecular analysis revealed that IMP inhibited apoptosis through the down regulation of Bax, Caspase-3 and upregulation of Bcl-2. Meanwhile, IMP-treatment markedly improved synaptic ultrastructure morphology, increased the SAZ length, PSD thickness and up-regulated PSD-95 expression. Collectively, our findings demonstrated that IMP was effective in the treatment of 2VO-induced VD via inhibiting apoptosis of hippocampus neurons and reducing the synaptic plasticity destroy.

Sign in / Sign up

Export Citation Format

Share Document