scholarly journals Shikonin Attenuates Chronic Cerebral Hypoperfusion-Induced Cognitive Impairment by Inhibiting Apoptosis via PTEN/Akt/CREB/BDNF Signaling

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Yanqiu Jia ◽  
Zhe Li ◽  
Tianjun Wang ◽  
Mingyue Fan ◽  
Jiaxi Song ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Signaling Pathway ◽  
Hippocampal Neurons ◽  
Sham Group ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Vehicle Group ◽  
Nissl Staining ◽  
Bdnf Signaling

Shikonin (SK) exerts neuroprotective effects; however, to date, its protective effect against chronic cerebral hypoperfusion- (CCH-) induced vascular dementia (VaD) has not been investigated. Therefore, the current study investigated whether SK could mitigate the cognitive deficits caused by CCH. The effects of SK treatment on the PTEN/Akt/CREB/BDNF signaling pathway and apoptosis in hippocampal neurons were examined in a rat model of VaD established via bilateral common carotid artery occlusion (BCCAO). Fifty-two rats were randomly divided into 4 groups: sham, vehicle, SK-L (10 mg/kg SK per day), and SK-H (25 mg/kg SK per day). SK was regularly administered by gavage for 2 weeks. The results of the water maze test revealed that the escape latency in the vehicle group was significantly longer than that in the sham group, and rats in the vehicle group spent a smaller proportion of time in the target quadrant than those in the sham group. SK treatment reduced the escape latencies and increased the proportion of time spent in the target quadrant. Nissl staining showed morphological damage in the CA1 areas of the hippocampus in the vehicle group. SK treatment alleviated the injuries to hippocampal neurons. Western blot analysis showed higher p-PTEN and lower p-Akt, p-CREB, and BDNF expression in the vehicle group than in the sham group. SK administration reversed the upregulation of p-PTEN and the downregulation of p-Akt, p-CREB, and BDNF. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling- (TUNEL-) positive cells in the hippocampal CA1 region of the vehicle group was significantly increased. Treatment with SK decreased the number of positive cells. Furthermore, as marker proteins of apoptosis, bcl-2 expression was decreased and bax expression was increased; thus, the ratio of bcl-2/bax was decreased in the vehicle group. SK treatment upregulated the expression of bcl-2 and downregulated the expression of bax, thereby elevating the bcl-2/bax ratio. Moreover, the aforementioned effects of SK were dose-dependent. The effect of 25 mg/kg per day was more obvious than that of 10 mg/kg per day. In conclusion, SK inhibited hippocampal neuronal apoptosis to protect against CCH-induced injury by regulating the PTEN/Akt/CREB/BDNF signaling pathway, consequently improving cognitive impairment.

scholarly journals Nicotinamide Improves Cognitive Function in Mice With Chronic Cerebral Hypoperfusion

2021 ◽  
Vol 12 ◽  
Author(s):  
Bin Liu ◽  
Guifeng Zhao ◽  
Ling Jin ◽  
Jingping Shi
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Function ◽  
White Matter ◽  
Western Blotting ◽  
Blood Supply ◽  
Sham Group ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Morris Water Maze Test ◽  
White Matter Damage

Normal brain function requires steady blood supply to maintain stable energy state. When blood supply to the brain becomes suboptimal for a long period of time, chronic cerebral hypoperfusion (CCH) and a variety of brain changes may occur. CCH causes white matter injury and cognitive impairment. The present study investigated the effect of nicotinamide (NAM) on CCH-induced cognitive impairment and white matter damage in mice. Male C57Bl/6J mice aged 10–12 weeks (mean age = 11 ± 1 weeks) and weighing 24 - 29 g (mean weight = 26.5 ± 2.5 g) were randomly assigned to three groups (eight mice/group): sham group, CCH group and NAM group. Chronic cerebral hypoperfusion (CCH) was induced using standard methods. The treatment group mice received intraperitoneal injection of NAM at a dose of 200 mg/kg body weight (bwt) daily for 30 days. Learning, memory, anxiety, and depression-like behaviors were measured using Morris water maze test (MWMT), open field test (OFT), sucrose preference test (SPT), and forced swim test (FST), respectively. White matter damage and remodeling were determined via histological/ immunohistochemical analyses, and western blotting, respectively. The results showed that the time spent in target quadrant, number of crossings and escape latency were significantly lower in CCH group than in sham group, but they were significantly increased by NAM (p < 0.05). Mice in NAM group moved significantly faster and covered longer distances, when compared with those in CCH group (p < 0.05). The percentage of time spent in open arms and the number of entries to the open arms were significantly lower in CCH group than in NAM group (p < 0.05). Moreover, anhedonia and histologic scores (index of myelin injury) were significantly higher in CCH group than in sham group, but they were significantly reduced by NAM (p < 0.05). The results of immunohistochemical staining and Western blotting showed that the protein expressions of 2′, 3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase) and synaptophysin were significantly downregulated in CCH group, relative to sham group, but they were significantly upregulated by NAM (p < 0.05). These results indicate that NAM improves cognitive function in mice with CCH.

Connexin43 promotes angiogenesis through activating the HIF-1α/VEGF signaling pathway under chronic cerebral hypoperfusion

2021 ◽  
pp. 0271678X2110103
Author(s):  
Weiwei Yu ◽  
Haiqiang Jin ◽  
Wei Sun ◽  
Ding Nan ◽  
Jianwen Deng ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Signaling Pathway ◽  
Connexin 43 ◽  
Hypoxia Inducible Factor ◽  
White Matter Lesions ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Junction Protein

Chronic cerebral hypoperfusion, a major vascular contributor to vascular cognitive impairment and dementia, can exacerbate small vessel pathology. Connexin43, the most abundant gap junction protein in brain tissue, has been found to be critically involved in the pathological changes of vascular cognitive impairment and dementia caused by chronic cerebral hypoperfusion. However, the precise mechanisms underpinning its role are unclear. We established a mouse model via bilateral common carotid arteries stenosis on connexin43 heterozygous male mice and demonstrated that connexin43 improves brain blood flow recovery by mediating reparative angiogenesis under chronic cerebral hypoperfusion, which subsequently reduces the characteristic pathologies of vascular cognitive impairment and dementia including white matter lesions and irreversible neuronal injury. We additionally found that connexin43 mediates hypoxia inducible factor-1α expression and then activates the PKA signaling pathway to regulate vascular endothelial growth factor-induced angiogenesis. All the above findings were replicated in bEnd.3 cells treated with 375 µM CoCl2 in vitro. These results suggest that connexin 43 could be instrumental in developing potential therapies for vascular cognitive impairment and dementia caused by chronic cerebral hypoperfusion.

scholarly journals Dl-3-n-Butylphthalide Alleviates Hippocampal Neuron Damage in Chronic Cerebral Hypoperfusion via Regulation of the CNTF/CNTFRα/JAK2/STAT3 Signaling Pathways

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenxian Li ◽  
Di Wei ◽  
Zheng Zhu ◽  
Xiaomei Xie ◽  
Shuqin Zhan ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Signaling Pathways ◽  
Neuronal Death ◽  
Neuronal Apoptosis ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Stat3 Pathway ◽  
Stat3 Signaling

Chronic cerebral hypoperfusion (CCH) contributes to cognitive impairments, and hippocampal neuronal death is one of the key factors involved in this process. Dl-3-n-butylphthalide (D3NB) is a synthetic compound originally isolated from the seeds of Apium graveolens, which exhibits neuroprotective effects against some neurological diseases. However, the protective mechanisms of D3NB in a CCH model mimicking vascular cognitive impairment remains to be explored. We induced CCH in rats by a bilateral common carotid artery occlusion (BCCAO) operation. Animals were randomly divided into a sham-operated group, CCH 4-week group, CCH 8-week group, and the corresponding D3NB-treatment groups. Cultured primary hippocampal neurons were exposed to oxygen-glucose deprivation/reperfusion (OGD/R) to mimic CCH in vitro. We aimed to explore the effects of D3NB treatment on hippocampal neuronal death after CCH as well as its underlying molecular mechanism. We observed memory impairment and increased hippocampal neuronal apoptosis in the CCH groups, combined with inhibition of CNTF/CNTFRα/JAK2/STAT3 signaling, as compared with that of sham control rats. D3NB significantly attenuated cognitive impairment in CCH rats and decreased hippocampal neuronal apoptosis after BCCAO in vivo or OGD/R in vitro. More importantly, D3NB reversed the inhibition of CNTF/CNTFRα expression and activated the JAK2/STAT3 pathway. Additionally, JAK2/STAT3 pathway inhibitor AG490 counteracted the protective effects of D3NB in vitro. Our results suggest that D3NB could improve cognitive function after CCH and that this neuroprotective effect may be associated with reduced hippocampal neuronal apoptosis via modulation of CNTF/CNTFRα/JAK2/STAT3 signaling pathways. D3NB may be a promising therapeutic strategy for vascular cognitive impairment induced by CCH.

scholarly journals Combination of isoflurane and propofol, a means for general anesthesia in the orthopedic surgery of perioperative cerebral hypoperfusion rats to avoid cognitive impairment Anesthesia of perioperative cerebral hypoperfusion

2020 ◽  
Author(s):  
Xinyue Bu ◽  
Tang Li ◽  
Haiyun Wang ◽  
Zhengyuan Xia ◽  
Di Guo ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Function ◽  
Er Stress ◽  
General Anesthesia ◽  
Underlying Mechanism ◽  
Cerebral Hypoperfusion ◽  
Nissl Staining ◽  
Aging Rats ◽  
Biochemical Analyses ◽  
Common Carotid Arteries

Abstract Background: Perioperative cerebral hypoperfusion often occurs. However, the underlying mechanism of cognitive impairment resulting when perioperative cerebral hypoperfusion occurs remain mostly to be determined. Anesthetic isoflurane induces neuronal injury via endoplasmic reticulum (ER) stress, whereas sub-anesthetic dose of propofol improves postoperative cognitive function. However, the effects of the combination of isoflurane plus propofol, which is a common combination of anesthesia for patient, on ER stress and the associated cognitive function remain unknown. Methods: We therefore set out to determine the effects of isoflurane plus propofol on the ER stress and cognitive function in the rats insulted by cerebral hypoperfusion. A ligation of bilateral common carotid arteries (CCA) surgery was adopted to prepare rats as cerebral hypoperfusion (CH) animal model. A second surgery, open reduction and internal fixation (ORIF), requiring general anesthesia, was operated 30 days later so that the effects of anesthetics on cognitive function of these CH rats could be assessed. The rats received isoflurane alone (1.9%), propofol alone (40 mg·kg -1 ·h -1 ) or a combination of isoflurane and propofol (1% and 20 mg·kg -1 ·h -1 or 1.4% and 10 mg·kg -1 ·h -1 ). Behavior studies (Fear Conditioning test), histological analyses (Nissl staining) and biochemical analyses (western blotting for the harvested rat brain tissues) were employed in the studies. Results: We found that the combination of 1% isoflurane plus 20 mg·kg -1 ·h -1 propol did not aggravate the cognitive impairment and the ER stress in aging rats with cerebral hypoperusion and being subjected to an ORIF surgery. Conclusions: These data suggest that ER stress contributes to the underlying mechanism of cognitive impairment and the combination of isoflurane and propofol did not aggravate the cognitive impairment and the ER stress in aging rats with cerebral hypoperfusion and being subjected to an ORIF surgery.

Therapeutic Benefits of Methylene Blue on Cognitive Impairment during Chronic Cerebral Hypoperfusion

2014 ◽  
Vol 42 (s4) ◽  
pp. S525-S535 ◽  
Author(s):  
Allison Auchter ◽  
Justin Williams ◽  
Bryan Barksdale ◽  
Marie H. Monfils ◽  
Francisco Gonzalez-Lima
Keyword(s):  
Methylene Blue ◽  
Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Therapeutic Benefits

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.

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