Chronic cerebral hypoperfusion induces vascular plasticity and hemodynamics but also neuronal degeneration and cognitive impairment.
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ABSTRACT:
SUBMITTER: Jing Z
PROVIDER: S-EPMC4528009 | biostudies-other | 2015 Aug
REPOSITORIES: biostudies-other
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Project description:Rationale: Mitochondrial dysfunction and oxidative stress occur in vascular dementia (VaD), but the specific molecular mechanism regulating these events remains unclear. Peroxisome proliferator-activated receptor-? co-activator-1? (PGC-1?) is a master regulator for mitochondrial function. This study aims to investigate whether PGC-1? is involved in the pathophysiology of VaD. Methods: We firstly generated PGC-1? f/f Eno2-Cre mice to induce neuron-specific overexpression of PGC-1? by crossbreeding PGC-1? f/f mice with Eno2-cre mice. Then, the mice were subjected to bilateral common carotid artery stenosis to induce chronic cerebral hypoperfusion. Neurological function and hippocampal PGC-1? expression was evaluated. Next, RNA-Seq analysis and Seahorse assay were performed on the hippocampal neurons. In addition, mitochondrial antioxidants, uncoupling proteins, ROS production and the activation of glial cells were also measured. Results: Our results showed that hippocampal PGC-1? expression is down-regulated in the mouse VaD model induced by chronic cerebral hypoperfusion. In contrast, neuronal PGC-1? overexpression significantly ameliorated cognitive deficits. RNA-Seq analysis indicated that PGC-1? improved energy metabolism of neurons under hypoxic condition, and Seahorse assay confirmed that PGC-1? increases the metabolic activity of neurons. Further study demonstrated that PGC-1? boosted the expressions of mitochondrial antioxidants and uncoupling proteins (UCPs), including SOD2, Prx3, GPx1, UCP2, UCP4 and UCP5, which in turn reduced reactive oxygen species (ROS) production. Moreover, the activation of microglia and astrocytes was also found to decrease in the hippocampus. All of these changes greatly contributed to protect hippocampal neurons against ischemic insults. Conclusions: PGC-1? could suppress the excessive ROS and neuroinflammation in the hippocampus, opening up a potential therapeutic target for cognitive impairment.
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Project description:ObjectiveCurrently, most models of vascular cognitive impairment are established by occluding the carotid arteries uni- or bilaterally to reduce the cerebral blood flow mimicking chronic cerebral hypoxia. Due to the sudden blood flow interruption, a gradual narrowing of the carotid artery cannot be completely imitated. This paper aims to establish a bilateral carotid stenosis model with mild cognitive dysfunction and mild white matter changes to simulate patients with vascular predementia.MethodsAged Wistar rats (18 months old) underwent either bilateral common carotid artery stenosis (BCAS) or occlusion (BCAO) surgery or a sham operation (control group). The cerebral blood flow in the frontal cortex was measured using Doppler flowmetry. Thirty days after surgery, cognitive function impairments were determined with the Morris water maze; cerebral magnetic resonance imaging was performed to detect changes in fractional anisotropy to assess white matter injuries, and histological studies were performed.ResultsThe aged rats in the BCAS group showed a more gradual cerebral blood flow reduction and a lower mortality rate (11%) compared to rats in the BCAO group. The water maze test revealed a more marginal impairment affecting spatial learning and memory in rats with BCAS than in rats with BCAO. Diffusion tensor imaging detected white matter injuries in the hippocampus and cerebral cortex of BCAS rats. Particularly, a small portion of nerve fibers of the lateral somatosensory cortex was significantly different between rats of the BCAO and BCAS groups. In the BCAS group, the microscopic structure of the hippocampal CA1 region changed slightly after 30 days and sustained a slight mitochondrial crista crack. Fluorescence staining indicated that the number of GFAP-positive cells was increased in rat brains of the BCAS group, and this phenomenon was even more pronounced in the BCAO group. The hnRNPA2/B1 and GABAAR-α1 expression levels were significantly decreased in the hippocampus of rats with BCAS compared to those of controls.ConclusionSevere bilateral carotid stenosis induced mild cognitive dysfunction and slight structural changes in the brains of aged rats. Thus, a chronic cerebral hypoperfusion model was successfully established.
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Project description:Vascular dementia (VaD) is a progressive cognitive impairment caused by a reduced blood supply to the brain. Chronic cerebral hypoperfusion (CCH) is one cause of VaD; it induces oxidative stress, neuroinflammation, and blood-brain barrier (BBB) disruption, damaging several brain regions. Vitamin C plays a vital role in preventing oxidative stress-related diseases induced by reactive oxygen species, but it is easily oxidized and loses its antioxidant activity. To overcome this weakness, we have developed a vitamin C/DNA aptamer complex (NXP031) that increases vitamin C's antioxidant efficacy. Aptamers are short single-stranded nucleic acid polymers (DNA or RNA) that can interact with their corresponding target with high affinity. We established an animal model of VaD by permanent bilateral common carotid artery occlusion (BCCAO) in 12 week old Wistar rats. Twelve weeks after BCCAO, we injected NXP031 into the rats intraperitoneally for two weeks at moderate (200 mg/4 mg/kg) and high concentrations (200 mg/20 mg/kg). NXP031 administration alleviates cognitive impairment, microglial activity, and oxidative stress after CCH. NXP031 increased the expression of basal lamina (laminin), endothelial cell (RECA-1, PECAM-1), and pericyte (PDGFRβ); these markers maintain the BBB integrity. We found that NXP031 administration activated the Nrf2-ARE pathway and increased the expression of SOD-1 and GSTO1/2. These results suggest that this new aptamer complex, NXP031, could be a therapeutic intervention in CCH-induced VaD.
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Project description:Chronic cerebral hypoperfusion (CCH) is identified as a critical risk factor of dementia in patients with cerebrovascular disease. Xiaoshuan enteric-coated capsule (XSECC) is a compound Chinese medicine approved by Chinese State Food and Drug Administration for promoting brain remodeling and plasticity after stroke. The present study aimed to explore the potential of XSECC to improve cognitive function after CCH and further investigate the underlying mechanisms. CCH was induced by bilateral common carotid artery occlusion (BCCAO) in rats. XSECC (420 or 140 mg/kg) treatment remarkably reversed BCCAO-induced cognitive deficits. Notably, after XSECC treatment, magnetic resonance angiography combined with arterial spin labeling noninvasively demonstrated significantly improved hippocampal hemodynamics, and 18F-FDG PET/CT showed enhanced hippocampal glucose metabolism. In addition, XSECC treatment markedly alleviated neuropathologies and improved neuroplasticity in the hippocampus. More importantly, XSECC treatment facilitated axonal remodeling by regulating the phosphorylation of axonal growth related proteins including protein kinase B (AKT), glycogen synthase kinase-3β (GSK-3β) and collapsin response mediator protein-2 (CRMP2) in the hippocampus. Taken together, the present study demonstrated the beneficial role of XSECC in alleviating BCCAO-induced cognitive deficits by enhancing hippocampal glucose metabolism, hemodynamics and neuroplasticity, suggesting that XSECC could be a useful strategy in cerebral hypoperfusion state and dementia.
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Project description:BackgroundAlzheimer's disease (AD) is one of the most severe neurodegenerative diseases leading to dementia in the elderly. Cerebral atrophy and hypoperfusion are two important pathophysiological characteristics. However, it is still unknown about the area-specific causal pathways between regional gray matter atrophy, cerebral hypoperfusion, and cognitive impairment in AD patients.MethodForty-two qualified AD patients and 49 healthy controls (HC) were recruited in this study. First, we explored voxel-wise inter-group differences in gray matter volume (GMV) and arterial spin labeling (ASL) -derived cerebral blood flow (CBF). Then we explored the voxel-wise associations between GMV and Mini-Mental State Examination (MMSE) score, GMV and CBF, and CBF and MMSE to identify brain targets contributing to cognitive impairment in AD patients. Finally, a mediation analysis was applied to test the causal pathways among atrophied GMV, hypoperfusion, and cognitive impairment in AD.ResultsVoxel-wise permutation test identified that the left middle temporal gyrus (MTG) had both decreased GMV and CBF in the AD. Moreover, the GMV of this region was positively correlated with MMSE and its CBF, and CBF of this region was also positively correlated with MMSE in AD (p < 0.05, corrected). Finally, mediation analysis revealed that gray matter atrophy of left MTG drives cognitive impairment of AD via the mediation of CBF (proportion of mediation = 55.82%, β = 0.242, 95% confidence interval by bias-corrected and accelerated bootstrap: 0.082 to 0.530).ConclusionOur findings indicated suggested that left MTG is an important hub linking gray matter atrophy, hypoperfusion, and cognitive impairment for AD, and might be a potential treatment target for AD.
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Project description:ObjectivesThis study investigated the ability of immunity- and matrix- regulatory cells (IMRCs) to improve cognitive function in a rat model of vascular cognitive impairment.Materials and methodsA chronic cerebral hypoperfusion (CCH) model was established in rats via permanent bilateral occlusion of the common carotid arteries (two-vessel occlusion, 2VO). The rats then received intravenous injections of IMRCs or saline. A single injection of different doses of IMRCs (1 × 106 cells/rat, 2 × 106 cells/rat, or 4 × 106 cells/rat) was administered via tail vein 72 h after establishment of the model. To evaluate functional recovery, the rats were subjected to behavioural tests after 30 days of CCH. Imaging, western blotting, immunofluorescence staining, and quantitative real-time PCR were used to analyse neuroinflammation and white matter injury after 14 and 40 days of CCH. RNA sequencing (RNA-seq) was used to profile gene expression changes in copine 1 (CPNE1) in response to IMRCs treatment.ResultsIntravenous injection of 4 × 106 IMRCs alleviated white matter damage and ameliorated cognitive deficits in rats subjected to CCH. Immunofluorescence staining suggested that activation of microglia and astrocytes was reduced, and RNA sequencing showed that CPNE1 expression was significantly elevated following treatment with IMRCs.ConclusionsIntravenous injection of IMRCs protected against CCH-induced white matter injury and cognitive impairment inhibition of microglial activation and regulation of microglia polarization.
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Project description:Chronic cerebral hypoperfusion (CCH), featuring in most of the Alzheimer's disease spectrum, plays a detrimental role in brain amyloid-? (A?) homeostasis, cerebrovascular morbidity, and cognitive decline; therefore, early management of cerebrovascular pathology is considered to be important for intervention in the impending cognitive decline. S-nitrosoglutathione (GSNO) is an endogenous nitric oxide carrier modulating endothelial function, inflammation, and neurotransmission. Therefore, the effect of GSNO treatment on CCH-associated neurocognitive pathologies was determined in vivo by using rats with permanent bilateral common carotid artery occlusion (BCCAO), a rat model of chronic cerebral hypoperfusion. We observed that rats subjected to permanent BCCAO showed a significant decrease in learning/memory performance and increases in brain levels of A? and vascular inflammatory markers. GSNO treatment (50 ?g/kg/day for 2 months) significantly improved learning and memory performance of BCCAO rats and reduced the A? levels and ICAM-1/VCAM-1 expression in the brain. Further, in in vitro cell culture studies, GSNO treatment also decreased the cytokine-induced proinflammatory responses, such as activations of NF?B and STAT3 and expression of ICAM-1 and VCAM-1 in endothelial cells. In addition, GSNO treatment increased the endothelial and microglial A? uptake. Additionally, GSNO treatment inhibited the ?-secretase activity in primary rat neuron cell culture, thus reducing secretion of A?, suggesting GSNO mediated mechanisms in anti-inflammatory and anti-amyloidogenic activities. Taken together, these data document that systemic GSNO treatment is beneficial for improvement of cognitive decline under the conditions of chronic cerebral hypoperfusion and suggests a potential therapeutic use of GSNO for cerebral hypoperfusion associated mild cognitive impairment in Alzheimer's disease.
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