Comprehensive Evaluation of White Matter Damage and Neuron Death and Whole-Transcriptome Analysis of Rats With Chronic Cerebral Hypoperfusion

Abstract

Background/Aims Chronic cerebral hypoperfusion (CCH) is induced by chronic deficit of brain perfusion, contributes to a persistent or progressive cognitive dysfunction, which is characterized by diverse neuropathological manifestations. There are currently no effective medications available. White matter damage (WMD) and cortical neuron death may be caused by CCH, which are related to cognitive impairment, while the underlying molecular mechanisms remain unclear. In the study, a database of the transcriptome level was built to determine potential biomarkers in cortex of CCH. Methods CCH was induced in male Sprague-Dawley rats by permanent occlusion of the bilateral common carotid arteries. Rats were randomly divided into three groups: Sham-operated group ( n = 24), the 4th and 8th week of CCH groups (total = 56, n = 28 for each group). Cognitive function was evaluated using the Morris water maze task. WMD and neuron damage were detected using diffusion tensor imaging and histological analysis, respectively. Western blotting analysis of various markers was used to examine neuronal death. Whole-transcriptome microarray was performed to assess mRNA, circRNA, and lncRNA expression profiles at 4th and 8th weeks after CCH. Diversified bioinformatic tools were performed to analyze and predict the key biological processes and signaling pathways of differentially expressed RNAs and co-expressed potential target genes. Co-expression networks of mRNA–circRNA–miRNA and lncRNA–mRNA were constructed. Results Compared to the sham group, cognitive impairment, disintegration of white matter, blood-brain barrier damage and neuron death were induced by CCH. Neuron death including apoptosis and necroptosis might occur in the cortex of CCH. We constructed the regulatory networks of whole-transcriptomic including differentially expressed mRNAs, circRNAs, and lncRNAs, and related biological functions and pathways involved in neurological disease, cell death and survival, energy and metabolism, et al. Our results also indicated that Cyr61 mRNA may play a role in the CCH-related cortical neuronal death. Conclusion WMD and cortical neuronal death are worthy of attention in the pathogenesis of CCH. Additionally, the present results provide potential evidence at the whole-transcription level for CCH, offering candidate biomarkers and therapeutic targets.

Recombinant Adiponectin Peptide Ameliorates Cortical Neuron Damage Induced by Chronic Cerebral Hypoperfusion by Inhibiting NF-κB Signaling and Regulating Microglial Polarization

“…The onset of CCH is in the associative cortical areas; then, it spreads throughout the brain via the neuronal network, affecting cognitive function [33]. Our previous studies also showed that CCH resulted in hypoperfusion of cortical cerebral blood flow in rats, as well as white matter fiber injury and neuron death in the cortex [7,9]. Considering cerebral white matter is comprised of nerve fibers that interconnect neurons in the cortex or the deep structures [34], pathological changes in the cerebral cortex caused by CCH could also be associated with cognitive impairment.…”

“…Unfortunately, the neurorestorative potential of the adult brain is very limited [8]. Previous studies have reported that neuronal death is the key factor for cognitive impairment in CCH [7,9,10], with CCH patients often suffering long-term neurological deficits and cognitive impairment in the process of cerebral hypoperfusion [2]. Indeed, a previous study indicated that patients with vascular cognitive impairment exhibited typical neuron loss [11].…”

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

“…The MWM test was conducted in a black and circular pool that was partially filled with water at a temperature of 23 ± 1°C. The test methods have been described previously (Li et al, 2019a , b ). All experimental rats performed four training sessions each day for five consecutive days.…”

“…The stages of CCH are mainly characterized by pathological changes, such as oxidative stress, glial cell activation, inflammatory factor release, energy metabolism disorders, abnormal neuronal electrical activity, white matter damage (Li et al, 2019a ), and hippocampal neuronal damage that result in cognitive impairment (Li et al, 2019a , b ). Neuronal death is a hallmark of cognitive disorders that are induced by CCH, especially at later stages (Chen et al, 2017 ; Li et al, 2019a , b ). These changes can also be accompanied by or lead to abnormal brain structure and function at later stages of CCH.…”

Curcumin Protects Against Cognitive Impairments in a Rat Model of Chronic Cerebral Hypoperfusion Combined with Diabetes Mellitus by Suppressing Neuroinflammation, Apoptosis, and Pyroptosis

“…At present, the potential mechanisms of CCH-induced VaD are related to hippocampal neuronal injury, white matter damage, neuroin ammation, and oxidative stress. Among these factors, neuroin ammation has recently received increased attention [12][13][14][15] . Neuroin ammation mainly occurs through the activation of microglia and subsequent production of neurotoxic pro-in ammatory cytokines, which further induce neuronal damage and even neuronal death, resulting in brain damage [16,17] .…”