scholarly journals L-Carnitine Enhances Axonal Plasticity and Improves White-Matter Lesions after Chronic Hypoperfusion in Rat Brain

2015 ◽  
Vol 35 (3) ◽  
pp. 382-391 ◽  
Author(s):  
Yuji Ueno ◽  
Masato Koike ◽  
Yoshiaki Shimada ◽  
Hideki Shimura ◽  
Kenichiro Hira ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cognitive Impairment ◽  
White Matter ◽  
Oxidative Dna Damage ◽  
White Matter Lesions ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Axonal Plasticity ◽  
Morris Water Maze Task ◽  
Phosphorylated Akt

Chronic cerebral hypoperfusion causes white-matter lesions (WMLs) with oxidative stress and cognitive impairment. However, the biologic mechanisms that regulate axonal plasticity under chronic cerebral hypoperfusion have not been fully investigated. Here, we investigated whether L-carnitine, an antioxidant agent, enhances axonal plasticity and oligodendrocyte expression, and explored the signaling pathways that mediate axonal plasticity in a rat chronic hypoperfusion model. Adult male Wistar rats subjected to ligation of the bilateral common carotid arteries (LBCCA) were treated with or without L-carnitine. L-carnitine-treated rats exhibited significantly reduced escape latency in the Morris water maze task at 28 days after chronic hypoperfusion. Western blot analysis indicated that L-carnitine increased levels of phosphorylated high-molecular weight neurofilament (pNFH), concurrent with a reduction in phosphorylated phosphatase tensin homolog deleted on chromosome 10 (PTEN), and increased phosphorylated Akt and mammalian target of rapamycin (mTOR) at 28 days after chronic hypoperfusion. L-carnitine reduced lipid peroxidation and oxidative DNA damage, and enhanced oligodendrocyte marker expression and myelin sheath thickness after chronic hypoperfusion. L-carnitine regulates the PTEN/Akt/mTOR signaling pathway, and enhances axonal plasticity while concurrently ameliorating oxidative stress and increasing oligodendrocyte myelination of axons, thereby improving WMLs and cognitive impairment in a rat chronic hypoperfusion model.

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

2019 ◽  
Vol 13 ◽  
Author(s):  
Wenxian Li ◽  
Di Wei ◽  
Jianye Liang ◽  
Xiaomei Xie ◽  
Kangping Song ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
White Matter ◽  
Neuronal Death ◽  
Chronic Cerebral Hypoperfusion ◽  
Differentially Expressed ◽  
Cerebral Hypoperfusion ◽  
Neuron Death ◽  
White Matter Damage ◽  
Morris Water Maze Task ◽  
Whole Transcriptome

Background/AimsChronic 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.MethodsCCH 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.ResultsCompared 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.ConclusionWMD 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.

scholarly journals Leptin Receptor Deficiency Protects Mice against Chronic Cerebral Hypoperfusion-Induced Neuroinflammation and White Matter Lesions

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Yu Du ◽  
Yufei Song ◽  
Xiaojie Zhang ◽  
Yan Luo ◽  
Wenying Zou ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
White Matter ◽  
Cell Line ◽  
Leptin Receptor ◽  
White Matter Lesions ◽  
Cytokine Expression ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
M2 Microglia ◽  
Anti Inflammatory

Leptin participates in the inflammatory responses in multiple cell types and animal models. Chronic cerebral hypoperfusion (CCH) induces inflammation in the central nervous system (CNS), which acts as one of the main reasons for CCH-induced white matter lesions (WMLs). But whether leptin participates in the pathogenesis of CCH-induced WMLs remains unknown. Therefore, we performed bilateral common carotid artery stenosis (BCAS) to induce CCH on the leptin receptor- (LepR-) deficient db/db mice, aiming to evaluate the possible involvement of leptin in CCH-induced cognitive impairment, WMLs, and neuroinflammation, and further explore the effect of leptin on chronic hypoxia-induced inflammation using the BV2 microglial cell line. After four weeks of BCAS, wild-type mice showed significant working memory deficits, WMLs, activation of microglia and astrocytes, decrease in the number of oligodendrocytes, downregulation of myelin basic protein expression, and increase in the expression of TNF-α and IL-1β; however, four weeks of BCAS failed to induce significant changes in the LepR-deficient db/db mice but elevated the production of anti-inflammatory cytokines and activated the M2 microglia. We further confirmed that leptin would aggravate the hypoxia-induced proinflammatory cytokine expression in the BV2 microglia cell line. These results suggested that LepR deficiency would protect mice against the CCH-induced cognitive impairment and WMLs by inhibiting glial activation and suppressing proinflammatory responses as well as promoting anti-inflammatory cytokine expression and M2 microglia activation in the white matter.

scholarly journals Chronic Cerebral Hypoperfusion Induces MMP-2 but Not MMP-9 Expression in the Microglia and Vascular Endothelium of White Matter

2001 ◽  
Vol 21 (7) ◽  
pp. 828-834 ◽  
Author(s):  
Masafumi Ihara ◽  
Hidekazu Tomimoto ◽  
Makoto Kinoshita ◽  
Junseo Oh ◽  
Makoto Noda ◽  
...  
Keyword(s):  
White Matter ◽  
Corpus Callosum ◽  
Optic Tract ◽  
White Matter Lesions ◽  
Chronic Cerebral Hypoperfusion ◽  
Motor Dysfunction ◽  
Cerebral Hypoperfusion ◽  
Matrix Metalloproteinase 2 ◽  
Capillary Endothelial Cells ◽  
Common Carotid Arteries

White matter lesions are closely associated with cognitive impairment and motor dysfunction in the aged. To explore the pathophysiology of these lesions, the authors examined the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 in the white matter in a rat model of chronic cerebral hypoperfusion. After bilateral clipping of the common carotid arteries, myelin staining revealed demyelinating changes in the optic tract and the corpus callosum on day 7. Zymographic analyses indicated an increase in the level of MMP-2, but not MMP-9, after the hypoperfusion. Immunohistochemical analyses revealed the presence (most abundantly on day 3) of MMP-2–expressing activated microglia in the optic tract and corpus callosum. In contrast, the capillary endothelial cells expressed MMP-2 later. IgM-immunoreactive glial cells were absent in the sham-operated animals, but were present in the hypoperfused animals by day 3, reflecting the disrupted blood–brain barrier. These findings suggest that the main sources of the elevated MMP-2 were the microglia and the endothelium, and that these cells may contribute to the remodeling of the white matter myelin and microvascular beds in chronic cerebral hypoperfusion.

scholarly journals White Matter Lesions and Glial Activation in a Novel Mouse Model of Chronic Cerebral Hypoperfusion

Stroke ◽  
2004 ◽  
Vol 35 (11) ◽  
pp. 2598-2603 ◽  
Author(s):  
Masunari Shibata ◽  
Ryo Ohtani ◽  
Masafumi Ihara ◽  
Hidekazu Tomimoto
Keyword(s):  
White Matter ◽  
Mouse Model ◽  
White Matter Lesions ◽  
Glial Activation ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion
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