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 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 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

scholarly journals Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia

2017 ◽  
Vol 131 (19) ◽  
pp. 2451-2468 ◽  
Author(s):  
Jessica Duncombe ◽  
Akihiro Kitamura ◽  
Yoshiki Hase ◽  
Masafumi Ihara ◽  
Raj N. Kalaria ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
White Matter ◽  
Small Vessel Disease ◽  
Amyloid Β ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Pathophysiological Mechanism ◽  
Rodent Models ◽  
Recent Refinement

Increasing evidence suggests that vascular risk factors contribute to neurodegeneration, cognitive impairment and dementia. While there is considerable overlap between features of vascular cognitive impairment and dementia (VCID) and Alzheimer’s disease (AD), it appears that cerebral hypoperfusion is the common underlying pathophysiological mechanism which is a major contributor to cognitive decline and degenerative processes leading to dementia. Sustained cerebral hypoperfusion is suggested to be the cause of white matter attenuation, a key feature common to both AD and dementia associated with cerebral small vessel disease (SVD). White matter changes increase the risk for stroke, dementia and disability. A major gap has been the lack of mechanistic insights into the evolution and progress of VCID. However, this gap is closing with the recent refinement of rodent models which replicate chronic cerebral hypoperfusion. In this review, we discuss the relevance and advantages of these models in elucidating the pathogenesis of VCID and explore the interplay between hypoperfusion and the deposition of amyloid β (Aβ) protein, as it relates to AD. We use examples of our recent investigations to illustrate the utility of the model in preclinical testing of candidate drugs and lifestyle factors. We propose that the use of such models is necessary for tackling the urgently needed translational gap from preclinical models to clinical treatments.

scholarly journals Deletion of B-cell translocation gene 2 (BTG2) alters the responses of glial cells in white matter to chronic cerebral hypoperfusion

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Kaoru Suzuki ◽  
Mitsuru Shinohara ◽  
Yoshihiro Uno ◽  
Yoshitaka Tashiro ◽  
Ghupurjan Gheni ◽  
...  
Keyword(s):  
White Matter ◽  
B Cell ◽  
Vascular Dementia ◽  
Glial Cells ◽  
White Matter Lesions ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Brdu Incorporation ◽  
Wild Type

Abstract Background Subcortical ischemic vascular dementia, one of the major subtypes of vascular dementia, is characterized by lacunar infarcts and white matter lesions caused by chronic cerebral hypoperfusion. In this study, we used a mouse model of bilateral common carotid artery stenosis (BCAS) to investigate the role of B-cell translocation gene 2 (BTG2), an antiproliferation gene, in the white matter glial response to chronic cerebral hypoperfusion. Methods Btg2−/− mice and littermate wild-type control mice underwent BCAS or sham operation. Behavior phenotypes were assessed by open-field test and Morris water maze test. Brain tissues were analyzed for the degree of white matter lesions and glial changes. To further confirm the effects of Btg2 deletion on proliferation of glial cells in vitro, BrdU incorporation was investigated in mixed glial cells derived from wild-type and Btg2−/− mice. Results Relative to wild-type mice with or without BCAS, BCAS-treated Btg2−/− mice exhibited elevated spontaneous locomotor activity and poorer spatial learning ability. Although the severities of white matter lesions did not significantly differ between wild-type and Btg2−/− mice after BCAS, the immunoreactivities of GFAP, a marker of astrocytes, and Mac2, a marker of activated microglia and macrophages, in the white matter of the optic tract were higher in BCAS-treated Btg2−/− mice than in BCAS-treated wild-type mice. The expression level of Gfap was also significantly elevated in BCAS-treated Btg2−/− mice. In vitro analysis showed that BrdU incorporation in mixed glial cells in response to inflammatory stimulation associated with cerebral hypoperfusion was higher in Btg2−/− mice than in wild-type mice. Conclusion BTG2 negatively regulates glial cell proliferation in response to cerebral hypoperfusion, resulting in behavioral changes.

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