White matter change in an animal model of chronic cerebral hypoperfusion

Object. A new experimental model of chronic cerebral hypoperfusion was developed to study the effects of systemic arterial shunting and obstruction of the primary vessel that drains intracranial venous blood on cerebral perfusion pressure (CPP), as well as cerebral pathological changes during restoration of normal perfusion pressure. Methods. Twenty-four Sprague—Dawley rats were randomly assigned to either a sham-operated group, an arteriovenous fistula (AVF) group, or a model group (eight rats each). The animal model was readied by creating a fistula through an end-to-side anastomosis between the right distal external jugular vein (EJV) and the ispilateral common carotid artery (CCA), followed by ligation of the left vein draining the transverse sinus and bilateral external carotid arteries. Systemic mean arterial pressure (MAP), draining vein pressure (DVP), and CPP were monitored and compared among the three groups preoperatively, immediately postoperatively, and again 90 days later. Following occlusion of the fistula after a 90-day interval, blood—brain barrier (BBB) disruption and water content in the right cortical tissues of the middle cerebral artery territory were confirmed and also quantified with transmission electron microscopy. Formation of a fistula resulted in significant decreases in MAP and CPP, and a significant increase in DVP in the AVF and model groups. Ninety days later, there were still significant increases in DVP and decreases in CPP in the model group compared with the other groups (p < 0.05). Damage to the BBB and brain edema were noted in animals in the model group during restoration of normal perfusion pressure by occlusion of the fistula. Electron microscopy studies revealed cerebral vasogenic edema and/or hemorrhage in various amounts, which correlated with absent astrocytic foot processes surrounding some cerebral capillaries. Conclusions. The results demonstrated that an end-to-side anastomosis between the distal EJV and CCA can induce a decrease in CPP, whereas a further chronic state of cerebral hypoperfusion may be caused by venous outflow restriction, which is associated with perfusion pressure breakthrough. This animal model conforms to the basic hemodynamic characteristics of human cerebral arteriovenous malformations.

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Adenosine A1-Receptors Modulate mTOR Signaling to Regulate White Matter Inflammatory Lesions Induced by Chronic Cerebral Hypoperfusion

Neurochemical Research ◽

10.1007/s11064-016-2056-0 ◽

2016 ◽

Vol 41 (12) ◽

pp. 3272-3277 ◽

Cited By ~ 3

Author(s):

Pengfei Cheng ◽

Xuzheng Zuo ◽

Yifei Ren ◽

Shunjie Bai ◽

Weiju Tang ◽

...

Keyword(s):

White Matter ◽

Mtor Signaling ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion ◽

Adenosine A1 Receptors ◽

Inflammatory Lesions ◽

Adenosine A1

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Role of HMGB1 in an Animal Model of Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion

International Journal of Molecular Sciences ◽

10.3390/ijms21062176 ◽

2020 ◽

Vol 21 (6) ◽

pp. 2176 ◽

Cited By ~ 1

Author(s):

Amelia Nur Vidyanti ◽

Jia-Yu Hsieh ◽

Kun-Ju Lin ◽

Yao-Ching Fang ◽

Ismail Setyopranoto ◽

...

Keyword(s):

Animal Model ◽

Cognitive Impairment ◽

Cognitive Decline ◽

Chronic Phase ◽

Vascular Cognitive Impairment ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion ◽

Hippocampal Atrophy ◽

Tnf Α

The pathophysiology of vascular cognitive impairment (VCI) is associated with chronic cerebral hypoperfusion (CCH). Increased high-mobility group box protein 1 (HMGB1), a nonhistone protein involved in injury and inflammation, has been established in the acute phase of CCH. However, the role of HMGB1 in the chronic phase of CCH remains unclear. We developed a novel animal model of CCH with a modified bilateral common carotid artery occlusion (BCCAO) in C57BL/6 mice. Cerebral blood flow (CBF) reduction, the expression of HMGB1 and its proinflammatory cytokines (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-1β, and IL-6), and brain pathology were assessed. Furthermore, we evaluated the effect of HMGB1 suppression through bilateral intrahippocampus injection with the CRISPR/Cas9 knockout plasmid. Three months after CCH induction, CBF decreased to 30–50% with significant cognitive decline in BCCAO mice. The 7T-aMRI showed hippocampal atrophy, but amyloid positron imaging tomography showed nonsignificant amyloid-beta accumulation. Increased levels of HMGB1, TNF-α, IL-1β, and IL-6 were observed 3 months after BCCAO. HMGB1 suppression with CRISPR/Cas9 knockout plasmid restored TNF-α, IL-1β, and IL-6 and attenuated hippocampal atrophy and cognitive decline. We believe that HMGB1 plays a pivotal role in CCH-induced VCI pathophysiology and can be a potential therapeutic target of VCI.

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The Effects of Astrocyte and Oligodendrocyte Lineage Cell Interaction on White Matter Injury under Chronic Cerebral Hypoperfusion

Neuroscience ◽

10.1016/j.neuroscience.2019.03.004 ◽

2019 ◽

Vol 406 ◽

pp. 167-175 ◽

Cited By ~ 7

Author(s):

Shunsuke Magami ◽

Nobukazu Miyamoto ◽

Yuji Ueno ◽

Kenichiro Hira ◽

Ryota Tanaka ◽

...

Keyword(s):

White Matter ◽

Cell Interaction ◽

Chronic Cerebral Hypoperfusion ◽

White Matter Injury ◽

Cerebral Hypoperfusion

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200107000-00008 ◽

2001 ◽

Vol 21 (7) ◽

pp. 828-834 ◽

Cited By ~ 71

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.

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