Chronic cerebral hypoperfusion induces white matter lesions and loss of oligodendroglia with DNA fragmentation in the rat

Abstract

Cerebrovascular white matter lesions represent an age-related neurodegenerative condition that appears as a hyperintense signal on magnetic resonance images. These lesions are frequently observed in aging, hypertension and cerebrovascular disease, and are responsible for cognitive decline and gait disorders in the elderly population. In humans, cerebrovascular white matter lesions are accompanied by apoptosis of oligodendroglia, and have been thought to be caused by chronic cerebral ischemia. In the present study, we tested whether chronic cerebral hypoperfusion induces white matter lesions and apoptosis of oligodendroglia in the rat. Doppler flow meter analysis revealed an immediate reduction of cerebral blood flow ranging from 30% to 40% of that before operation; this remained at 52-64% between 7 and 30 days after operation. Transferrin-immunoreactive oligodendroglia decreased in number and the myelin became degenerated in the medial corpus callosum at 7 days and thereafter. Using the TUNEL method, the number of cells showing DNA fragmentation increased three- to eightfold between 3 and 30 days post-surgery compared to sham-operated animals. Double labeling with TUNEL and immunohistochemistry for markers of either astroglia or oligodendroglia showed that DNA fragmentation occurred in both of these glia. Messenger RNA for caspase-3 increased approximately twofold versus the sham-operated rats between 1 and 30 days post-surgery. Immunohistochemistry revealed up-regulation of caspase-3 in the oligodendroglia of the white matter, and also in the astroglia and neurons of the gray matter. Molecules involved in apoptotic signaling such as TNF-alpha and Bax were also up-regulated in glial cells. These results indicate that chronic cerebral hypoperfusion induces white matter degeneration in association with DNA fragmentation in oligodendroglia.

Diazoxide and dimethyl sulphoxide alleviate experimental cerebral hypoperfusion-induced white matter injury in the rat brain

“…The findings of such studies have compellingly demonstrated that chronic cerebral hypop-erfusion can initiate a wide array of neuropathological white matter changes. For instance, axonal degeneration, myelin and oligodendrocyte damage, astrogliosis and microglial activation have been identified in the optic tract and the corpus callosum of rats with occluded carotid arteries [8,17,18]. Our own results emphasized the specific involvement of the optic tract in ischemic white matter damage in the rat brain, and pointed to the marked proliferation of the astrocytes and to the activation of the microglia in the region [8].…”

“…Further, these lesions have been suggested to originate from a variety of vascular causes ranging from hypertension to cerebral microinfarcts and ischemia [5,7]. To support the ischemic theory of white matter injury, experimental animal models have been employed, such as bilateral occlusion of the common carotid arteries of rats [8,17,18]. The findings of such studies have compellingly demonstrated that chronic cerebral hypop-erfusion can initiate a wide array of neuropathological white matter changes.…”

Hypoxia-Induced Neuroinflammatory White-Matter Injury Reduced by Minocycline in SHR/SP

“…Bilateral carotid occlusion in the normotensive rat results in hypoxic hypoperfusion with injury to the WM. 36 Placing a small coil around the carotid arteries of the mouse restricts blood flow, leading to WM damage. 8 However, hypertensive small vessel disease seen in SHR/SP most closely resembles the pathologic changes in VCI patients with WM disease.…”

Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1

“…Evidence is evolving that mitochondrial failure and oxidative stress play a crucial role in the axonal degeneration in MS (20,21). In animals, chronic cerebral hypoperfusion also generates white matter lesions with apoptosis of oligodendrocytes, myelin breakdown, inflammatory reactions, and gliosis, which are all pathological features of MS (22)(23)(24). Some actively demyelinating lesions in MS show histological characteristics that are similar to acute white matter ischemic lesions, with a preferential loss of myelin-associated glycoprotein and apoptotic-like oligodendrocyte destruction (25,26).…”