Experimental cerebral hypoperfusion induces white matter injury and microglial activation in the rat brain

Abstract

Though cerebral white matter injury is a frequently described phenomenon in aging and dementia, the cause of white matter lesions has not been conclusively determined. Since the lesions are often associated with cerebrovascular risk factors, ischemia emerges as a potential condition for the development of white matter injury. In the present study, we induced experimental cerebral hypoperfusion by permanent, bilateral occlusion of the common carotid arteries of rats (n=6). A sham-operated group served as control (n=6). Thirteen weeks after the onset of occlusion, markers for astrocytes, microglia, and myelin were found to be labeled by means of immunocytochemistry in the corpus callosum, the internal capsule, and the optic tract. The ultrastructural integrity and oligodendrocyte density in the optic tract were investigated by electron microscopy. Quantitative analysis revealed that chronic cerebral hypoperfusion caused mild astrogliosis in the corpus callosum and the internal capsule, while astrocytic disintegration in the optic tract increased by 50%. Further, a ten-fold increase in microglial activation and a nearly doubled oligodendrocyte density were measured in the optic tract of the hypoperfused rats as compared with the controls. Finally, vacuolization and irregular myelin sheaths were observed at the ultrastructural level in the optic tract. In summary, the rat optic tract appears to be particularly vulnerable to ischemia, probably because of the rat brain's angioarchitecture. Since the detected glial changes correspond with those reported in vascular and Alzheimer dementia, this model of cerebral hypoperfusion may serve to characterize the causal relationship between ischemia and white matter damage.

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.…”

“…Immunocytochemical staining was performed as described earlier [8]. Briefly, free-floating coronal sections at Bregma −3.14 mm were cut at 20 m thickness on a cryostat microtome.…”

The neuron-astrocyte-microglia triad in CA3 after chronic cerebral hypoperfusion in the rat: Protective effect of dipyridamole

“…During chronic cerebral hypoperfusion astrogliosis is generally considered a late-emerging event (Farkas et al 2007;Farkas et al 2004Farkas et al , 2006Pappas et al 1996;Schmidt-Kastner et al 2005) in the hippocampus. Consistently, we found significant increase of astrocytes in SP and SR of 2VO-vehicle rats and in SP, SL and SR of 2VO-dypiridamole treated rats.…”

Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury

“…Since the visual pathway is injured by carotid artery occlusion, some standard behavioral tests would not be suitable for assessing neurologic function. 21 Unilateral carotid artery occlusion model has also been used for evaluating white-matter ischemic stroke in rats. 26 Similar to the rat bilateral common carotid artery occlusion model, the unilateral model shows myelin/oligodendrocyte loss, immature oligodendrocyte increase, MMPs increase, and BBB damage.…”