Oligodendroglial cell death with DNA fragmentation in the white matter under chronic cerebral hypoperfusion: comparison between normotensive and spontaneously hypertensive rats
Introduction
Cerebral white matter lesions in various neuropathological conditions have become widespread by the recent advance in neuroradiologic diagnostic techniques, such as computerized tomography or magnetic resonance imaging (Pantoni and Garcia, 1997, Englund, 1998). Binswanger's disease is one of these neurological disorders and is characterized pathologically by lesions of subcortical white matter with severe atheromatosis of the arteries, enlarged ventricles and normal cortex (Jellinger and Neumayer, 1964, Roman, 1987). This disease is also characterized clinically by the presence of hypertension that is one of the risk factors of vascular dementia and ischemic white matter lesions (Skoog, 1998, de Leeuw et al., 1999). Although these subcortical white matter lesions may result from primary myelinopathy, or from axonopathy including Wallerian degeneration, or from oligodendropathy (Yamanouchi, 1991, Akiguchi et al., 1997), the exact mechanism of Binswanger's disease remains to be known. Recently, many reports demonstrated that oligodendrocytes might possibly be sensitive and vulnerable to ischemia or hypoperfusion in the cerebral white matter (Pantoni et al., 1996, Irving et al., 1997, Petito et al., 1998), and that it could be one of the pathogenic factors for the diffuse white matter changes in Binswanger's disease. Chronic cerebral hypoperfusion is likely to be diffuse white matter lesions (Kawamura et al., 1991). In fact, experimental white matter lesions have been reported to occur in normal young animals, such as rat (Wakita et al., 1994, Wakita et al., 1995), gerbil (Hattori et al., 1992, Kudo et al., 1990), and dog (Yoshioka et al., 1994), after bilateral common carotid artery occlusion. However, no report about the relationship between ischemic white matter changes and vascular risk factors such as hypertension has been published so far. In the present study, using normotensive and spontaneously hypertensive rats, we investigated the effect of hypertension on white matter lesions after bilateral common carotid artery ligation (BCAL). In addition, we also examine the mechanisms of white matter changes including apoptosis-like oligodendroglial cell death in both normotensive and spontaneously hypertensive rats after BCAL.
Section snippets
Animal preparation
Male 20-week-old Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) were used (Charles River Japan, Yokohama, Japan). Experiments were carried out following the NIH guidelines for the care and use of laboratory animals, and approved by the local ethics committees of the BF Research Institute. All animals were maintained under specific pathogen-free conditions and fed regular rat chow (CE-2, Clea Japan, Tokyo, Japan) and tap water ad libitum. Arterial blood pressure was measured by a
Blood pressure
Average values of mean arterial blood pressure (MABP) of WKY and SHR at various time intervals following BCAL and their normal controls are summarized in Table 1. At 1 week after BCAL, MABP of both WKY and SHR rose significantly compared to those of the controls, and maintained higher levels than those in the controls of each strain for at least 4 weeks.
Standard histological and immunohistochemical findings
Three days after BCAL, the GFAP-positive astrocytes and lectin-positive microglia were more frequent than in sham-operated animals in the white
Discussion
In the present study, we demonstrated that after BCAL, spontaneous hypertension might accelerate white matter lesions with vacuolation, microglial activation and oligodendroglial DNA fragmentation after BCAL. Furthermore, to the best of our knowledge, there is no previous study that compares white matter rarefaction between WKY and SHR instead of the cerebral infarction (Ogata et al., 1976).
Because of the lack of apparent DNA fragmentation in the normal controls, the development of
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