Oligodendroglial cell death with DNA fragmentation in the white matter under chronic cerebral hypoperfusion: comparison between normotensive and spontaneously hypertensive rats

We investigated the neuropathological and biochemical changes in the white matter of normotensive Wistar Kyoto (WKY) and spontaneously hypertensive ra ts (SHR) after bilateral carotid artery ligation (BCAL). One week after BCA L, both WKY and SHR showed white matter rarefaction and vacuolation with re duced oligodendrocytes, but there was no difference between WKY and SHR. On the other hand, vacuoles formed by oligodendroglial cell death were increa sed significantly from 2 to 4 weeks in the optic tract and fimbria fornix o f hypoperfused SHR. Furthermore, terminal deoxynucleotidyl transferase-medi ated dUTP in situ nick end labeling (TUNEL)-positive cells and lectin-posit ive microglia increased in number and intensities of staining more markedly in SHR than in WKY. In situ cell death detection ELISA supported these res ults quantitatively. RT-PCR represented the expression of TNF-alpha, TNF re ceptor 1 (p55), caspase-2 (Ich-l) and -3 (CF'P32) mRNAs in both WKY and SHR brains after BCAL. Immunohistochemical analyses revealed that TNF-alpha, T NF receptor 1 (p55), Ich-l and CPP32 immunoreactive cells could also be det ected in the white matter regions of hypoperfused SHR. These results sugges ted that local production of TNF-alpha by the activated microglia might sel ectively induce oligodendroglial cell death through the death domain-contai ning TNF receptor 1 (p55), caspase-2 or -3 activation, resulting in white m atter changes as a primary pathological feature. (C) 2001 Elsevier Science Ireland Ltd and the Japan Neuroscience Society. All rights reserved.