Pharmacological Studies for animal model of Binswanger's disease (encephalopathy)

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We have established a chronic cerebral hypoperfusion model that is produced by permanent occlusion of bilateral common carotide arteries (2VO) in rats. The 2VO rats exhibited impairment of learning and memory, rarefaction in the white matter and increase of the glial makers, suggesting that this 2VO model has possibility to be a model of Binswannger's disease (encephalopathy). In this study, we tried to identify the intrinsic factors related with the disease in the 2VO rats using the differentianl display RT-PCR methods. The increased expression clones of 11 and of 12 were isolated form the rat brain 4 days and 4 months after 2VO treatment, respectively. All of these isolated clones were clarified the sequences, which were still partial sequences, and quantified the expression levels by semi-quantitative PCR methods. The factors of which expressions were markedly enhanced by 2VO for 4 days and 4 months were named vof -21 and vof-16, respectively. The sequences of 1,600 bp of vof-21 and 780 bp of vof-16 were clarified. These were novels, although the coding site sequences are still unknown. The expression levels of vof-21 reached maximum at 7 days after 2VO and returned to the control level at 14 days. The expression of vof-16 was abundant in the hippocampus, the tenia tecta, the piriform cortex and the area around the aorta. The existance of both vof-16 and vof-21 in NG108-15 cells were identified by RT-PCR methods. The cells seems to be useful to clarify the cellular functions of both factors by antisenseoligodeoxynucleotides (asODN) methods. The basic examinations for delivery of asODN revealed that pH-sensitive liposomes were useful. We are now studing to clarify the whole sequence and cellular functions of vof-16 and vof-21. Basic examination of delivery of asODN to rat brain are also studying.