Abstract 118: Effect of Interferon Regulatory Factor-1 on Vascular Dementia Using Mouse Chronic Cerebral Hypoperfusion Model

Abstract

Objective: Accumulation of inflammatory cells around the damaged blood vessels is an important feature of the pathophysiology of Binswanger disease due to hypoxic conditions. Recent reports indicate that expression of interferon regulatory factor (IRF)-1-dependent genes in neurons plays a role in ischemic neuronal death. However, the roles of IRF-1 in vascular dementia are not well investigated. Therefore, we assessed the effect of IRF-1 on cognitive function using vascular dementia mouse model by chronic cerebral hypoperfusion. Methods: Male 10-week-old C57BL/6 (wild-type; WT) and IRF-1-knockout (IRF-1KO) mice were used in this study. Chronic cerebral hypoperfusion mouse model was generated by bilateral common carotid artery stenosis (BCAS). Six weeks after BCAS, the mice were subjected to the Morris water maze test 5 times a day for 5 days. After the Morris water maze task, cerebral blood flow (CBF) was evaluated by laser speckle flowmetry. Expression of NADPH oxidase subunits and inflammatory cytokines in cortex and hippocampus were determined by real-time RT-PCR. Results: Body weight before and 6 weeks after BCAS operation did not differ in all groups. In the Morris water maze task, escape latency was significantly prolonged in sham-operated IRF-1KO mice compared with sham-operated WT mice. Moreover, BCAS-treated IRF-1KO mice exhibited more prolonged escape latency compared with sham-operated IRF-1KO and BCAS-treated WT mice. Although BCAS treatment reduced CBF in WT mice, there was no significant difference in CBF between sham-operated WT and IRF-1KO mice. On the other hand, after BCAS treatment, CBF was more markedly decreased in IRF-1KO mice than WT mice. In sham-operated groups, mRNA expression of NDADPH oxidase subunits and inflammatory cytokines in the brain did not differ between WT and IRF-1KO mice. In contrast, BCAS-treated IRF-1KO mice showed the tendency to increase mRNA expression of p22phox, p47phox, TNF-α and MCP-1 than BCAS-treated WT mice. Conclusion: These results suggest that IRF-1 has a protective effect on cognitive decline due to the prevention of CBF reduction, and the increases in NADPH oxidase and inflammatory cytokines in mouse chronic cerebral hypoperfusion model.