57. Degeneration of the serotonergic system in Alzheimer's disease

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2,4-Diamino-6-hydroxypyrimidine (DAHP) is considered a specific inhibitor of BH4 biosynthesis and is widely used in order to elucidate the possible biological function of BH4 in various cells. In the present study, we found that both the synthesis of tetrahydrobiopterin (BH4) and expression of vascular cell adhesion molecule 1 (VCAM-1) were increased in human umbilical vein endothelial cells (HUVEC) treated with proinflammatory cytokines. Thus we examined the effects of DAHP to clarify whether BH4 might be involved in the expression of VCAM-1 in HUVEC. DAHP reduced the levels of both BH4 and VCAM-1 induced by TNF-α and IFN-γ. However, the dose–response curves of DAHP for the suppression of the VCAM-1 level and that of BH4 level were markedly different. Supplementation with sepiapterin failed to restore the depressed VCAM-1 level, although it completely restored the BH4 level. Furthermore, DAHP significantly reduced the VCAM-1 level under the experimental conditions using TNF-α alone, which failed to induce BH4 production. Taken together, these results indicate that DAHP inhibited the expression of VCAM-1 in a BH4-independent manner in HUVEC. In the present study, we also found that DAHP significantly suppressed the accumulation of cytokine-induced NF-κB (p65) in the nucleus as well as the mRNA levels of VCAM-1 and GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme of BH4 synthesis. The data obtained in this study suggest that DAHP reduced VCAM-1 and GTPCH protein synthesis at least partially via suppressing the NF-κB level in the nucleus of HUVEC.