ANGIOGENIC INHIBITION OF SPINORPHIN , A POTENT ANALGESIC AND ANTIINFLAMMATORY SUBSTANCE

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Angiogenesis is the formation of new blood vessels and is essential for tissue development, regeneration and remodeling. Angiogenesis also plays an important role in many pathological processes, such as growth and metastasis of solid tumor, diabetic retinopathy, rheumatoid arthritis and psoriasis. The inhibition of angiogenesis results in suppression of these diseases. On the other hand, we previously found a small peptide with inhibiting activity against proteases that degraded endogenous opioid peptide, enkephalin in human spinal fluid and purified it named as spinorphin from bovine spinal cord. Spinorphin is a peptide that consists seven amino acid residues, LVVYPWT. Spinorphin potently inhibited enkephalin-degrading enzymes and exhibited analgesic activity in mice and inflammatory responses such as chemotaxis, O_2-generation and exocytosis by human polymorphonuclear nutrophils.In this study, we investigated the antiangiogenic activity of spinorphin using in vivo and in vitro assays … More . First we examined its antiangiogenic activity using a chick embryo chorioallantoic membrane (CAM). Spinorphin potently inhibited angiogenesis, dose-dependently. This activity increased by simultaneous addition of an aminopeptidase inhibitor, leuhistin since spinorphin was degraded by aminopeptidase in CAM assay. The mechanism of this inhibition was examined using endothelial cells. This compound did not inhibit proliferation or tube formation of bovine pulmonary artcrial endothelial (BPAE)cells. Previously, spinorphin was reported to inhibit bradykinin-induced nociceptive flexor responses in mice. This suggested that spinorphin may bind bradykinin receptors. We examined antiangiogenic activity of bradykinin antagonists and they showed potent inhibition of angiogenesis in CAM. However, spinorphin did not inhibit binding of bradykinin to bradykinin receptors. Moreover, a specific receptor for spinorphin was suggested to exist in rat spinal cord. In contrast, some inhibitors of angiotensin-converting enzyme (ACE) or aminopeptidase (AP) suppressed angiogenesis in CAM. As spinorphin inhibits enzyme activities of ACE and AP, antiangiogenic activity of spinorphin may depend on its enzyme regulation. Less