Neuroprotection of the developing brain by systemic administration of vasoactive intestinal peptide derivatives

Periventricular leukomalacia (PVL), a necrotic and often cystic lesion of t he cerebral white matter occurring in very premature babies, is the leading cause of cerebral palsy in this population. Increased glutamate release an d the excitotoxic cascade thus triggered may be critical factors in the dev elopment of PVL. The glutamatergic analog ibotenate injected intracerebrall y into newborn mice produces white matter cysts that mimic human PVL. Conco mitant injection of vasoactive intestinal peptide (VIP), a trophic factor, protects the white matter against excitotoxic lesions. The goal of the pres ent study was to assess the protective properties of systemically injected VIP analogs against ibotenate-induced excitotoxic white matter lesions in n ewborn mice. VIP analogs were selected on the basis of their low susceptibi lity to endopeptidases and their potential ability to cross biological memb ranes. RO-25-1553, a long-lasting cyclic VIP analog, and stearyl-norleucine -VIP, a fatty derivative of VIP, reduced ibotenate-induced white matter cys ts by up to 87% and 84%, respectively, when injected i.p. immediately after ibotenate. By comparison, i.p. coadministration of VIP and ibotenate was n ot protective against the excitotoxic insult. Furthermore, RO-25-1553 and s tearyl-norleucine-VIP still induced significant neuroprotection of the deve loping white matter when injected systemically 8 and 12 h, respectively, af ter ibotenate, establishing these peptides as therapeutic agents in this mu rine model. VIP analogs may have therapeutic potential in human premature b abies at high risk for PVL.