Abstract
Periventricular leukomalacia (PVL), a necrotic and often cystic lesion of the cerebral white matter occurring in very premature babies, is the leading cause of cerebral palsy in this population. Increased glutamate release and the excitotoxic cascade thus triggered may be critical factors in the development of PVL. The glutamatergic analog ibotenate injected intracerebrally into newborn mice produces white matter cysts that mimic human PVL. Concomitant injection of vasoactive intestinal peptide (VIP), a trophic factor, protects the white matter against excitotoxic lesions. The goal of the present study was to assess the protective properties of systemically injected VIP analogs against ibotenate-induced excitotoxic white matter lesions in newborn mice. VIP analogs were selected on the basis of their low susceptibility to endopeptidases and their potential ability to cross biological membranes. RO-25-1553, a long-lasting cyclic VIP analog, and stearyl-norleucine-VIP, a fatty derivative of VIP, reduced ibotenate-induced white matter cysts by up to 87% and 84%, respectively, when injected i.p. immediately after ibotenate. By comparison, i.p. coadministration of VIP and ibotenate was not protective against the excitotoxic insult. Furthermore, RO-25-1553 and stearyl-norleucine-VIP still induced significant neuroprotection of the developing white matter when injected systemically 8 and 12 h, respectively, after ibotenate, establishing these peptides as therapeutic agents in this murine model. VIP analogs may have therapeutic potential in human premature babies at high risk for PVL.
Footnotes
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Send reprint requests to: Dr. Pierre Gressens, Service de Neuropédiatrie, Hôpital Robert-Debré, 48 Blvd. Sérurier, F-75019 Paris, France. E-mail:pierre.gressens{at}rdb.ap-hop-paris.fr
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↵1 This work was supported by the Institut National de la Santé et de la Recherche Médicale (France), an Interuniversity Poles of Attraction Program, Belgian state, Prime Minister’s Office, Federal Office for Scientific, Technical and Cultural Affairs, and by Accord Communauté Française de Belgique, Institut National de la Santé et de la Recherche Médicale.
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↵2 Present address: Laboratoire de Chimie Biologique et de la Nutrition, University of Brussels Medical School, Brussels, Belgium.
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↵3 Present address: Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
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↵4 Present address: Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, Israel.
- Abbreviations:
- PVL
- periventricular leukomalacia
- VIP
- vasoactive intestinal peptide
- PACAP
- pituitary adenylate cyclase-activating peptide
- Received June 10, 1998.
- Accepted October 19, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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