VASOACTIVE-INTESTINAL-PEPTIDE PREVENTS EXCITOTOXIC CELL-DEATH IN THE MURINE DEVELOPING BRAIN

Excitotoxic damage may be a critical factor in the formation of brain lesions associated with cerebral palsy. When injected at birth, the gl utamatergic analog ibotenate induces mouse brain lesions that striking ly mimic human microgyria. When ibotenate is injected at postnatal day 5, it produces transcortical necrosis and white matter cysts that mim ic human perinatal hypoxic-like lesions. Vasoactive intestinal peptide (VIP) has potent growth-related actions and neuroprotective propertie s that influence mitosis and neuronal survival in culture. The goal of this study was to assess the protective role of VIP against excitotox ic lesions induced by ibotenate in developing mouse brain. VIP cotreat ment reduced ibotenate-induced microgyric-like cortical lesions and wh ite matter cysts by up to 77 and 85%, respectively. VIP protective eff ects were reproduced by a peptide derived from activity-dependent neur otrophic factor (ADNF), a trophic factor released by VIP-stimulated as trocytes, and by stearyl norleucine VIP, a specific VIP agonist that d oes not activate adenylate cyclase. Neither forskolin, an adenylate cy clase activator, nor pituitary adenylate cyclase-activating peptide, p rovided VIP-like protection. VIP and neurotrophic analogs, acting thro ugh a cAMP-independent mechanism and inducing ADNF release, could repr esent new avenues in the understanding and prevention of human cerebra l palsy.