REGULATION OF NEUROPROTECTIVE ACTION OF VASOACTIVE-INTESTINAL-PEPTIDEIN THE MURINE DEVELOPING BRAIN BY PROTEIN-KINASE-C AND MITOGEN-ACTIVATED PROTEIN-KINASE CASCADES - IN-VIVO AND IN-VITRO STUDIES

Intracerebral administration of the excitotoxin ibotenate to newborn m ice induces white matter lesions mimicking periventricular leukomalaci a, the most frequent brain lesion occurring in premature human babies. In this model, coinjection of vasoactive intestinal peptide prevents white matter lesions. In the present study, coadministration of iboten ate, vasoactive intestinal peptide, and selective transduction inhibit ors showed that protein kinase C and mitogen-associated protein kinase pathways were critical for neuroprotection. In vivo and in vitro immu nocytochemistry revealed that vasoactive intestinal peptide activated protein kinase C in astrocytes and neurons, and mitogen-associated pro tein kinase in neurons. In vitro neuronal transduction activation was indirect and required medium conditioned by astrocytes in which protei n kinase C had been activated by vasoactive intestinal peptide. Althou gh vasoactive intestinal peptide did not prevent the initial in vivo a ppearance of white matter lesion, it promoted a secondary repair of th is lesion with axonal regrowth. Through protein kinase C activation, v asoactive intestinal peptide also prevented ibotenate-induced white ma tter astrocyte death. These data support the following hypothetical mo del: Vasoactive intestinal peptide activates protein kinase C in astro cytes, which promotes astrocytic survival and release of soluble facto rs; these released factors activate neuronal mitogen-associated protei n kinase and protein kinase C, which will permit axonal regrowth.