VIP neuroprotection against excitotoxic lesions of the developing mouse brain.

Intracerebral administration of the excitotoxin ibotenate to new-born mice induced white-matter lesions mimicking the periventricular leukomalacia occurring in human premature babies. In this model, co-injection of vasoactive intestinal peptide (VIP) prevented white-matter lesions. VIP did not prevent the initial appearance of white-matter lesion, but promoted a secondary repair with axonal regrowth. Co-administration of ibotenate, VIP, and transduction inhibitors showed that protein kinase C (PKC) and mitogen-associated protein kinase (MAPK) pathways were critical for neuroprotection. The combination of in vitro and in vivo studies suggested the following model: VIP activates PKC in astrocytes, which release soluble factors; these released factors activate neuronal MAPK and PKC, which will permit axonal regrowth. Previous studies had shown that VIP-treated cultured astrocytes release growth factors including activity-dependent neurotrophic factor (ADNF) and that a 14-amino-acid peptide derived from ADNF protected the developing white matter against ibotenate. However, co-treatment with ibotenate, VIP, and anti-ADNF antibodies did not abolish VIP-induced protection, suggesting that ADNF does not mediate VIP protective properties in the present model.