Activity-dependent neurotrophic factor-14 requires protein kinase C and mitogen-associated protein kinase kinase activation to protect the developingmouse brain against excitotoxicity

Activity-dependent neurotrophic factor (ADNF) is a newly identified compoun d that prevents in vitro neuronal death when present in fentomolar concentr ations. ADNF-14, a 14 amino acid peptide derived from ADNF, has the same ef fects on growth as the parent molecule. However, the transduction pathways and target cells for these highly potent trophic factors are still unknown. We previously described a mouse model of excitotoxic lesions of the develo ping neocortex mimicking several hypoxic or hypoxic-like brain lesions obse rved in human fetuses and neonates. In this model, cotreatment with the exc itotoxin ibotenate and ADNF-14 prevented both neuronal death in pups inject ed on the day of birth and white matter cystic lesions in pups treated 5 d after birth. In the present study, coadministration of ibotenate, ADNF-14, and selective transduction pathway inhibitors showed that activation of pro tein kinase C (PKC) and mitogen-associated protein kinase kinase was critic al for neuroprotection. Immunocytochemistry revealed that ADNF-14 activated PKC and mitogen-associated protein kinase in cortical neurons on the day o f birth and in white matter astrocytes on the fifth postnatal day. Taken in concert, these data identify PKC and mitogen-associated protein kinase pat hways as critical to ADNF-14-induced neuroprotection of the developing brai n against excitotoxic damage.