BDNF protects the neonatal brain from hypoxic-ischemic injury in vivo via the ERK pathway

Neurotrophins activate several different intracellular signaling pathways t hat in some way exert neuroprotective effects. In vitro studies of sympathe tic and cerebellar granule neurons have demonstrated that the survival effe cts of neurotrophins can be mediated via activation of the phosphatidylinos itol 3-kinase (PI3-kinase) pathway. Neurotrophin-mediated protection of oth er neuronal types in vitro can be mediated via the extracellular signal-rel ated protein kinase (ERK) pathway. Whether either of these pathways contrib utes to the neuroprotective effects of neurotrophins in the brain in vivo h as not been determined. Brain-derived neurotrophic factor (BDNF) is markedl y neuroprotective against neonatal hypoxic-ischemic (H-I) brain injury in v ivo. We assessed the role of the ERK and PI3-kinase pathways in neonatal H- I brain injury in the presence and absence of BDNF. Intracerebroventricular administration of BDNF to postnatal day 7 rats resulted in phosphorylation of ERK1/2 and the PI3-kinase substrate AKT within minutes. Effects were gr eater on ERK activation and occurred in neurons. Pharmacological inhibition of ERK, but not the PI3-kinase pathway, inhibited the ability of BDNF to b lock H-I-induced caspase-3 activation and tissue loss. These findings sugge st that neuronal ERK activation in the neonatal brain mediates neuroprotect ion against H-I brain injury, a model of cerebral palsy.