Despite significant advances in perinatal medicine, and a decrease in the perinatal mortality, the incidence of psychomotor deficits among survivors of very low birth weight infants (BW less than 1500gm) has risen more than 3-fold recently. The most common ischemic brain lesion in these infants is periventricular leucomalacia (PVL) and the incidence has been reported to be as high as 60%. Unfortunately, the cellular mediators responsible for PVL are not known. However, recent studies suggest that perturbations of endogenous neurotrophic factors (an enhanced opioid system activity or decreased nerve growth factors i.e. nerve growth factor 'NGF', brain derived neurotrophic factor 'BDNF') may mediate the ischemic brain injury. Thus, the purpose of the present proposal with treatment trials is to establish whether, there is indeed, a causal relationship between perturbed endogenous NTF and subsequent evolution of PVL. Newborn dogs lesser 7 day old under surgical anesthesia will be subjected to bilateral common, external and internal carotid arteries ligations to produce the ischemic PVL. CSF endorphins, EEG, brain diffusion and perfusion-weighted magnetic resonance imagings, and phosphorus magnetic resonance spectrum will be monitored for functional and neural tissue integrity and metabolic status; these data will be used to define an optimal therapeutic window. A dose- escalation study will be used for both Naloxone and NGF trials. Neurological function and the incidence of PVL will be compared between treated and untreated animals. We hope that the study can offer a therapeutic break-through for premature infants who are at high risk for ischemic PVL, and thereby lowering the devastating consequences of psychomotor deficits.
