The effects of NGF on neonatal hypoxic-ischemic injury: Hypoxic-ischemic brain injury is one of the most common causes of neurological morbidity in the neonate. This type of injury often leads to permanent motor deficits (cerebral palsy) with or without accompanying mental impairment and seizures. The neuropathology of hypoxic-ischemic injury in the perinatal period differs from that seen in the adult. In neonates, the basal ganglia including the striatum (caudate-putamen) and globus pallidus is selectively vulnerable. This region has an important role in the control of movement and focal damage is thought to be responsible for many of the movement disorders seen in patients with cerebral palsy. Despite an increased understanding of the role of excitatory amino acids and free radicals in the pathophysiology of hypoxic-ischemic brain injury, there is no effective treatment. A novel approach to preventing cell loss and restoring neuronal function in hypoxic-ischemic injury is suggested by the biology of the neurotrophins, molecules which support the survival and maintenance of developing and mature neurons. Nerve growth factor (NGF) is the most well characterized neurotrophin. In addition to its action in the normal animal, NGF has been shown to protect responsive neuronal populations against a variety of cellular insults including axotomy, toxins, exicitotoxicity, and free radical damage. In the central nervous system (CNS), NGF has been shown to have actions in the striatum. Neurons in this region express NGF-receptors and respond to NGF both during development and in the adult. Interestingly, it appears that excitotoxin- induced injury in the neonatal and adult striatum can be markedly reduced by the administration of exogenous NGF. This proposal will test the hypothesis that NGF can ameliorate striatal brain damage secondary to hypoxia-ischemia. Recent data suggests that neurotrophins and their receptors are increased in the adult brain after trauma and hypoxia. Experiments to characterize hypoxic-ischemic brain injury in the striatum with regard to NGF and its receptors will give insight into the normal pathophysiology of this injury. The Levine model in which 7 day old rats undergo unilateral common carotid artery ligation followed by exposure to a hypoxic environment will be utilized. To assess whether NGF can ameliorate hypoxic-ischemic injury, NGF or vehicle will be administered to post-natal day 7 rats just prior to hypoxic-ischemic injury utilizing the Levine model. Effects will be assessed with regard to extent of overall pathology in both the striatum and cortex. Particular neuronal sub- populations and other markers of neuronal injury will be analyzed. To better assess the mechanisms by which NGF may be acting on the striatum under hypoxic-ischemic conditions, its effects on cultured striatal neurons subjected to either hypoxic or excitotoxin-induced neuronal damage will be assessed. The survival of both cholinergic and other neuronal populations, as well as the dose dependency of NGF effects, will be determined. These studies should provide new insights as to whether neurotrophins may serve as a novel form of therapy in the treatment of neonatal hypoxic-ischemic brain injury.
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