CNS Drug Reviews

Neurotrophic factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and neurotrophin-4/5 (NT4/5) play an important role in the regulation of nervous system development and adult nervous system plasticity, maintenance of structural integrity, and mediation of defensive responses after CNS injuries. NGF, probably the most widely studied neurotrophic factor, has been found to support both peripheral sympathetic and sensory neurons (17,46,47,65), and to promote the survival of basal forebrain cholinergic neurons (16), which project from the septum-diagonal band and basal nucleus to the hippocampus and cerebral cortex, respectively (25,30). Under physiological conditions, the highest NGF concentration is found in the hippocampus, whereas the basal forebrain contains a low level of NGF, suggesting that NGF is produced in these cholinergic target regions and then retrogradely transported to the cell bodies in the basal forebrain. It has been previously reported that NGF is able to prevent hypoglycemic damage of cultured cortical and hippocampal neurons (8) and glutamate excitotoxicity (67,68). Intraventricular or intrahippocampal administration of NGF can protect rat hippocampus and cortex from ischemic damage (5,27,28,69). Alternatively, Ishimaru et al. (37) showed that NGF infused into the cerebroventricular system delayed rather than prevented neuronal death in the hippocampus after ischemia. The neuroprotective potency of NGF in vivo seems to be correlated with the available amount of NGF and the maintenance of NGF in brain tissue. Thus, it is well-established that NGF possesses a protective function in those brain regions which are particularly vulnerable to cerebral ischemia and chronic neurodegenerative disorders. NGF can be quickly induced in brain tissue in response to seizures, hypoglycemia, or ischemia (24,40). Accordingly, Hellweg et al. (31) proposed a time course of NGF ex-