Neurotrophic factor mediated protection from excitotoxicity and disturbances in calcium and free radical metabolism

Abstract

Several conventional and novel growth factors (GFs) canprotect neurons against an array of insults including excitotoxins, hypoglycemia, hypoxia, free radicals and β-amyloid peptide. In tissue culture experiments basic fibroblast growth factor (bFGF), nerve growth factor (NGF) and insulin-like growth factors (IGFs) protected neurons from several brain regions from metabolic/excitotoxic insults. In each case, the GF prevented the sustained elevation of [Ca2+]i that was causally involved in cell injury. Oxidative damage induced by iron, H2O2, 6-hydroxydopamine and MPP+ was attenuated by one or more GFs including bFGF, NGF, IGFs, and brain-derived neurotrophic factor (BDNF). Secreted forms of β-amyloid precursor protein (APPss) reduced [Ca2+]i and protected rat and human brain cells against excitotoxicity. The data indicate that: (1) neuroprotection is a major function of GFs in the brain; (2) the neuroprotective mechanism of GFs involves stabilization of [Ca2+]i and suppression of free radicals; (3) activation of GF signal transduction pathways may reduce brain damage in both acute (e.g. stroke and trauma) and chronic (e.g. Alzheimer's, Parkinson's and Huntington's diseases) neurodegenerative conditions.