MARKED DIVERSITY IN THE ACTION OF GROWTH-FACTORS ON N-METHYL-D-ASPARTATE-INDUCED NEURONAL DEGENERATION

Neuronal degeneration was induced in cultured rat hippocampal neurons by a 20-min exposure to the glutamatergic agonist, N-methyl-D-aspartat e (NMDA; 100 mu M), and the neuroprotective activity of a set of growt h factors and cytokines was compared. During the early stages of degen eration, NMDA induced changes that were characteristic of neuronal nec rosis, including swelling and darkening of the neuronal soma and swell ing of neurites, leading to the formation of beaded varicosities ('ble bs'). These changes were followed by nuclear pyknosis, formation of do uble-stranded DNA breaks and loss of membrane integrity. Only transfor ming growth factor-beta 1 (TGF-beta 1; 1-10 ng/ml) and tumor necrosis factor-alpha (TNF-alpha; 30 ng/ml) protected the hippocampal neurons a gainst NMDA neurotoxicity after short-term (60 min) pre-treatments. In terleukin-1 beta (10-100 ng/ml) and fibroblast growth factor-2 (FGF-2; 50 ng/ml) were clearly effective when administered 24 h prior to the NMDA exposure, but not when given 60 min before the insult. Interestin gly, the protective effect of interleukin-1 beta was significantly red uced in the presence of a neutralizing antibody to TGF-beta. Of note, short-term pre-treatment with brain-derived neurotrophic factor (BDNF; 5-50 ng/ml) significantly potentiated NMDA-induced neurodegeneration. These experiments demonstrate marked diversity in the actions of grow th factors on NMDA-induced neuronal degeneration.