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Isoform-Specific Effects of Transforming Growth Factors-β on Degeneration of Primary Neuronal Cultures Induced by Cytotoxic Hypoxia or Glutamate


Address correspondence and reprint requests to Prof. Dr. Dr. J. Krieglstein al Institut für Pharmakologie und Toxikologie. Philipps-Universitat. Ketzerbach 63. W-3550 Marburg. F.R.G.


Abstract: The transforming growth factors-β (TGFs-β) are multifunctional peptide-growth factors that have been localized in neuronal and glial cells of the C'NS of mice. rats, and chick embryos. We tested the TGF-β isoforms 1. 2. and 3 for their protective ctlects against neuronal degeneration caused by cytotoxic hypoxia or by the excitatory amino acid i -glutamate. A cytotoxic hypoxia was induced in cultured chick embryo telencephalic neurons by adding I m.l/ sodium cyanide to the culture medium tor a period of 30min. I reatment with TGF-81 (1-30 ng/ml) led to a statistically significant increase in cell viability, neuronal ATP levels. and protein content of the cultures assessed 72 h after the toxic insult. TGF-33 was able to reduce the cyanide-induced neuronal damage at concentrations of 0.3 and 1 ng/ ml. whereas TGF-33, only showed neuroprotective activity at concentrations of 30 and 50 ng/ml. Both pre- and posttreatment with TGF-31, also prevented the degeneration of cultured chick embryo telencephalic neurons that had been exposed to I mM L-glutamate in a buffered salt solution for a period of 60 min. Furthermore, TGF-β1 (0.3-3 ng/ml). and to a lesser extent TGF-β3 (0.1-1 ng/ml). significantly reduced excitotoxic injury of cultured neurons from rat cerebral cortex that had been exposed to serum-free culture medium supplemented with 1 m.M L-glutamate. These results demonstrate that the TGFs-β are able to prevent the degeneration of primary neuronal cultures, which was caused by energy depletion and activation of glutamate receptors, in an isoform-specific manner.