The transforming growth factors-beta (TGFs-beta) are multifunctional peptide growth factors that have been localized in neuronal and glial cells of the CNS of mice, rats, and chick embryos. We tested the TGF-beta isoforms 1, 2, and 3 for their protective effects against neuronal degeneration caused by cytotoxic hypoxia or by the excitatory amino acid L-glutamate. A cytotoxic hypoxia was induced in cultured chick embryo telencephalic neurons by adding 1 mM sodium cyanide to the culture medium for a period of 30 min. Treatment with TGF-beta 1 (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-beta 3 was able to reduce the cyanide-induced neuronal damage at concentrations of 0.3 and 1 ng/ml, whereas TGF-beta 2 only showed neuroprotective activity at concentrations of 30 and 50 ng/ml. Both pre- and post-treatment with TGF-beta 1 also prevented the degeneration of cultured chick embryo telencephalic neurons that had been exposed to 1 mM L-glutamate in a buffered salt solution for a period of 60 min. Furthermore, TGF-beta 1 (0.3-3 ng/ml), and to a lesser extent TGF-beta 3 (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 mM L-glutamate. These results demonstrate that the TGFs-beta 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.