ISOFORM-SPECIFIC EFFECTS OF TRANSFORMING GROWTH FACTORS-BETA ON DEGENERATION OF PRIMARY NEURONAL CULTURES INDUCED BY CYTOTOXIC HYPOXIA OR GLUTAMATE

The transforming growth factors-beta (TGFs-beta) are multifunctional p eptide growth factors that have been localized in neuronal and glial c ells of the CNS of mice, rats, and chick embryos. We tested the TGF-be ta isoforms 1, 2, and 3 for their protective effects against neuronal degeneration caused by cytotoxic hypoxia or by the excitatory amino ac id L-glutamate. A cytotoxic hypoxia was induced in cultured chick embr yo telencephalic neurons by adding 1 mM sodium cyanide to the culture medium for a period of 30 min. Treatment with TGF-beta1 (1-30 ng/ml) l ed to a statistically significant increase in cell viability, neuronal ATP levels, and protein content of the cultures assessed 72 h after t he toxic insult. TGF-beta3 was able to reduce the cyanide-induced neur onal damage at concentrations of 0.3 and 1 ng/ml, whereas TGF-beta2 on ly showed neuroprotective activity at concentrations of 30 and 50 ng/m l. Both pre- and post-treatment with TGF-beta1 also prevented the dege neration of cultured chick embryo telencephalic neurons that had been exposed to 1 mM L-glutamate in a buffered salt solution for a period o f 60 min. Furthermore, TGF-beta1 (0.3-3 ng/ml), and to a lesser extent TGF-beta3 (0.1-1 ng/ml), significantly reduced excitotoxic injury of cultured neurons from rat cerebral cortex that had been exposed to ser um-free culture medium supplemented with 1 mM L-glutamate. These resul ts demonstrate that the TGFs-beta are able to prevent the degeneration of primary neuronal cultures, which was caused by energy depletion an d activation of glutamate receptors, in an isoform-specific manner.