Opposite effects of TGF-beta 1 on rapidly- and slowly-triggered excitotoxic injury

Transforming growth factor-beta (TGF-beta) has been shown to protect central neurons against diverse metabolic and excitotoxic challenges. We induced different types of excitotoxic injury on cultured rat hippocampal neurons and investigated TGF-beta 1 for its protective activity. TGF-beta 1 (0.3-10 ng/ml) effectively blocked excitotoxic injury of cultured rat hippocampal neurons induced by short-term exposure to the selective agonist N-methyl-D-aspartate (NMDA; 100 microM, 20 min). Excitotoxic injury caused by long-term exposure to the non-NMDA agonists kainate (50 microM, 24 hr) or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; 10 microM, 24 hr) caused a similar reduction in neuronal viability. However, treatments with TGF-beta 1 (0.1-10 ng/ml) actually potentiated this slowly-triggered excitotoxic injury. Cultures of rat cerebellar neurons enriched for Purkinje cells have been shown to express AMPA/kainate receptors with significant permeability to Ca2+ and to be uniquely sensitive to non-NMDA receptor-mediated neurotoxicity. In this culture system, short-term exposure to kainate (100 microM; 30 min) in Na(+)-free extracellular solution caused a pronounced decrease in neuronal viability, and this toxicity was also significantly reduced in cultures treated with TGF-beta 1 (10 ng/ml). These results suggest that TGF-beta 1 has the capacity to protect neurons against rapidly-triggered, Ca(2+)-mediated excitotoxic injury, but significantly potentiates slowly-triggered types of excitotoxic injury. This complex action of TGF-beta 1 could have important implications for the use of TGF-beta s and related growth factors in the treatment of neurodegenerative diseases.