OPPOSITE EFFECTS OF TGF-BETA-1 ON RAPIDLY-TRIGGERED AND SLOWLY-TRIGGERED EXCITOTOXIC INJURY

Transforming growth factor-beta (TGF-beta) has been shown to protect c entral neurons against diverse metabolic and excitotoxic challenges. W e induced different types of excitotoxic injury on cultured rat hippoc ampal neurons and investigated TGF-beta 1 for its protective activity. TGF-beta 1 (0.3-10 ng/ml) effectively blocked excitotoxic injury of c ultured rat hippocampal neurons induced by short-term exposure to the selective agonist N-methyl-D-aspartate (NMDA; 100 mu M, 20 min). Excit otoxic injury caused by long-term exposure to the non-NMDA agonists ka inate (50 mu M, 24 hr) or lpha-amino-3-hydroxy-5-methyl-4-isoxazolepro pionic acid (AMPA; 10 mu M, 24 hr) caused a similar reduction in neuro nal viability. However, treatments with TGF-beta 1 (0.1-10 ng/ml) actu ally 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 Ca2and to be uniquely sensitive to non-NMDA receptor-mediated neurotoxici ty. In this culture system, short-term exposure to kainate (100 mu M; 30 min) in Na+-free extracellular solution caused a pronounced decreas e in neuronal viability, and this toxicity was also significantly redu ced in cultures treated with TGF-beta 1 (10 ng/ml). These results sugg est that TGF-beta 1 has the capacity to protect neurons against rapidl y-triggered, Ca2+-mediated excitotoxic injury, but significantly poten tiates slowly-triggered types of excitotoxic injury. This complex acti on of TGF-beta 1 could have important implications for the use of TGF- beta s and related growth factors in the treatment of neurodegenerativ e diseases. Copyright (C) 1996 Elsevier Science Ltd.