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.
Prehn
J H
JH
Department of Pharmacology and Toxicology, Philipps-University, Germany.
Miller
R J
RJ
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects*; D007608:Kainic Acid / Q000633:toxicity; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects*; D011689:Purkinje Cells / Q000187:drug effects; D051381:Rats; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
D018690:Excitatory Amino Acid Agonists; D016212:Transforming Growth Factor beta; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007608:Kainic Acid