Opposite effects of TGF-β1 on rapidly- and slowly-triggered excitotoxic injury

doi:10.1016/0028-3908(96)00001-9

Neuropharmacology

Volume 35, Issue 3, March 1996, Pages 249-256

https://doi.org/10.1016/0028-3908(96)00001-9 Get rights and content

Abstract

Transforming growth factor-β (TGF-β) 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-β1 for its protective activity. TGF-β1 (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 μM, 20 min). Excitotoxic injury caused by long-term exposure to the non-NMDA agonists kainate (50 μM, 24 hr) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; 10 μM, 24 hr) caused a similar reduction in neuronal viability. However, treatments with TGF-β1 (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 μM; 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-β1 (10 ng/ml). These results suggest that TGF-β1 has the capacity to protect neurons against rapidly-triggered, Ca²⁺-mediated excitotoxic injury, but significantly potentiates slowly-triggered types of excitotoxic injury. This complex action of TGF-β1 could have important implications for the use of TGF-βs and related growth factors in the treatment of neurodegenerative diseases.

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Opposite effects of TGF-β1 on rapidly- and slowly-triggered excitotoxic injury

Abstract

Biochem. Biophys. Res. Comm.

Trends Cell Biol.

FEBS Lett.

Neurosci. Lett.

Biochem. Biophys. Res. Comm.

Trends Neurosci.

Exp. Neural.

Cell

Cell. Signal.

Neuroscience

Brain Res.

Cell

Int. Rev. Cytol.

Excitotoxicity induced by enhanced excitatory neurotransmission in cultured hippocampal pyramidal neurons

Neuron

Regulation of gene expression in hippocampal neurons by distinct calcium signaling pathways

Science

Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-d-aspartate or nitric oxide/superoxide in cortical cell cultures

The properties of intracellular Ca2+ stores in cultured rat cerebellar neurons

J. Neurosci.

Calcium directly permeates kainate/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in cultured cerebellar Purkinje Neurons

Molec. Pharmacol.

Ca2+ entry via AMPA/KA receptors and excitotoxicity in cultured cerebellar Purkinje cells

J. Neurosci.

Effects of transforming growth factor-β on murine astrocyte glutamine synthetase activity

J. Clin. Invest.

Ionic dependence of glutamate neurotoxicity

J. Neurosci.

Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists

J. Neurosci.

The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death

A. Rev. Neurosci.

Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures

The properties of intracellular Ca²⁺ stores in cultured rat cerebellar neurons

Ca²⁺ entry via AMPA/KA receptors and excitotoxicity in cultured cerebellar Purkinje cells