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Neurotrophic Factors Attenuate Glutamate‐Induced Accumulation of Peroxides, Elevation of Intracellular Ca 2+ Concentration, and Neurotoxicity and Increase Antioxidant Enzyme Activities in Hippocampal Neurons
Author(s) -
Mattson Mark P.,
Lovell Mark A.,
Furukawa Katsutoshi,
Markesbery William R.
Publication year - 1995
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1995.65041740.x
Subject(s) - excitotoxicity , glutamate receptor , neurotoxicity , chemistry , neurotrophic factors , nmda receptor , nerve growth factor , brain derived neurotrophic factor , glutathione peroxidase , reactive oxygen species , neurotrophin , biochemistry , superoxide dismutase , endocrinology , pharmacology , medicine , biology , antioxidant , receptor , toxicity , organic chemistry
Exposure of cultured rat hippocampal neurons to glutamate resulted in accumulation of cellular peroxides (measured using the dye 2,7‐dichlorofluorescein). Peroxide accumulation was prevented by an N ‐methyl‐ d ‐aspartate (NMDA) receptor antagonist and by removal of extracellular Ca 2+ , indicating the involvement of NMDA receptor‐induced Ca 2+ influx in peroxide accumulation. Glutamate‐induced reactive oxygen species contributed to loss of Ca 2+ homeostasis and excitotoxic injury because antioxidants (vitamin E, propyl gallate, and N‐tert ‐butyl‐α‐phenylnitrone) suppressed glutamate‐induced elevation of intracellular Ca 2+ concentration ([Ca 2+ ] i ) and cell death. Basic fibroblast growth factor (bFGF), nerve growth factor (NGF), and brain‐derived neurotrophic factor (BDNF), but not ciliary neurotrophic factor, each suppressed accumulation of peroxides induced by glutamate and protected neurons against excitotoxicity. bFGF, NGF, and BDNF each increased (to varying degrees) activity levels of superoxide dismutases and glutathione reductase. NGF increased catalase activity, and BDNF increased glutathione peroxidase activity. The ability of the neurotrophic factors to suppress glutamate toxicity and glutamate‐induced peroxide accumulation was attenuated by the tyrosine kinase inhibitor genistein, indicating the requirement for tyrosine phosphorylation in the neuroprotective signal transduction mechanism. The data suggest that glutamate toxicity involves peroxide production, which contributes to loss of Ca 2+ homeostasis, and that induction of antioxidant defense systems is a mechanism underlying the [Ca 2+ ] i ‐stabilizing and excitoprotective actions of neurotrophic factors.