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Neurotrophins Rescue Cerebellar Granule Neurons from Oxidative Stress‐Mediated Apoptotic Death: Selective Involvement of Phosphatidylinositol 3‐Kinase and the Mitogen‐Activated Protein Kinase Pathway
Author(s) -
Skaper Stephen D.,
Floreani Maura,
Negro Alessandro,
Facci Laura,
Giusti Pietro
Publication year - 1998
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.1471-4159.1998.70051859.x
Subject(s) - neurotrophin , neurotrophic factors , nerve growth factor , neurotrophin 3 , glutamate receptor , cerebellum , biology , microbiology and biotechnology , programmed cell death , brain derived neurotrophic factor , granule (geology) , apoptosis , medicine , chemistry , endocrinology , biochemistry , receptor , paleontology
Abstract: Cerebellar granule neurons maintained in medium containing serum and 25 m M K + reliably undergo an apoptotic death when switched to serum‐free medium with 5 m M K + . New mRNA and protein synthesis and formation of reactive oxygen intermediates are required steps in K + deprivation‐induced apoptosis of these neurons. Here we show that neurotrophins, members of the nerve growth factor gene family, protect from K + /serum deprivation‐induced apoptotic death of cerebellar granule neurons in a temporally distinct manner. Switching granule neurons, on day in vitro (DIV) 4, 10, 20, 30, or 40, from high‐K + to low‐K + /serum‐free medium decreased viability by >50% when measured after 30 h. Treatment of low‐K + granule neurons at DIV 4 with nerve growth factor, brain‐derived neurotrophic factor (BDNF), neurotrophin‐3, or neurotrophin‐4/5 (NT‐4/5) demonstrated concentration‐dependent (1–100 ng/ml) protective effects only for BDNF and NT‐4/5. Between DIV 10 and 20, K + ‐deprived granule neurons showed decreasing sensitivity to BDNF and no response to NT‐4/5. Cerebellar granule neuron death induced by K + withdrawal at DIV 30 and 40 was blocked only by neurotrophin‐3. BDNF and NT‐4/5 also circumvented glutamate‐induced oxidative death in DIV 1–2 granule neurons. Granule neuron death caused by K + withdrawal or glutamate‐triggered oxidative stress was, moreover, limited by free radical scavengers like melatonin. Neurotrophin‐protective effects, but not those of antioxidants, were blocked by selective inhibitors of phosphatidylinositol 3‐kinase or the mitogen‐activated protein kinase pathway, depending on the nature of the oxidant stress. These observations indicate that the survival‐promoting effects of neurotrophins for central neurons, whose cellular antioxidant defenses are challenged, require activation of distinct signal transduction pathways.