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The Journal of Neuroscience, May 1, 2001, 21(9):3024-3033
Neuroprotection Mediated by Glial Cell Line-Derived Neurotrophic
Factor: Involvement of a Reduction of NMDA-Induced Calcium
Influx by the Mitogen-Activated Protein Kinase Pathway
Olivier
Nicole,
Carine
Ali,
Fabian
Docagne,
Laurent
Plawinski,
Eric T.
MacKenzie,
Denis
Vivien, and
Alain
Buisson
Université de Caen, Unité Mixte de Recherche, Centre
National de la Recherche Scientifique 6551, 14074 Caen Cedex,
France
The glial cell line-derived neurotrophic factor (GDNF) is
first characterized for its trophic activity on dopaminergic neurons. Recent data suggested that GDNF could modulate the neuronal death induced by ischemia. The purpose of this study was to characterize the
influence of GDNF on cultured cortical neurons subjected to two
paradigms of injury (necrosis and apoptosis) that have been identified
during cerebral ischemia and to determine the molecular mechanisms
involved. First, we demonstrated that both neurons and astrocytes
express the mRNA and the protein for GDNF and its receptor complex
(GFR -1 and c-Ret). Next, we showed that the application of
recombinant human GDNF to cortical neurons and astrocytes induces the
activation of the MAP kinase (MAPK) pathway, as visualized by an
increase in the phosphorylated forms of extracellular signal-regulated
kinases (ERKs). Thereafter, we demonstrated that GDNF fails to
prevent apoptotic neuronal death but selectively attenuates slowly
triggered NMDA-induced excitotoxic neuronal death via a direct effect
on cortical neurons. To further characterize the neuroprotective
mechanisms of GDNF against NMDA-mediated neuronal death, we showed that
a pretreatment with GDNF reduces NMDA-induced calcium influx. This
effect likely results from a reduction of NMDA receptor activity rather
than an enhanced buffering or extrusion capacity for calcium. Finally,
we also demonstrated that an ERKs activation pathway is
necessary for GDNF-mediated reduction of the NMDA-induced calcium
response. Together, these results describe a novel mechanism by which
the activation of MAPK induced by GDNF modulates NMDA receptor
activity, a mechanism that could be responsible for the neuroprotective
effect of GDNF in acute brain injury.
Key words:
GDNF; excitotoxicity; apoptosis; NMDA receptor; Fura-2; MAPK
Copyright © 2001 Society for Neuroscience 0270-6474/01/2193024-10$05.00/0
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