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

Abstract

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.

Duplicate preconditioning with sevoflurane in vitro improves neuroprotection in rat brain via activating the extracellular signal-regulated protein kinase

“…We presume that sevoflurane induces preconditioning probably through activating this signal pathway, and our results confirm this hypothesis. MEK-ERK1/2 links growth factor receptors with nerve growth factor and brain-derived neurotrophic factor, to exert neuroprotective effects such as NMDA receptor modulation and reduction of glutamate excitotoxicity [29] . MEK-ERK1/2 also phosphorylates hypoxia-inducible factor 1, a transcription factor required for the cell adaptation to acute and chronic hypoxia [30] .…”

Alginate Composition Effects on a Neural Stem Cell–Seeded Scaffold

“…Importantly, these neurotrophic factors are known to support neuronal survival and plasticity in various models of axonopathy and neuropathy. [42][43][44][45][46] Quantitative analysis of constitutive neurotrophic factor release from NSCs is relatively rarely reported in the literature, despite the popular theory that release of these proteins and their effects on compromised host tissue is a potential mechanism behind the cells' restorative capacity. 8,9,11,14,16 Time courses of release are generally lacking, as are release profiles from scaffolded cells.…”

The upregulation of GLAST-1 is an indirect antiapoptotic mechanism of GDNF and neurturin in the adult CNS

“…In the present study, we show that the MAPK pathway was required for axotomized RGC survival after GDNF treatment. Nicole et al 37 reported that GDNF reduces the conductance of the NMDA receptor through activation of the MAPK pathway, protecting cultured cells against glutamate excitotoxicity. This may be an additional MAPKdependent survival mechanism of GDNF after optic nerve transection.…”