Role of N-Methyl-d-aspartate Receptors in the Neuroprotective Activation of Extracellular Signal-regulated Kinase 1/2 by Cisplatin

Agata Gozdz,Agata Habas,Jacek Jaworski,Magdalena Zielinska,Jan Albrecht,Marcin Chlystun,Ahmad Jalili,Michal Hetman

doi:10.1074/jbc.m301554200

Abstract

Neurons are exposed to damaging stimuli that can trigger cell death and subsequently cause serious neurological disorders. Therefore, it is important to define defense mechanisms that can be activated in response to damage to reduce neuronal loss. Here we report that cisplatin (CPDD), a neurotoxic anticancer drug that damages DNA, triggered apoptosis and activated the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway in cultured rat cortical neurons. Inhibition of ERK1/2 activation using either pharmacological inhibitors or a dominant-negative mutant of the ERK1/2 activator, mitogen-activated protein kinase kinase 1, increased the toxicity of CPDD. Interestingly, N-methyl-d-aspartate (NMDA) receptor (NMDAR) antagonists reduced the ERK1/2 activation and exacerbated apoptosis in CPDD-treated neurons. Pre-treatment with CPDD increased ERK1/2 activation triggered by exogenous NMDA, suggesting that CPDD augmented NMDAR responsiveness. CPDD-enhanced response of NMDAR and CPDD-mediated ERK1/2 activation were both decreased by inhibition of poly(ADP-ribose) polymerase (PARP). Interestingly, PARP activation did not produce ATP depletion, suggesting involvement of a non-energetic mechanism in NMDAR regulation by PARP. Finally, CPDD toxicity was reduced by brain-derived neurotrophic factor, and this protection required ERK1/2. In summary, our data identify a novel compensatory circuit in central nervous system neurons that couples the DNA injury, through PARP and NMDAR, to the defensive ERK1/2 activation.

Highlights

The central nervous system is exposed to damaging stimuli that may trigger neuronal death and cause serious neurological diseases [1]
To evaluate whether poly(ADP-ribose) polymerase (PARP) activation can contribute to the protective extracellular signal-regulated kinase 1/2 (ERK1/2) activation by CPDD, we studied the effects of the PARP inhibitors, 3-ABA (5 mM) or PHEN (50 ␮M), on CPDD-induced ERK1/2 activation or cell death. 3-ABA or PHEN reduced ERK1/2 activation in response to CPDD (Fig. 6D) and increased neuronal apoptosis triggered by CPDD (Fig. 6E)
To further support the idea that PARP activation contributes to the increased responsiveness of NMDA receptor (NMDAR) in CPDD-treated neurons, we evaluated the effects of 3-ABA on ERK1/2 activation by NMDA in cells that were pretreated with CPDD (5 ␮g/ml)

Summary

Introduction

The central nervous system is exposed to damaging stimuli that may trigger neuronal death and cause serious neurological diseases [1]. We report that cisplatin (CPDD), a neurotoxic anticancer drug that damages DNA, triggered apoptosis and activated the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway in cultured rat cortical neurons. N-methyl-Daspartate (NMDA) receptor (NMDAR) antagonists reduced the ERK1/2 activation and exacerbated apoptosis in CPDD-treated neurons. CPDD-enhanced response of NMDAR and CPDD-mediated ERK1/2 activation were both decreased by inhibition of poly(ADP-ribose) polymerase (PARP).

Results

Conclusion