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NMDA but not non-NMDA excitotoxicity is mediated by Poly(ADP-ribose) polymerase
A S Mandir1, M F Poitras, A R Berliner
1Departments of Neurology, Neuroscience, and Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Abstract:
Poly(ADP-ribose) polymerase (PARP-1), a nuclear enzyme that facilitates DNA repair, may be instrumental in acute neuronal cell death in a variety of insults including, cerebral ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, and CNS trauma. Excitotoxicity is thought to underlie these and other toxic models of neuronal death. Different glutamate agonists may trigger different downstream pathways toward neurotoxicity. We examine the role of PARP-1 in NMDA- and non-NMDA-mediated excitotoxicity. NMDA and non-NMDA agonists were stereotactically delivered into the striatum of mice lacking PARP-1 and control mice in acute (48 hr) and chronic (3 week) toxicity paradigms. Mice lacking PARP-1 are highly resistant to the excitoxicity induced by NMDA but are as equally susceptible to AMPA excitotoxicity as wild-type mice. Restoring PARP-1 protein in mice lacking PARP-1 by viral transfection restored susceptibility to NMDA, supporting the requirement of PARP-1 in NMDA neurotoxicity. Furthermore, Western blot analyses demonstrate that PARP-1 is activated after NMDA delivery but not after AMPA administration. Consistent with the theory that nitric oxide (NO) and peroxynitrite are prominent in NMDA-induced neurotoxicity, PARP-1 was not activated in mice lacking the gene for neuronal NO synthase after NMDA administration. These results suggest a selective role of PARP-1 in glutamate excitoxicity, and strategies of inhibiting PARP-1 in NMDA-mediated neurotoxicity may offer substantial acute and chronic neuroprotection.
Insights
Poly(ADP-ribose) polymerase-1 (PARP-1) is crucial for NMDA-induced excitotoxicity but not AMPA excitotoxicity. Inhibiting PARP-1 may protect against NMDA-mediated neurotoxicity.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in DNA repair.
- Neuronal cell death from insults like ischemia and trauma may involve PARP-1.
- Excitotoxicity, mediated by glutamate agonists, is a key mechanism in neurotoxicity.
Purpose of the Study:
- To investigate the role of PARP-1 in NMDA- and non-NMDA-mediated excitotoxicity.
- To determine if PARP-1 inhibition offers neuroprotection in excitotoxicity models.
Main Methods:
- Stereotactic delivery of NMDA and non-NMDA agonists into the striatum of PARP-1 knockout and wild-type mice.
- Acute (48 hr) and chronic (3 week) toxicity assessments.
- Viral transfection to restore PARP-1 expression.
- Western blot analysis to detect PARP-1 activation.
- Assessment in mice lacking neuronal nitric oxide synthase.
Main Results:
- Mice lacking PARP-1 showed significant resistance to NMDA-induced excitotoxicity.
- PARP-1 knockout mice were as susceptible to AMPA excitotoxicity as wild-type mice.
- Restoring PARP-1 expression in knockout mice reinstated NMDA excitotoxicity susceptibility.
- PARP-1 activation was observed after NMDA delivery but not AMPA.
- PARP-1 activation was absent in mice lacking neuronal nitric oxide synthase after NMDA administration.
Conclusions:
- PARP-1 plays a selective role in NMDA-mediated excitotoxicity.
- PARP-1 is not involved in AMPA-induced excitotoxicity.
- Nitric oxide and peroxynitrite pathways are implicated in NMDA neurotoxicity via PARP-1 activation.
- Inhibiting PARP-1 may provide significant neuroprotection against NMDA-mediated damage.