From the Neuroprotection Research Laboratory, Departments of Neurology
and Radiology, Harvard Medical School, Massachusetts General Hospital,
Charlestown, Mass.
Correspondence to Eng H. Lo, PhD, Neuroprotection Research Laboratory, Harvard Medical School, MGH East Building 149, Room 2322, Charlestown, MA 02129. E-mail eng{at}cipr.mgh.harvard.edu
Background and Purpose—The nuclear
enzyme poly(ADP-ribose) polymerase (PARP) may play a role in DNA
repair. However, in cerebral ischemia, excessive PARP
activation may lead to energy depletion and exacerbation of neuronal
damage. We examined the effect of inhibiting PARP on (1) the degree of
cerebral injury in a rat model of transient focal ischemia and
(2) the degree of neurotransmitter dysregulation induced by local
cortical perfusion of
N-methyl-D-aspartate (NMDA).
Methods—In experiment 1, rats were subjected to transient
ischemia for 90 minutes by occlusion of the middle cerebral
artery. After 22.5 hours of reperfusion, lesions were quantified by
tetrazolium staining. Untreated rats were compared with those treated
with the PARP inhibitor 3-aminobenzamide (10 mg/kg). In
experiment 2, rats were implanted with microdialysis probes in the
cortex, and 1 mmol/L NMDA was perfused for 2 hours. Extracellular
concentrations of neurotransmitter and neuromodulator amino acids were
measured. Untreated rats were compared with those given 10 mg/kg
3-aminobenzamide.
Results—In experiment 1, PARP inhibition significantly reduced
lesion volumes: 204±43 mm3 (untreated) versus
90±24 mm3 (treated). Neuroprotection was primarily
manifested in the cortex. In experiment 2, NMDA perfusion resulted in
large elevations of glutamate, taurine, and the lipid component
phosphoethanolamine. Levels of the NMDA site modulator
D-serine were reduced, and glycine levels appeared
unchanged. 3-Aminobenzamide significantly attenuated the elevations in
glutamate and phosphoethanolamine but had no effects on
D-serine and glycine.
Conclusions—Inhibition of PARP reduced injury after transient
focal ischemia in rats and attenuated NMDA-induced glutamate
efflux and overall neurotransmitter dysregulation. The deleterious
effects of excessive PARP activation may be related in part to
amplification of excitotoxicity, possibly by cellular energy depletion
and additional transmitter release and/or reduced reuptake.
Department
of Biochemistry and Biophysics,
University of Rochester,
School of Medicine and Dentistry,
Rochester, New York
© 1998 American Heart Association, Inc.
Original Contributions
Inhibition of Poly(ADP-Ribose) Polymerase
Reduction of Ischemic Injury and Attenuation of N-Methyl-D-Aspartate–Induced Neurotransmitter Dysregulation
Editorial Comment
Reduction of Ischemic Injury and Attenuation of N-Methyl-D-Aspartate–Induced Neurotransmitter Dysregulation
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