NMDA Receptor Activation Mediates Hydrogen Peroxide-Induced Pathophysiology in Rat Hippocampal Slices

• Published in: Journal of neurophysiology Vol. 87; no. 6; pp. 2896 - 2903
• Main Authors: Avshalumov, Marat V, Rice, Margaret E
• Format: Journal Article
• Language: English
• Published: United States Am Phys Soc 01.06.2002
• Subjects: 2-Amino-5-phosphonovalerate - pharmacology; Animals; Epilepsy - pathology; Epilepsy - physiopathology; Excitatory Amino Acid Antagonists - pharmacology; Glutamic Acid - metabolism; Hippocampus - drug effects; Hippocampus - pathology; Hippocampus - physiopathology; Hydrogen Peroxide - toxicity; Male; Organ Culture Techniques; Oxidants - toxicity; Rats; Rats, Long-Evans; Reactive Oxygen Species - metabolism; Receptors, N-Methyl-D-Aspartate - physiology
• ISSN: 0022-3077; 1522-1598
• DOI: 10.1152/jn.2002.87.6.2896

Departments of Physiology and Neuroscience and Neurosurgery, New York University School of Medicine, New York, New York 10016 Avshalumov, Marat V. and Margaret E. Rice. NMDA Receptor Activation Mediates Hydrogen Peroxide-Induced Pathophysiology in Rat Hippocampal Slices. J. Neurophysiol. 87: 2896-2903, 2002. Endogenous reactive oxygen species (ROS) can act as modulators of neuronal activity, including synaptic transmission. Inherent in this process, however, is the potential for oxidative damage if the balance between ROS production and regulation becomes disrupted. Here we report that inhibition of synaptic transmission in rat hippocampal slices by H 2 O 2 can be followed by electrical hyperexcitability when transmission returns during H 2 O 2 washout. As in previous studies, H 2 O 2 exposure (15 min) reversibly depressed the extracellular population spike (PS) evoked by Schaffer collateral stimulation. Recovery of PS amplitude, however, was typically accompanied by mild epileptiform activity. Inclusion of ascorbate (400 µM) during H 2 O 2 washout prevented this pathophysiology. No protection was seen with isoascorbate, which is a poor substrate for the stereoselective ascorbate transporter and thus remains primarily extracellular. Epileptiform activity was also prevented by the N -methyl- D -aspartate (NMDA) receptor antagonist, DL -2-amino-5-phosphonopentanoic acid (AP5) during H 2 O 2 washout. Once hyperexcitability was induced, however, AP5 did not reverse it. When present during H 2 O 2 exposure, AP5 did not alter PS depression by H 2 O 2 but did inhibit the recovery of PS amplitude seen during pulse-train stimulation (10 Hz, 5   s) in H 2 O 2 . Inhibition of glutamate uptake by l- trans -2,4-pyrrolidine dicarboxylate (PDC; 50 µM) during H 2 O 2 washout markedly enhanced epileptiform activity; coapplication of ascorbate with PDC prevented this. These data indicate that H 2 O 2 exposure can cause activation of normally silent NMDA receptors, possibly via inhibition of redox-sensitive glutamate uptake. When synaptic transmission returns during H 2 O 2 washout, enhanced NMDA receptor activity leads to ROS generation and consequent oxidative damage. These data reveal a pathological cycle that could contribute to progressive degeneration in neurological disorders that involve oxidative stress, including cerebral ischemia.