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Volume 17, Number 18, Issue of September 15, 1997 pp. 6908-6917
Copyright ©1997 Society for Neuroscience

Mechanisms of Reduced Striatal NMDA Excitotoxicity in Type I Nitric Oxide Synthase Knock-Out Mice

Received May 23, 1997; revised June 25, 1997; accepted July 7, 1997.

Cenk Ayata¹, Gamze Ayata¹, Hideaki Hara¹, Russel T. Matthews², M. Flint Beal², Robert J. Ferrante^{5, 6}, Matthias Endres¹, Albert Kim¹, Richard H. Christie³, Christian Waeber¹, Paul L. Huang⁴, Bradley T. Hyman³, and Michael A. Moskowitz¹

¹ Stroke and Neurovascular Regulation Laboratory, ² Neurochemistry Laboratory, ³ Alzheimer's Disease Research Unit, and ⁴ Cardiovascular Research Center, Departments of Medicine, Neurosurgery, and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, 02129, ⁵ Geriatric Research and Extended Care Center Unit, Bedford Veterans Affairs Medical Center, Bedford, Massachusetts 01730, and ⁶ Departments of Neurology and Pathology, Boston University School of Medicine, Boston, Massachusetts, 02118

We investigated the role of neuronal (type I) nitric oxide synthase (nNOS) in NMDA-mediated excitotoxicity in wild-type (SV129 and C57BL/6J) and type I NOS knock-out (nNOS^/) mice and examined its relationship to apoptosis. Excitotoxic lesions were produced by intrastriatal stereotactic NMDA microinjections (10-20 nmol). Lesion size was dose- and time-dependent, completely blocked by MK-801 pretreatment, and smaller in nNOS knock-out mice compared with wild-type littermates (nNOS^+/+, 11.7 ± 1.7 mm³; n = 8; nNOS^/, 6.4 ± 1.8 mm³; n = 7). The density and distribution of striatal NMDA binding sites, determined by NMDA receptor autoradiography, did not differ between strains. Pharmacological inhibition of nNOS by 7-nitroindazole (50 mg/kg, i.p.) decreased NMDA lesion size by 32% in wild-type mice (n = 7). Neurochemical and immunohistochemical measurements of brain nitrotyrosine, a product of peroxynitrite formation, were increased markedly in wild-type but not in the nNOS^/ mice. Moreover, elevations in 2,3- and 2,5-dihydroxybenzoic acid levels were significantly reduced in the mutant striatum, as a measure of hydroxyl radical production.

The importance of apoptosis to NMDA receptor-mediated toxicity was evaluated by DNA laddering and by quantitative histochemistry [terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) staining]. DNA laddering was first detected within lesioned tissue after 12-24 hr. TUNEL-positive cells were first observed at 12 hr, increased in number at 48 hr and 7 d, and were located predominantly in proximity to the lesion border. The density was significantly lower in nNOS^/ mice. Hence, oligonucleosomal DNA breakdown suggesting apoptosis develops as a late consequence of NMDA microinjection and is reduced in nNOS mutants. The mechanism of protection in nNOS^/ mice may relate to decreased oxygen free radical production and related NO reaction products and, in part, involves mechanisms of neuronal death associated with the delayed appearance of apoptosis.

Key words: NMDA; excitotoxicity; striatum; neuronal nitric oxide synthase; knock-out mice; nitrotyrosine; hydroxyl radical; apoptosis; DNA laddering; TUNEL staining

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