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The Journal of Neuroscience, September 24, 2003, 23(25):8733-8742

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Cellular/Molecular
Neurodegeneration in Striatum Induced by the Mitochondrial Toxin 3-Nitropropionic Acid: Role of Matrix Metalloproteinase-9 in Early Blood-Brain Barrier Disruption?

Gyung W. Kim,^1,2 Yvan Gasche,^1,3 Susanna Grzeschik,¹ Jean-Christophe Copin,^1,3 Carolina M. Maier,¹ and Pak H. Chan¹

¹Department of Neurosurgery, Department of Neurology and Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Stanford, California 94305-5487, ²Department of Neurology, Yonsei University College of Medicine, 134 Sinchon-dong, Seodaemun-gu, Seoul, Korea, and ³Laboratory of Neurocritical Care Medicine, Divisions of Medical and Surgical Critical Care Medicine, Geneva University Hospital, 1211 Geneva 14, Switzerland

Blood-brain barrier (BBB) dysfunction is a potential mechanism involved in progressive striatal damage induced by the mitochondrial excitotoxin, 3-nitropropionic acid (3-NP). After activation by proteases and free radicals, matrix metalloproteinases (MMPs), particularly MMP-9 and -2, can digest the endothelial basal lamina leading to BBB opening. Using CD-1 mice, we show that MMP-9 expression by zymography is increased in the injured striatum compared with the contralateral striatum 2 hr after 3-NP injection [133.50 ± 57.17 vs 50.25 ± 13.56; mean ± SD of optical densities in arbitrary units (A.U.); p < 0.005] and remains elevated until 24 hr (179.33 ± 78.24 A.U.). After 4 hr, MMP-9 expression and activation are accompanied by an increase in BBB permeability. MMP inhibition attenuates BBB disruption, swelling, and lesion volume compared with vehicle-treated controls. There is a clear spatial relationship between MMP-9 expression and oxidized hydroethidine, indicating reactive oxygen species (ROS) production. Furthermore, transgenic mice that overexpress copper/zinc-superoxide dismutase (SOD1) show decreased lesion size and edema along with decreased immunoreactivity for MMP-9, compared with wild-type littermates (lesion: 38.8 ± 15.1 and 53.3 ± 10.3, respectively, p 0.05; edema: 21.8 ± 11.2 and 35.28 ± 11, respectively, p 0.05; MMP-9-positive cells: 352 ± 57 and 510 ± 45, respectively, p 0.005), whereas knock-out mice deficient in SOD1 display significantly greater swelling (48.65 ± 17; p 0.05). We conclude that early expression and activation of MMP-9 by ROS may be involved in early BBB disruption and progressive striatal damage after 3-NP treatment.

Key words: matrix metalloproteinase; 3-nitropropionic acid; blood-brain barrier; Evans blue extravasation; oxidative stress; striatum

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Received April 24, 2003; revised July 23, 2003; accepted August 12, 2003.

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