Work

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

Year: 2003

Type: article

Abstract: 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 < or = 0.05; edema: 21.8 +/- 11.2 and 35.28 +/- 11, respectively, p < or = 0.05; MMP-9-positive cells: 352 +/- 57 and 510 +/- 45, respectively, p < or = 0.005), whereas knock-out mice deficient in SOD1 display significantly greater swelling (48.65 +/- 17; p < or = 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.

Source: Journal of Neuroscience

DOI: 10.1523/jneurosci.23-25-08733.2003

Authors: Gyung W. Kim, Yvan Gasche, Susanna Grzeschik, Jean-Christophe Copin, Carolina M. Maier, Pak H. Chan