RT Journal Article
SR Electronic
T1 Neurodegeneration in Striatum Induced by the Mitochondrial Toxin 3-Nitropropionic Acid: Role of Matrix Metalloproteinase-9 in Early Blood-Brain Barrier Disruption?
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 8733
OP 8742
DO 10.1523/JNEUROSCI.23-25-08733.2003
VO 23
IS 25
A1 Gyung W. Kim
A1 Yvan Gasche
A1 Susanna Grzeschik
A1 Jean-Christophe Copin
A1 Carolina M. Maier
A1 Pak H. Chan
YR 2003
UL http://www.jneurosci.org/content/23/25/8733.abstract
AB 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.