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

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.

Role of Nrf2 in protection against intracerebral hemorrhage injury in mice

“…8-hydroxyguanosine (8-OHG) is a reliable and commonly used biomarker for oxidative DNA damage caused by superoxide anion, as shown previously after various forms of brain injury [27][28][29], including ICH [28,30]. Here, 8-OHG-positive cells were detected around the injury site 24 h post-ICH in WT and Nrf2 −/− mice (Fig.…”

Neurological Diseases in Relation to the Blood–Brain Barrier

“…Scavenging O 2 À. radicals using recombinant superoxide dismutase (SOD) or polyethylene glycol-SOD reduces ischemia-induced BBB injury and vasogenic edema. Superoxide dismutase 1-overexpressing mice also have reduced activation of MMP-9 by reactive oxygen species, which may be involved in early BBB disruption and progressive striatal damage induced by the mitochondrial excitotoxin, 3-nitropropionic acid (Kim et al, 2003).…”

Oxidative stress in glaucomatous neurodegeneration: Mechanisms and consequences

“…Matrix metalloproteinase activity in association with ROS production has been linked to various tissue remodeling events, which may also have important implications in glaucomatous neurodegeneration. For example, ROS-regulated matrix metalloproteinase activity has been associated with the disruption of blood-brain barrier through digestion of the endothelial basal lamina (Kim et al, 2003). Increased matrix metalloproteinases in the perivascular area of glaucomatous eyes may similarly influence the blood-eye barrier in these eyes.…”