Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases which are capable of degrading many types of extracellular matrix proteins and involved in the process of tissue remodeling in various pathologic conditions, including inflammatory diseases, tumor cell invasion, and angiogenesis. Previous studies suggest that MMPs, in particular MMP-2 and MMP-9, are deleterious in the brain after stroke (Power et al. 2003;Svedin et al. 2007). In acute stage after ischemic stroke, the effect of MMP activity is correlated to degradation of neurovascular matrix and opening of blood-brain barrier (BBB), which promotes vasogenic edema and results in neurological deficits. However, recent studies suggest that MMPs were also indicated to be involved in the repairing phase in the delayed stage after cerebral ischemia, including neuroblasts migration and neuronal plasticity (Lee et al. 2006;Zhao et al. 2006 AbstractThe present study was designed to investigate the role of matrix metalloproteinases (MMPs) in the immature brain and the long term effects of early MMPs inhibition after hypoxicischemic (HI) injury. HI was induced by unilateral ligation of the right carotid artery followed by hypoxia (8% O 2 for 2 h) in P7 rat pups. GM6001, a broad spectrum MMPs inhibitor, was injected (50 mg/kg or 100 mg/kg) intraperitoneally at 2 h and 24 h after HI injury. Blood-brain barrier (BBB) integrity, brain edema, MMP-2/-9 activity, TIMP-1/-2 and tight junction protein (TJP) level were evaluated using IgG staining, Evan's blue extravasation, brain water content, zymography and western blot. Doxycycline, another MMPs inhibitor, was injected (10 mg/kg or 30 mg/kg) intraperitoneally at 2 h after HI, then BBB integrity and brain edema were measured at 48 h post-HI using brain water content measurement and IgG staining. The long-term effects of early MMPs inhibition (GM6001, 100 mg/ kg) were evaluated by neurobehavioral tests, body weight, and brain atrophy measurement. GM6001 attenuated brain edema and BBB disruption at the dosage of 100 mg/kg. MMP-2 activity increased at 24 h and peaked at 48 h after HI, whereas MMP-9 activity peaked at 24 h and tapered by 48 h after HI. MMP-9/-2 activities were significantly attenuated by GM6001 at 24 h and 48 h after HI. The degradation of TJPs (ZO-1 and occludin) at 48 h after HI was reversed by GM6001 treatment. Early MMPs inhibition had long-term effects that attenuated ipsilateral brain tissue loss, and improved neurobehavioral outcomes after HI. These results suggest that early MMPs inhibition with a broad-spectrum inhibitor provides both acute and long-term neuroprotection in the developing brain by reducing TJPs degradation, preserving BBB integrity, and ameliorating brain edema after neonatal HI injury. Keywords: blood-brain barrier, hypoxic/ischemic, matrix metalloproteinase, neonatal.

Clinical studies suggest that traumatic brain injury (TBI) hastens cognitive decline and development of neuropathology resembling brain aging. Blood-brain barrier (BBB) disruption following TBI may contribute to the aging process by deregulating substance exchange between the brain and blood. We evaluated the effect of juvenile TBI (jTBI) on these processes by examining long-term alterations of BBB proteins, β-amyloid (Aβ) neuropathology, and cognitive changes. A controlled cortical impact was delivered to the parietal cortex of male rats at postnatal day 17, with behavioral studies and brain tissue evaluation at 60 days post-injury (dpi). Immunoglobulin G extravasation was unchanged, and jTBI animals had higher levels of tight-junction protein claudin 5 versus shams, suggesting the absence of BBB disruption. However, decreased P-glycoprotein (P-gp) on cortical blood vessels indicates modifications of BBB properties. In parallel, we observed higher levels of endogenous rodent Aβ in several brain regions of the jTBI group versus shams. In addition at 60 dpi, jTBI animals displayed systematic search strategies rather than relying on spatial memory during the water maze. Together, these alterations to the BBB phenotype after jTBI may contribute to the accumulation of toxic products, which in turn may induce cognitive differences and ultimately accelerate brain aging.

Spontaneous cerebellar hemorrhage (SCH) represents approximately 10% of all intracerebral hemorrhage (ICH), and is an important clinical problem of which little is known. This study stereotaxically infused collagenase (type VII) into the deep cerebellar paramedian white matter, which corresponds to the most common clinical injury region. Measures of hemostasis (brain water, hemoglobin assay, Evans blue, collagen-IV, ZO-1, and MMP-2 and MMP-9) and neurodeficit were quantified twenty-four hours later (Experiment 1). Long-term functional outcomes were measured over thirty days using the ataxia scale (modified Luciani), open field, wire suspension, beam balance and inclined plane (Experiment 2). Neurocognitive ability was assessed on the third week using the rotarod (motor learning), T-maze (working memory) and water-maze (spatial learning and memory) (Experiment 3), followed by a histopathological analysis one week later (Experiment 4). Stereotaxic collagenase infusion caused dose-dependent elevations in brain edema, neurodeficit, hematoma volume and blood-brain barrier rupture, while physiological variables remained stable. Most functional outcomes normalized by third week, while neurocognitive testing showed deficits parallel to the cystic-cavitary lesion at thirty days. All animals survived until sacrifice, and obstructive hydrocephalus did not develop. These results suggest that the model can generate important translational information about this subtype of ICH, and could be used for future investigations of therapeutic mechanisms after cerebellar hemorrhage.

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This study has implications for improving neurorehabilitation treatment, as targeting sleep dysfunction for early intervention may facilitate cognitive recovery.