Matrix metalloproteinases inhibition provides neuroprotection against hypoxia‐ischemia in the developing brain

Abstract

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.

Morphine Tolerance and Physical Dependence Are Altered in Conditional HIV-1 Tat Transgenic Mice

“…Furthermore, a significant DOX effect was noted for platform jumping, with the sensitivity of placebo-pelleted C57 mice to acute morphine being reduced after DOX administration. It is possible that chronic morphine-induced inflammatory effects, such as increases in IL-1b or other cytokines (Liu et al, 2011;Merighi et al, 2013) might be reduced by DOX itself because DOX is reported to have modest anti-inflammatory effects at high doses (Chen et al, 2009;Chaudhry et al, 2010). Further, DOX increased the ED 50 on the %MPE in the tail-flick assay for all morphine-pelleted groups (no increase was noted in placebopelleted mice).…”

Increased MMP-9 and TIMP-1 in mouse neonatal brain and plasma and in human neonatal plasma after hypoxia–ischemia: a potential marker of neonatal encephalopathy

“…This balance between the two molecules is thought to reduce brain damage in HI events by protecting the blood-brain barrier (7). MMP inhibition provides neuroprotection against HI in the developing brain (21). A neuroprotective role for TIMP-1 in excitotoxic damage and ischemia has been previously proposed (10,11,22).…”

Occludin: One Protein, Many Forms

“…For the endothelium, much in vivo evidence exists to support a role for MMP-mediated occludin proteolysis, particularly during blood-brain barrier (BBB) pathologies. Rodent models of cerebral ischemic injury, for example, demonstrate elevated levels of MMP-2/9 leading to occludin fragmentation in brain microvessels, with resultant elevated leakage and brain edema (13,20,64,114,128). Yang et al (128) went on to describe the temporal dynamics of these events, confirming that constitutively active MMP-2 is responsible for occludin cleavage and TJ "loosening" during the early transient phase of the ischemia (3 h), while MMP-9 and other products of extended neuroinflammation and reperfusion injury (e.g., reactive oxygen species) cause further occludin degradation and more long-term (24-h) alterations to BBB integrity.…”