Just got this through from the Journal of Cerebral Blood Flow and Metabolism. It shows how hypoxia breaks down the blood brain barrier.
Blood–brain barrier (BBB) disruption, resulting from loss of tight junctions (TJ) and activation of matrix metalloproteinases (MMPs), is associated with edema formation in ischemic stroke. Cerebral edema develops in a phasic manner and consists of both vasogenic and cytotoxic components. Although it is contingent on several independent mechanisms, involving hypoxic and inflammatory responses, the single effect of prolonged hypoxia on BBB integrity in vivo was not addressed so far. Exposing mice to normobaric hypoxia (8% oxygen for 48 h) led to a significant increase in vascular permeability associated with diminished expression of the TJ protein occludin. Immunofluorescence studies revealed that hypoxia resulted in disrupted continuity of occludin and zonula occludens-1 (Zo-1) staining with significant gap formation. Hypoxia increased gelatinolytic activity specifically in vascular structures and gel zymography identified MMP-9 as enzymatic source. Treatment with an MMP inhibitor reduced vascular leakage and attenuated disorganization of TJ. Inhibition of vascular endothelial growth factor (VEGF) attenuated vascular leakage and MMP-9 activation induced by hypoxia. In conclusion, our data suggest that hypoxia-induced edema formation is mediated by MMP-9-dependent TJ rearrangement by a mechanism involving VEGF. Therefore, inhibition of MMP-9 might provide the basis for therapeutic strategies to treat brain edema.[color=blue]
It's also on Pubmed but the url is just generic to the site for some reason.
I believe minocycline inhibits MMP9 as does salvia miltiorrhiza:
Zhong Xi Yi Jie He Xue Bao. 2009 Feb;7(2):145-50.
Salvianolic acid B in vitro inhibited matrix metalloproteinases-1, -2, and -9 activities.[color=blue]
Liang YH, Li P, Huang QF, Zhao JX, Liu X, Dai MK.
Department of Pathology, School of Preclinical Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
OBJECTIVE: Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases, which as a group can degrade essentially all extracellular matrix components. The proteolytic property of the MMPs is important during wound healing to remove debris and facilitate cell migration. Targeting towards the decreased MMPs activities is a new treatment strategy for healing chronic wounds. Salvia miltiorrhiza is a popular Chinese herb that could promote chronic ulcers healing for topical use. Salvianolic acid B (Sal B) is the most abundant bioactive component in Salvia miltiorrhiza. The research was designed to explore the inhibitory effects of Sal B on MMP-1, MMP-2 and MMP-9 activities. METHODS: Pure human interstitial collagenase (MMP-1) or gelatinase A (MMP-2) was activated by p-aminophenylmercuric acetate (APMA), and was incubated with Sal B for 1 h. The activities were observed by quenched fluorescent substrate. Gelatinase B (MMP-9) is rich in polymorphonuclear neutrophils (PMN), so the rat PMN was used as a source of MMP-9 for MMPs activity assays. In vitro MMP-9 from rats' PMN lysate was incubated with Sal B for 1 h, and its activity was tested by gelatin zymography. RESULTS: Sal B dose-dependently inhibited the human MMP-1 and MMP-2 activities in the range of 0.002 4 to 0.3 g/L, with 50% inhibiting concentration (IC(50)) of (0.090<0.015) g/L and (0.080<0.005) g/L respectively. In the range of 0.003 to 0.3 g/L, Sal B could inhibit the MMP-9 activity (P<0.01). CONCLUSION: The broad-spectrum inhibitory effects of Sal B on MMPs may reveal one of the mechanisms for the effects of Salvia miltiorrhiza on chronic wounds.
PMID: 19216858 [PubMed - in process]
J Am Coll Cardiol. 2010 Mar 23;55(12):1240-9.[color=blue]
Effect of an antimicrobial agent on atherosclerotic plaques: assessment of metalloproteinase activity by molecular imaging.
Ohshima S, Fujimoto S, Petrov A, Nakagami H, Haider N, Zhou J, Tahara N, Osako MK, Fujimoto A, Zhu J, Murohara T, Edwards DS, Narula N, Wong ND, Chandrashekhar Y, Morishita R, Narula J.
University of California Irvine School of Medicine, Irvine, California, USA.
OBJECTIVES: Technetium-99m-labeled matrix metalloproteinase inhibitor (MPI) was used for the noninvasive assessment of matrix metalloproteinase (MMP) activity in atherosclerotic plaques after minocycline (MC) intervention. BACKGROUND: MMP activity in atherosclerosis contributes to plaque instability. Some antimicrobial agents may attenuate MMP activity. METHODS: Atherosclerotic lesions were produced in 38 rabbits with a high cholesterol diet for 4 months; 5 groups of rabbits, in the fourth month, received fluvastatin (FS) (n = 6), low-dose MC (n = 7), high-dose MC (n = 7), a combination of low-dose MC and FS (n = 6), or no intervention (n = 12); 8 unmanipulated rabbits were used as disease controls. Micro-single-photon emission computed tomography imaging was performed in all animals after intravenous MPI administration, followed by pathologic characterization of the aorta. A cell culture study evaluated the effect of MC on MMP production by activated human monocytes. RESULTS: MPI uptake was visualized best in untreated atherosclerotic animals (percent injected dose per gram MPI uptake, 0.11 +/- 0.04%). MPI uptake was reduced in the FS (0.06 +/- 0.01%; p < 0.0001), high-dose MC (0.05 +/- 0.01%; p < 0.0001), and MC-FS (0.05 +/- 0.005%; p < 0.0001) groups. Low-dose MC did not resolve MPI uptake significantly (0.08 +/- 0.02; p = 0.167). There was no incremental benefit of the combination of MC and FS. MPI uptake showed a significant correlation with plaque MMP-2, and MMP-9 activity. MMP-9 release from tumor necrosis factor-alpha-activated macrophages was abrogated by incubation with MC. CONCLUSIONS: Molecular imaging of MMP activity in atherosclerotic plaque allows for the study of the efficacy of therapeutic interventions. MC administration resulted in substantial reduction in plaque MMP activity and histologically verified plaque stabilization. MC was found to be equally effective as FS. Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
PMID: 20298932 [PubMed - in process]