TIMP-1 Attenuates Blood–Brain Barrier Permeability in Mice with Acute Liver Failure

Abstract

Blood–brain barrier (BBB) dysfunction in acute liver failure (ALF) results in increased BBB permeability that often precludes the patients from obtaining a life-saving liver transplantation. It remains controversial whether matrix metalloproteinase-9 (MMP-9) from the injured liver contributes to the deregulation of BBB function in ALF. We selectively upregulated a physiologic inhibitor of MMP-9 (TIMP-1) with a single intracerebroventricular injection of TIMP-1 cDNA plasmids at 48 and 72 hours, or with pegylated-TIMP-1 protein. Acute liver failure was induced with tumor necrosis factor-α and 𝒟-(+)-galactosamine in mice. Permeability of BBB was assessed with sodium fluorescein (NaF) extravasation. We found a significant increase in TIMP-1 within the central nervous system (CNS) after the administration of TIMP-1 cDNA plasmids and that increased TIMP-1 within the CNS resulted in an attenuation of BBB permeability, a reduction in activation of epidermal growth factor receptor and p38 mitogen-activated protein kinase signals, and a restoration of the tight junction protein occludin in mice with experimental ALF. Pegylated TIMP-1 provided similar protection against BBB permeability in mice with ALF. Our results provided a proof of principle that MMP-9 contributes to the BBB dysfunction in ALF and suggests a potential therapeutic role of TIMP-1 in ALF.

IgG dynamics of dietary antigens point to cerebrospinal fluid barrier or flow dysfunction in first-episode schizophrenia

“…Future work is required to examine this hypothesis as well as to evaluate the function and stability of the choroid plexus and arachnoid membrane in post-mortem and imaging studies in schizophrenia. Results from studies in the fields of stroke, brain injury and liver failure, have shown that such compounds as melatonin, idazoxan, an imidazoline 2 receptor ligand, and inhibitors of matrix metalloproteinases may protect against blood-brain barrier and choroid plexus pathologies induced by a variety of methods in cell culture experiments and rodent models (Chen et al, 2013; Turgut et al, 2007; Verma et al, 2010; Wang et al, 2014). Thus, based on this work, therapies aimed to remove the antigenic source and to normalize endothelial barrier functions may be applicable treatment modalities to explore for safety and efficacy trials in schizophrenia.…”

Therapeutic Potential of Matrix Metalloproteinase Inhibition in Breast Cancer

“…Dissection of this process revealed that MMP-3 directly activates EMT [Lochter et al 1997; Lochter et al 1997] by activating alternative splice pathways which result in the expression of Rac1b [Radisky et al 2005; Pelisch et al 2012; Cichon et al 2015]. Rac1b is an activated splice variant with unique tumor-promoting activities [Orlichenko et al 2010], which stimulates EMT by increasing levels of cellular reactive oxygen species [Radisky et al 2005; Nelson et al 2008; Cichon and Radisky 2014], through a process that depends upon cell-ECM interactions [Lee et al 2012; Batra et al 2013; Chen et al 2013]. Thus, MMPs can stimulate invasion through both extrinsic (ECM-targeting) and intrinsic (cell phenotype alteration) processes.…”

“…A final challenge, given the short serum half-life of unmodified recombinant TIMPs in vivo [Batra et al 2012], will be to develop formulations and delivery methods capable of achieving sustained therapeutic concentrations. Promising approaches reported to date include PEGylation [Batra et al 2012; Chen et al 2013], fusion to serum albumin [Kang et al 2007; Lee et al 2011], nanoparticle delivery [Chaturvedi et al 2012; Chaturvedi et al 2014], and encapsulation in peptide hydrogels [Chowdhury et al 2017] to enhance recombinant TIMP availability, stability and efficacy in vivo .…”

Circulating Matrix Metalloproteinase-9 Level Is Associated with Cerebral White Matter Hyperintensities in Non-Stroke Individuals

“…Several studies have demonstrated that increased circulating MMP-9 level is associated with the BBB permeability changes in hemorrhagic transformation in stroke after thrombolytic therapy [34,35] and in acute liver failure [36]. These findings indicate that circulating MMP-9 level may reflect the status of BBB permeability.…”