Inhibition of MMP-9 by a selective gelatinase inhibitor protects neurovasculature from embolic focal cerebral ischemia

Cui, Jiankun; Chen, Shanyan; Zhang, Chunyang; Meng, Fanjun; Wu, Wei; Hu, Rong; Hadass, Or; Lehmidi, Tareq; Blair, Gregory J.; Lee, Mijoon; Chang, Mayland; Mobashery, Shahriar; Sun, Grace Y.; Z, Gu

doi:10.1186/1750-1326-7-21

Cited by 104 publications

(118 citation statements)

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“…In fact, SB-3CT-treatment for 7 days in a permanent mouse model of ischemia is neuroprotective. 15 NXY-059, a free radical trapping agent that failed in clinical trials for acute ischemic stroke, has been reported to lack BBB penetration. 16 Recently, NXY-059 was shown to have limited brain penetration with maximal brain concentrations of 6 pmol/mg (equivalent to approximately 1% of plasma concentration) after continuous intravenous infusion to rats at 125 mg/kg.…”

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confidence: 99%

Selective Gelatinase Inhibitor Neuroprotective Agents Cross the Blood-Brain Barrier

Gooyit

Suckow

Schroeder

et al. 2012

ACS Chem. Neurosci.

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SB-3CT, a potent and selective inhibitor of matrix metalloproteinase-2 and -9, has shown efficacy in several animal models of neurological diseases. One of the greatest challenges in the development of therapeutics for neurological diseases is the inability of drugs to cross the blood-brain barrier. A sensitive bioanalytical method based on ultraperformance liquid chromatography with multiple-reaction monitoring detection was developed to measure levels of SB-3CT, its active metabolite, the α-methyl analogue, and its p-hydroxy metabolite in plasma and brain. The compounds are rapidly absorbed and are readily distributed to the brain. The pharmacokinetic properties of these gelatinase inhibitors and the efficacy shown by SB-3CT in animal models of stroke, subarachnoid hemorrhage, and spinal cord injury indicate that this class of compounds holds considerable promise in the treatment of diseases of the central nervous system. KEYWORDS: Gelatinase inhibitors, matrix metalloproteinases, brain delivery, SB-3CT S B-3CT (compound 1, Figure 1), is a thiirane-based inhibitor that is selective for matrix metalloproteinase (MMP)-2 and -9, 1 also known as gelatinases. This compound has shown efficacy in a number of neurological diseases, including blocking laminin degradation by MMP-9 and rescuing neurons from apoptosis after transient focal cerebral ischemia, 2 preventing laminin degradation after subarachnoid hemorrhage, 3 reducing cerebral vasopasm caused by subarachnoid hemorrhage, 4 reducing the infiltration of monocytes into the injured spinal cord, 5 and decreasing extravasation and apoptotic cell death after spinal cord injury. 6 The compounds of the thiirane class have a unique mechanism of action, involving ring-opening of the thiirane ring at the active site of gelatinases and generation of the thiolate, which is a picomolar and tight-binding inhibitor. 7The blood-brain barrier (BBB) forms a physical separation between circulating blood and the brain parenchyma and consists of tight junctions around endothelial cells surrounded by basement membrane. The BBB prevents pathogens and large hydrophilic molecules from entering the brain, while allowing transport of substances needed by the central nervous system (CNS) such as glucose, fatty acids, and vitamins. One of the most challenging issues in the development of therapeutics for neurological diseases is the inability of drugs to cross the BBB. In fact, greater than 98% of small-molecule drugs and 100% of large-molecule therapeutics do not cross the BBB. Only 5% of small-molecule drugs in the Comprehensive Medicinal Chemistry database treat a mere four CNS diseases: depression, schizophrenia, chronic pain, and epilepsy.9,10 The vast majority of CNS disorders, including debilitating diseases

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confidence: 99%

Selective Gelatinase Inhibitor Neuroprotective Agents Cross the Blood-Brain Barrier

Gooyit

Suckow

Schroeder

et al. 2012

ACS Chem. Neurosci.

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“…Nevertheless, we observed that MMP-9 was the predominant gelatinase under our experimental conditions. 8,20,21,32 It should be noted, however, that our present ACPPs do not discriminate between MMP-2 and MMP-9, although we are actively developing more selective ACPPs.…”

Section: Discussionmentioning

confidence: 99%

“…Two mouse models of focal cerebral ischemia were used in this study: a filament-occlusion model and an embolic ischemia model, representing mechanical blockage and clot-induced occlusion, respectively, as we have previously described. 20,21 All animal experiments were approved by the University of Missouri-Columbia Animal Care and Usage Committee and performed in accordance with the ARRIVE guidelines. Adult male C57BL/6J mice (8-10 weeks old from The Jackson Laboratory, Bar Harbor, ME), weighing 20-25 g, were housed in a 12-h light/dark cycle and permitted food and water intake ad libitum.…”

Section: Experimental Models Of Focal Cerebral Ischemiamentioning

confidence: 99%

“…The gelatinase selective inhibitor SB-3CT (12.5 mg/mL) was prepared as a suspension formulated in vehicle [25% DMSO/65% polyethylene glycol 200 (PEG-200)/10% H 2 O], as described previously. 20 Mice were intraperitoneally injected with 2 mL/gram body weight of this solution (equivalent to 25 mg/kg) 2 h after embolic ischemia, followed by an additional dose at 4 h. Animals were randomly assigned to different experimental groups.…”

Section: Experimental Models Of Focal Cerebral Ischemiamentioning

confidence: 99%

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Gelatinase activity imaged by activatable cell-penetrating peptides in cell-based and in vivo models of stroke

Chen

Cui

Jiang

et al. 2016

J Cereb Blood Flow Metab

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Matrix metalloproteinases (MMPs), particularly gelatinases (MMP-2/-9), are involved in neurovascular impairment after stroke. Detection of gelatinase activity in vivo can provide insight into blood-brain barrier disruption, hemorrhage, and nerve cell injury or death. We applied gelatinase-activatable cell-penetrating peptides (ACPP) with a cleavable L-amino acid linker to examine gelatinase activity in primary neurons in culture and ischemic mouse brain in vivo. We found uptake of Cy5-conjugated ACPP (ACPP-Cy5) due to gelatinase activation both in cultured neurons exposed to N-methyl-D-aspartate and in mice after cerebral ischemia. Fluorescence intensity was significantly reduced when cells or mice were treated with MMP inhibitors or when a cleavage-resistant ACPP-Cy5 was substituted. We also applied an ACPP dendrimer (ACPPD) conjugated with multiple Cy5 and/or gadolinium moieties for fluorescence and magnetic resonance imaging (MRI) in intact animals. Fluorescence analysis showed that ACPPD was detected in subfemtomole range in ischemic tissues. Moreover, MRI and inductively coupled plasma mass spectrometry revealed that ACPPD produced quantitative measures of gelatinase activity in the ischemic region. The resulting spatial pattern of gelatinase activity and neurodegeneration were very similar. We conclude that ACPPs are capable of tracing spatiotemporal gelatinase activity in vivo, and will therefore be useful in elucidating mechanisms of gelatinase-mediated neurodegeneration after stroke.

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“…Latronico and Liuzzi as the ability to prevent damage during cerebral ischemia 27 and to attenuate damage resulting from traumatic brain injury. 28 An attempt to develop specific inhibitors of MMP-2 and MMP-9 was made by synthesizing cyclic peptides corresponding to the frequently observed motifs in MMPactive sites, thus preventing substrate access.…”

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confidence: 99%

Metalloproteinases and their inhibitors as therapeutic targets for multiple sclerosis: current evidence and future perspectives

Latronico¹,

Liuzzi²

2017

MNM

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Abstract:The treatment of multiple sclerosis (MS) has seen important changes in the last two decades with the introduction of several drugs able to modify the evolution of this disease. Current MS therapies primarily target the peripheral immune response, although it has been suggested that their efficacy could be in part the result of the beneficial effect on other nonspecific targets, such as matrix metalloproteinases (MMPs). Numerous experimental studies have suggested that MMPs may be involved in MS pathogenesis by contributing to blood-brain barrier disruption, migration of leukocytes into the central nervous system, demyelination and axonal damage. Therefore, MMPs have been considered important therapeutic targets in the course of MS. In this respect, different attempts have been made to develop synthetic, low-molecular-weight inhibitors of MMPs for the potential treatment of diseases in which MMPs play a major role. However, technical difficulties, side effects and reduced patient compliance because of parenteral administration have greatly limited the development in the clinical practice of specific anti-MMP drugs. By contrast, interesting results have been obtained with compounds that are already used in the clinical practice, such as MS drugs and natural compounds with anti-inflammatory and antioxidant activity. Here, we discuss the evidence and potential mechanisms for altered MMP function in MS. Furthermore, we outline the possible medical implications for the use of compounds that target MMP activity and we propose that together with anti-MS drugs, other compounds with anti-inflammatory and antioxidant properties, such as natural ω3 fatty acids, polyphenols and tetracyclines, which inhibit MMP functions, might represent potential therapeutic approaches to mitigate MMP-related damage during MS.

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Inhibition of MMP-9 by a selective gelatinase inhibitor protects neurovasculature from embolic focal cerebral ischemia

Cited by 104 publications

References 47 publications

Selective Gelatinase Inhibitor Neuroprotective Agents Cross the Blood-Brain Barrier

Selective Gelatinase Inhibitor Neuroprotective Agents Cross the Blood-Brain Barrier

Gelatinase activity imaged by activatable cell-penetrating peptides in cell-based and in vivo models of stroke

Metalloproteinases and their inhibitors as therapeutic targets for multiple sclerosis: current evidence and future perspectives

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