sb-3ct-compound and Disease-Models--Animal

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Topics: Animals; Aquaporin 4; Blood-Brain Barrier; Brain Edema; Claudin-5; Disease Models, Animal; Enzyme Inhibitors; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Hallucinogens; Heterocyclic Compounds, 1-Ring; Low Density Lipoprotein Receptor-Related Protein-1; Magnetic Resonance Imaging; Male; Matrix Metalloproteinase 9; N-Methyl-3,4-methylenedioxyamphetamine; Permeability; Plasminogen; Rats; Sulfones; Time Factors

To investigate the roles of a selective MMP-2 and -9 inhibitor (SB-3CT) in corneal inflammatory lymphangiogenesis.. The expression of MMP-2 and -9 in the cornea after suture inplacement, treated with SB-3CT or negative control, was detected by real-time polymerase chain reaction (PCR). Inflammatory corneal neovascularization (NV) was induced by corneal suture placement. Mice were treated with SB-3CT eye drops (twice daily for 1 week, 5 μL per drop; 50, 100, or 200 μM). The outgrowth of blood and lymphatic vessels, and macrophage recruitment were analyzed by immunofluorescence assay. The expressions of vascular endothelial growth factor-C (VEGF-C) and its receptor VEGFR-3 were tested by real-time PCR.. MMP-2 and -9 expression were suppressed significantly by treatment with SB-3CT. The data demonstrated, for the first time, that SB-3CT strongly reduced corneal lymphangiogenesis and macrophage infiltration during inflammation. Furthermore, expressions of VEGF-C and its receptor VEGFR-3 were significantly inhibited by SB-3CT during corneal lymphangiogenesis.. These novel findings indicated that blockade of MMP-2 and -9 could inhibit lymphangiogenesis. Further investigation of this factor may provide novel therapies for transplant rejection and other lymphatic disorders.

Topics: Animals; Cornea; Corneal Neovascularization; Disease Models, Animal; Gene Expression Regulation; Heterocyclic Compounds, 1-Ring; Lymphangiogenesis; Lymphatic Vessels; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Real-Time Polymerase Chain Reaction; RNA; Sulfones

Tuberculous meningitis (TBM) is an outcome of neuroinflammatory degeneration caused due to Mycobacterium tuberculosis infection and leads to death or neurological disabilities in the affected individuals. It causes the highest morbidity and mortality amongst all forms of tuberculosis. Matrix metalloproteinase-9 levels increase and cause inflammatory destruction during progression of the disease. Although corticosteroids are usually given as an adjuvant therapy to overcome these complications, treatment outcome is contradictory. This study was designed to evaluate whether specific inhibition of MMP-9 can be beneficial in management of the disease. MMP-9 levels were inhibited using SB-3CT or dexamethasone along with conventional drugs for treatment of tuberculous meningitis. Both SB-3CT and dexamethasone decreased the elevated levels of MMP-9 in sera and tissues of the infected mice. However, dexamethasone administration had an inhibitory effect on bacillary clearance, while SB-3CT potentiated the bacillary clearance, suggesting that MMP-9, if specifically inhibited, can be beneficial in the management of TBM.

Topics: Animals; Antitubercular Agents; Dexamethasone; Disease Models, Animal; Drug Synergism; Heterocyclic Compounds, 1-Ring; Matrix Metalloproteinase 9; Mice; Mycobacterium tuberculosis; Protease Inhibitors; Sulfones; Tuberculosis, Meningeal

Our previous study determined that prominent cerebral vasospasm (CVS) may occur in an in vivo model of subarachnoid hemorrhage (SAH) in rats. Matrix metalloproteinase 9 (MMP‑9) expression levels in basilar arteries were upregulated in a similar manner to the development of CVS following SAH. To identify the changes that occur in the contractility of cerebrovascular smooth muscle cells and the expression levels of MMP‑9 in an in vitro model of SAH, rat cerebrovascular smooth muscle cells were isolated, cultured, and then stimulated with hemolysate. Additionally, 2-[(4-phenoxyphenylsulfonyl)methyl]thiirane (SB-3CT), a selective MMP-9 inhibitor, was used to determine the effect of MMP‑9 on the contractility of cerebrovascular smooth muscle cells. Cerebrovascular smooth muscle cells were successfully isolated and cultured in vitro, and hemolysate stimulation enhanced their contractility and increased MMP‑9 expression levels. The present study also revealed that pretreatment with SB‑3CT decreased MMP‑9 expression levels in cerebrovascular smooth muscle cells, and reduced their contractility upon hemolysate treatment. Therefore, the current study confirmed that MMP‑9 is important for the enhancement of the contractility of cerebrovascular smooth muscle cells in an in vitro rat model of SAH.

Topics: Animals; Basilar Artery; Cells, Cultured; Disease Models, Animal; Heterocyclic Compounds, 1-Ring; Humans; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Muscle Contraction; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Rats; Subarachnoid Hemorrhage; Sulfones

Retinitis Pigmentosa (RP) is one of the most common forms of inherited visual loss with the initial degeneration of rod photoreceptors, followed by a progressive cone photoreceptor deterioration. Coinciding with this visual loss, the extracellular matrix (ECM) is reorganized, which alters matrix metalloproteinase (MMP) activity levels. A potential pathological role of MMPs, MMP-9 in particular, involves an excitotoxicity-mediated physiological response. In the current study, we examine the MMP-9 and MMP-2 expression levels in the rhodopsin S334ter-line3 RP rat model and investigate the impact of treatment with SB-3CT, a specific MMP-9 and MMP-2 inhibitor, on rod cell survival was tested. Retinal MMP-9 and MMP-2 expression levels were quantified by immunoblot analysis from S334ter-line3 rats compared to controls. Gelatinolytic activities of MMP-9 and MMP-2 by zymography were examined. The geometry of rod death was further evaluated using Voronoi analysis. Our results revealed that MMP-9 was elevated while MMP-2 was relatively unchanged when S334ter-line 3 retinas were compared to controls. With SB-3CT treatment, we observed gelatinolytic activity of both MMPs was decreased and diminished clustering associated with rod death, in addition to a robust preservation of rod photoreceptors. These results demonstrate that up-regulation of MMP-9 in retinas of S334ter-line3 are associated with rod death. The application of SB-3CT dramatically interferes with mechanisms leading to apoptosis in an MMP-9-dependent manner. Future studies will determine the feasibility of using SB-3CT as a potential therapeutic strategy to slow progression of vision loss in genetic inherited forms of human RP.

Topics: Animals; Cells, Cultured; Disease Models, Animal; Female; Heterocyclic Compounds, 1-Ring; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Protease Inhibitors; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Retinal Degeneration; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa; Sulfones

SB-3CT is a potent and selective inhibitor of matrix metalloproteinase (MMP)-2 and -9, which has shown efficacy in an animal model of severe traumatic brain injury (TBI). However, SB-3CT is poorly water-soluble and is metabolized primarily to p-hydroxy SB-3CT (2), a more potent inhibitor than SB-3CT. We synthesized the O-phosphate prodrug (3) of compound 2 to enhance its water solubility by more than 2000-fold. The prodrug 3 was a poor MMP inhibitor, but readily hydrolyzed to the active 2 in human blood. Pharmacokinetics and brain distribution studies in mice showed that 2 crossed the blood-brain barrier (BBB) and achieved therapeutic concentrations in the brain. The prodrug 3/compound 2 was evaluated in a mouse model of severe TBI and found to significantly decrease the brain lesion volume and improve neurological outcomes. MMP-9 inhibition by a water-soluble thiirane inhibitor is a promising therapy for treatment of TBI.

Topics: Animals; Area Under Curve; Blood-Brain Barrier; Brain Injuries; Cell Line; Disease Models, Animal; Dose-Response Relationship, Drug; Heterocyclic Compounds, 1-Ring; Inhibitory Concentration 50; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred C57BL; Neurologic Examination; Psychomotor Performance; Solubility; Sulfones; Water

The gelatinases, matrix metalloproteinases (MMP)-2 and MMP-9, are thought to be key mediators of secondary damage in adult animal models of brain injury. Moreover, an acute increase in these proteases in plasma and brain extracellular fluid of adult patients with moderate-to-severe traumatic brain injuries (TBIs) is associated with poorer clinical outcomes and mortality. Nonetheless, their involvement after TBI in the pediatric brain remains understudied. Using a murine model of TBI at postnatal day 21 (p21), approximating a toddler-aged child, we saw upregulation of active and pro-MMP-9 and MMP-2 by gelatin zymography at 48 h post-injury. We therefore investigated the role of gelatinases on long-term structural and behavioral outcomes after injury after acute inhibition with a selective gelatinase inhibitor, p-OH SB-3CT. After systemic administration, p-OH SB-3CT crossed the blood-brain barrier at therapeutically-relevant concentrations. TBI at p21 induced hyperactivity, deficits in spatial learning and memory, and reduced sociability when mice were assessed at adulthood, alongside pronounced tissue loss in key neuroanatomical regions. Acute and short-term post-injury treatment with p-OH SB-3CT did not ameliorate these long-term behavioral, cognitive, or neuropathological deficits as compared to vehicle-treated controls, suggesting that these deficits were independent of MMP-9 and MMP-2 upregulation. These findings emphasize the vulnerability of the immature brain to the consequences of traumatic injuries. However, early upregulation of gelatinases do not appear to be key determinants of long-term recovery after an early-life injury.

Topics: Animals; Biological Transport; Blood-Brain Barrier; Brain Injuries; Child, Preschool; Disease Models, Animal; Gene Expression; Heterocyclic Compounds, 1-Ring; Humans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Maze Learning; Mice; Mice, Inbred C57BL; Prognosis; Recovery of Function; Social Isolation; Spatial Memory; Sulfones; Trauma Severity Indices; Treatment Failure

Blood-brain-barrier (BBB) breakdown and cerebral edema result from postischemic inflammation and contribute to mortality and morbidity after ischemic stroke. A functional role for the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in the regulation of reperfusion injury has not yet been demonstrated.. We sought to identify and characterize the relevance of CEACAM1-expressing inflammatory cells in BBB breakdown and outcome after ischemic stroke in Ceacam1(-/-) and wild-type mice.. Focal ischemia was induced by temporary occlusion of the middle cerebral artery with a microfilament. Using MRI and Evans blue permeability assays, we observed increased stroke volumes, BBB breakdown and edema formation, reduction of cerebral perfusion, and brain atrophy in Ceacam1(-/-) mice. This translated into poor performance in neurological scoring and high poststroke-associated mortality. Elevated neutrophil influx, hyperproduction, and release of neutrophil-related matrix metalloproteinase-9 in Ceacam1(-/-) mice were confirmed by immune fluorescence, flow cytometry, zymography, and stimulation of neutrophils. Importantly, neutralization of matrix metalloproteinase-9 activity in Ceacam1(-/-) mice was sufficient to alleviate stroke sizes and improve survival to the level of CEACAM1-competent animals. Immune histochemistry of murine and human poststroke autoptic brains congruently identified abundance of CEACAM1(+)matrix metalloproteinase-9(+) neutrophils in the ischemic hemispheres.. CEACAM1 controls matrix metalloproteinase-9 secretion by neutrophils in postischemic inflammation at the BBB after stroke. We propose CEACAM1 as an important inhibitory regulator of neutrophil-mediated tissue damage and BBB breakdown in focal cerebral ischemia.

Topics: Animals; Antigens, CD; Atrophy; Behavior, Animal; Blood-Brain Barrier; Brain Edema; Capillary Permeability; Carcinoembryonic Antigen; Cell Adhesion Molecules; Disease Models, Animal; Flow Cytometry; Heterocyclic Compounds, 1-Ring; Humans; Infarction, Middle Cerebral Artery; Inflammation Mediators; Magnetic Resonance Imaging; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Motor Activity; Neurologic Examination; Neutrophil Activation; Neutrophil Infiltration; Neutrophils; Sulfones; Time Factors

Cerebral ischemia has been shown to induce activation of matrix metalloproteinases (MMPs), particularly MMP-9, which is associated with impairment of the neurovasculature, resulting in blood-brain barrier breakdown, hemorrhage and neurodegeneration. We previously reported that the thiirane inhibitor SB-3CT, which is selective for gelatinases (MMP-2 and -9), could antagonize neuronal apoptosis after transient focal cerebral ischemia.. Here, we used a fibrin-rich clot to occlude the middle cerebral artery (MCA) and assessed the effects of SB-3CT on the neurovasculature. Results show that neurobehavioral deficits and infarct volumes induced by embolic ischemia are comparable to those induced by the filament-occluded transient MCA model. Confocal microscopy indicated embolus-blocked brain microvasculature and neuronal cell death. Post-ischemic SB-3CT treatment attenuated infarct volume, ameliorated neurobehavioral outcomes, and antagonized the increases in levels of proform and activated MMP-9. Embolic ischemia caused degradation of the neurovascular matrix component laminin and tight-junction protein ZO-1, contraction of pericytes, and loss of lectin-positive brain microvessels. Despite the presence of the embolus, SB-3CT mitigated these outcomes and reduced hemorrhagic volumes. Interestingly, SB-3CT treatment for seven days protected against neuronal laminin degradation and protected neurons from ischemic cell death.. These results demonstrate considerable promise for the thiirane class of selective gelatinase inhibitors as potential therapeutic agents in stroke therapy.

Topics: Animals; Brain Ischemia; Cerebrovascular Circulation; Disease Models, Animal; Heterocyclic Compounds, 1-Ring; Immunohistochemistry; Intracranial Embolism; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred C57BL; Sulfones

An increasing number of unruptured intracranial aneurysms are being detected, partly due to the increased use of brain imaging techniques. Pharmacological stabilization of aneurysms for the prevention of aneurysmal rupture could potentially be an attractive alternative approach to clipping or coiling in patients with unruptured intracranial aneurysms. We have developed a mouse model of intracranial aneurysm that recapitulates key features of intracranial aneurysms. In this model, subarachnoid hemorrhage from aneurysmal rupture causes neurological symptoms that can be easily detected by a simple neurological examination. Using this model, we tested whether anti-inflammatory agents such as tetracycline derivatives, or a selective inhibitor of matrix metalloproteinases-2 and -9 (SB-3CT), can prevent the rupture of intracranial aneurysms.. Aneurysms were induced by a combination of induced hypertension and a single injection of elastase into the cerebrospinal fluid in mice. Treatment with minocycline, doxycycline, or SB-3CT was started 6 days after aneurysm induction. Aneurysmal rupture was detected by neurological symptoms and confirmed by the presence of intracranial aneurysms with subarachnoid hemorrhage.. Minocycline and doxycycline significantly reduced rupture rates (vehicle versus doxycycline=80% versus 35%, P<0.05; vehicle versus minocycline=73% versus 24%, P<0.05) without affecting the overall incidence of aneurysms. However, SB-3CT did not affect the rupture rate (62% versus 55%, P=0.53).. Our data established the feasibility of using a mouse model of intracranial aneurysm to test pharmacological stabilization of aneurysms. Tetracycline derivatives could be potentially effective in preventing aneurysmal rupture.

Topics: Aneurysm, Ruptured; Animals; Blood Pressure; Disease Models, Animal; Doxycycline; Feasibility Studies; Gelatinases; Heterocyclic Compounds, 1-Ring; Intracranial Aneurysm; Male; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred C57BL; Minocycline; Neurologic Examination; Protease Inhibitors; Subarachnoid Hemorrhage; Sulfones; Survival Analysis; Tetracyclines

This study investigated the role of matrix metalloproteinase-9 (MMP-9) in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Sprague-Dawley male rats (n=30) between 250 and 300 g were used. SAH was produced by injecting autologous arterial blood into the prechiasmatic cistern. SB-3CT, a selective MMP-9 inhibitor, was injected intraperitoneally after SAH induction. MMP-9 protein expression was measured by western blot; laminin expression and neuronal cells in the cerebral cortex were studied by immunohistochemistry and TUNEL staining at 24h after SAH. MMP-9 expression was increased after SAH and decreased by SB-3CT inhibition at 24h after SAH (P<0.01). Laminin, the substrate of MMP-9, was decreased at 24h after SAH, and SB-3CT prevented laminin degradation. The number of TUNEL-positive neurons in cerebral cortex was increased after SAH and decreased by SB-3CT (P<0.01). MMP-9 may be involved in EBI after SAH and inhibition of MMP-9 may reduce EBI in cerebral cortex.

Topics: Analysis of Variance; Animals; Brain Injuries; Cerebral Cortex; Disease Models, Animal; Down-Regulation; Enzyme Inhibitors; Heterocyclic Compounds, 1-Ring; In Situ Nick-End Labeling; Laminin; Male; Matrix Metalloproteinase 9; Neurons; Rats; Rats, Sprague-Dawley; Subarachnoid Hemorrhage; Sulfones

The infiltration of monocytes into the lesioned site is a key event in the inflammatory response after spinal cord injury (SCI). We hypothesized that the molecular events governing the infiltration of monocytes into the injured cord involve cooperativity between the upregulation of the chemoattractant stromal cell-derived factor-1 (SDF-1)/CXCL12 in the injured cord and matrix metalloproteinase-9 (MMP-9/gelatinase B), expressed by infiltrating monocytes. SDF-1 and its receptor CXCR4 mRNAs were upregulated in the injured cord, while macrophages immunoexpressed CXCR4. When mice, transplanted with bone marrow cells from green fluorescent protein (GFP) transgenic mice, were subjected to SCI, GFP+ monocytes infiltrated the cord and displayed gelatinolytic activity. In vitro studies confirmed that SDF-1α, acting through CXCR4, expressed on bone marrow-derived macrophages, upregulated MMP-9 and stimulated MMP-9-dependent transmigration across endothelial cell monolayers by 2.6-fold. There was a reduction in F4/80+ macrophages in spinal cord-injured MMP-9 knock-out mice (by 36%) or wild-type mice, treated with the broad-spectrum MMP inhibitor GM6001 (by 30%). Mice were adoptively transferred with myeloid cells and treated with the MMP-9/-2 inhibitor SB-3CT, the CXCR4 antagonist AMD3100, or a combination of both drugs. While either drug resulted in a 28-30% reduction of infiltrated myeloid cells, the combined treatment resulted in a 45% reduction, suggesting that SDF-1 and MMP-9 function independently to promote the trafficking of myeloid cells into the injured cord. Collectively, these observations suggest a synergistic partnership between MMP-9 and SDF-1 in facilitating transmigration of monocytes into the injured spinal cord.

Topics: Animals; Benzylamines; Cell Movement; Cells, Cultured; Chemokine CXCL12; Cyclams; Disease Models, Animal; Enzyme Inhibitors; Female; Gene Expression Regulation; Green Fluorescent Proteins; Heterocyclic Compounds; Heterocyclic Compounds, 1-Ring; Macrophages; Matrix Metalloproteinase 9; Mice; Mice, Transgenic; Monocytes; RNA, Messenger; Spinal Cord Injuries; Sulfones; Time Factors

To explore the effect of inhibitor of matrix metalloproteinase-9 (MMP-9, SB-3CT) on blood brain barrier (BBB) after cardiopulmonary resuscitation (CPR) in rats.. Rats were randomly divided into three groups: the sham-operated group, the resuscitation control group, and the resuscitation treatment group. Cardiac arrest was produced by clamping the endotracheal intubation, and CPR was executed 1 minute later. In the resuscitation treatment group, SB-3CT (25 mg/kg) was injected intraperitoneally after the restoration of spontaneous circulation (ROSC). The rats were executed immediately, and 0, 3, 9, 24 and 48 hours after the treatment. BBB was examined, and the expression of MMP-9 protein and MMP-9 mRNA in brain tissue were detected, and the ultrastructure of brain tissue was studied with electron microscopy.. In the sham-operated group, the water content, Evans blue content, MMP-9 protein, and MMP-9 mRNA did not change significantly, and there was no obvious change in microstructure of brain tissue. The expression of MMP-9 protein and MMP-9 mRNA in the resuscitation control group were obviously up-regulated at 3 hours after CPR, peaking at 24 hours. There was also significant change in BBB. The differences were significant statistically compared with sham-operated group. The changes in the resuscitation treatment group were similar to the resuscitation control group, but the levels were lower than those of the resuscitation control group (P<0.05 or P<0.01).. The specific inhibitor of MMP-9 (SB-3CT) could decreased the expression of MMP-9, the injury of BBB, and cerebral edema in the cerebral ischemia model with CPR rats, and the protection of cerebral ischemia/reperfusion (I/R) injury after CPR is obvious.

Topics: Animals; Blood-Brain Barrier; Brain; Cardiopulmonary Resuscitation; Disease Models, Animal; Heterocyclic Compounds, 1-Ring; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sulfones

Matrix metalloproteinase inhibitors (MMPIs) reduce blood-brain barrier (BBB) disruption and prevent cell death. Animal models of multiple sclerosis, cerebral ischemia and hemorrhage, and bacterial meningitis respond to treatment with MMPIs. We have used the intracerebral injection of lipopolysaccharide (LPS) in rat, which induces MMP production and results in a delayed opening of the BBB, to screen MMPIs to identify therapeutic agents. We hypothesized that the mouse would respond similarly to LPS and that the mouse/LPS model of BBB damage would be more useful for screening of MMPIs. Therefore, we adapted the rat LPS model to the mouse and compared the response to LPS and treatment with MMPIs. Wistar-Kyoto rats (WKY) and three strains of mice had stereotactic injections of LPS into the caudate. (14)C-sucrose was used to measure permeability of the BBB 24 h after injection. Initially, we tested three broad-spectrum MMPIs in the rat, BB-1101, BB-94, and BB-2293, and a MMP-2 selective inhibitor, IW449; both BB-1101 and BB-94 significantly suppressed LPS-induced BBB damage (p<0.05). In the 3 mouse strains, C57/BL6, C57/BL10, and C57/BL10HIIIR2, LPS significantly opened the BBB in C57/BL6, and it was the only strain that showed a reduction in BBB permeability with BB-94. Treatment with methylprednisolone and several broad-spectrum MMPIs, including BB-1101, was ineffective in the C57/BL6. There was a significant reduction in BBB permeability seen with 10% dimethyl sulfoxide (DMSO) alone, which was used to dissolve the selective MMP-2 and-9 inhibitor, SB-3CT. The tetracycline derivative, minocycline, reduced the BBB injury in mouse by blocking the production of MMP-9. Our results show variability in rats and mice to LPS and MMPIs, which most likely is based on genetic make-up. Understanding these differences may provide important clues that could guide selection of MMPIs in treatment of neurological diseases.

Topics: Animals; Benzyl Compounds; Blood-Brain Barrier; Dexamethasone; Dimethyl Sulfoxide; Disease Models, Animal; Drug Combinations; Drug Evaluation, Preclinical; Encephalitis; Endothelial Cells; Enzyme Inhibitors; Genetic Variation; Heterocyclic Compounds, 1-Ring; Inflammation Mediators; Lipopolysaccharides; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Pentoxifylline; Phenylalanine; Rats; Rats, Inbred WKY; Solvents; Species Specificity; Succinates; Sulfones; Thiophenes

Matrix metalloproteinases (MMPs), and in particular gelatinases (MMP-2 and MMP-9), play a key role in cancer progression. However, clinical trials in which MMP inhibitors were tested in cancer patients have been disappointing. Whereas many reasons have been postulated to explain the failure of the clinical trials, lack of inhibitor selectivity was a major limitation. Thus, despite the consensus opinion that MMP-mediated proteolysis is essential for cancer progression and that certain MMPs represent important targets for intervention, effective and selective inhibition of those MMPs remains a major challenge in drug development. We previously reported the first mechanism-based MMP inhibitor, designated SB-3CT, which is a selective gelatinase inhibitor. Here we report that SB-3CT (5-50 mg/kg/d) is a potent inhibitor of liver metastasis and increases survival in an aggressive mouse model of T-cell lymphoma. This study shows that mechanism-based inhibition of gelatinases represents a novel approach to inhibitor design that promises to be a successful anticancer therapy.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Disease Models, Animal; Female; Heterocyclic Compounds, 1-Ring; Liver Neoplasms, Experimental; Lymphoma, T-Cell; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred DBA; Protease Inhibitors; Sulfones

Topics: Animals; Brain; Disease Models, Animal; Heterocyclic Compounds, 1-Ring; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Mice; Stroke; Sulfones