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1.
Bioconjug Chem ; 28(5): 1413-1421, 2017 05 17.
Article in English | MEDLINE | ID: mdl-28316241

ABSTRACT

Active targeting of nanoparticles through surface functionalization is a common strategy to enhance tumor delivery specificity. However, active targeting strategies tend to work against long polyethylene glycol's shielding effectiveness and associated favorable pharmacokinetics. To overcome these limitations, we developed a matrix metalloproteinase-2 sensitive surface-converting polyethylene glycol coating. This coating prevents nanoparticle-cell interaction in the bloodstream, but, once exposed to matrix metalloproteinase-2, i.e., when the nanoparticles accumulate within the tumor interstitium, the converting polyethylene glycol coating is cleaved, and targeting ligands become available for binding to tumor cells. In this study, we applied a comprehensive multimodal imaging strategy involving optical, nuclear, and magnetic resonance imaging methods to evaluate this coating approach in a breast tumor mouse model. The data obtained revealed that this surface-converting coating enhances the nanoparticle's blood half-life and tumor accumulation and ultimately results in improved tumor-cell targeting. Our results show that this enzyme-specific surface-converting coating ensures a high cell-targeting specificity without compromising favorable nanoparticle pharmacokinetics.


Subject(s)
Breast Neoplasms/pathology , Magnetic Resonance Imaging/methods , Matrix Metalloproteinase 2/metabolism , Multimodal Imaging/methods , Nanoparticles/administration & dosage , Spectrophotometry, Infrared/methods , Animals , Breast Neoplasms/metabolism , Cell Proliferation/drug effects , Female , Humans , Image Processing, Computer-Assisted/methods , Matrix Metalloproteinase 2/chemistry , Mice , Mice, Nude , Nanoparticles/chemistry , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
2.
ACS Nano ; 7(11): 9761-70, 2013 Nov 26.
Article in English | MEDLINE | ID: mdl-24127782

ABSTRACT

Low-density lipoprotein (LDL) plays a critical role in cholesterol transport and is closely linked to the progression of several diseases. This motivates the development of methods to study LDL behavior from the microscopic to whole-body level. We have developed an approach to efficiently load LDL with a range of diagnostically active nanocrystals or hydrophobic agents. We performed focused experiments on LDL labeled with gold nanocrystals (Au-LDL). The labeling procedure had minimal effect on LDL size, morphology, or composition. Biological function was found to be maintained from both in vitro and in vivo experiments. Tumor-bearing mice were injected intravenously with LDL, DiR-LDL, Au-LDL, or a gold-loaded nanoemulsion. LDL accumulation in the tumors was detected with whole-body imaging methods, such as computed tomography (CT), spectral CT, and fluorescence imaging. Cellular localization was studied with transmission electron microscopy and fluorescence techniques. This LDL labeling procedure should permit the study of lipoprotein biointeractions in unprecedented detail.


Subject(s)
Gold/chemistry , Lipoproteins, LDL/chemistry , Metal Nanoparticles/chemistry , Nanoparticles/chemistry , Animals , Carbocyanines/chemistry , Cholesterol/chemistry , Female , Flow Cytometry , Hep G2 Cells , Humans , Melanoma, Experimental , Mice , Mice, Knockout , Mice, Nude , Microscopy, Electron, Transmission , Microscopy, Fluorescence , Neoplasm Transplantation , Phospholipids/chemistry , Tomography, X-Ray Computed
3.
Bioconjug Chem ; 24(9): 1429-34, 2013 Sep 18.
Article in English | MEDLINE | ID: mdl-23957728

ABSTRACT

For advanced treatment of diseases such as cancer, multicomponent, multifunctional nanoparticles hold great promise. In the current study we report the synthesis of a complex nanoparticle (NP) system with dual drug loading as well as diagnostic properties. To that aim we present a methodology where chemically modified poly(lactic-co-glycolic) acid (PLGA) polymer is formulated into a polymer-lipid NP that contains a cytotoxic drug doxorubicin (DOX) in the polymeric core and an anti-angiogenic drug sorafenib (SRF) in the lipidic corona. The NP core also contains gold nanocrystals (AuNCs) for imaging purposes and cyclodextrin molecules to maximize the DOX encapsulation in the NP core. In addition, a near-infrared (NIR) Cy7 dye was incorporated in the coating. To fabricate the NP we used a microfluidics-based technique that offers unique NP synthesis conditions, which allowed for encapsulation and fine-tuning of optimal ratios of all the NP components. NP phantoms could be visualized with computed tomography (CT) and near-infrared (NIR) fluorescence imaging. We observed timed release of the encapsulated drugs, with fast release of the corona drug SRF and delayed release of a core drug DOX. In tumor bearing mice intravenously administered NPs were found to accumulate at the tumor site by fluorescence imaging.


Subject(s)
Angiogenesis Inhibitors/administration & dosage , Antibiotics, Antineoplastic/administration & dosage , Doxorubicin/administration & dosage , Drug Delivery Systems/methods , Neoplasms/drug therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/administration & dosage , Angiogenesis Inhibitors/pharmacokinetics , Animals , Antibiotics, Antineoplastic/pharmacokinetics , Doxorubicin/pharmacokinetics , Female , Human Umbilical Vein Endothelial Cells , Humans , Lactic Acid/chemistry , Mice , Mice, Nude , Nanoparticles/chemistry , Niacinamide/administration & dosage , Niacinamide/pharmacokinetics , Optical Imaging/methods , Phenylurea Compounds/pharmacokinetics , Polyglycolic Acid/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer , Sorafenib
4.
Chem Commun (Camb) ; 49(82): 9392-4, 2013 Oct 21.
Article in English | MEDLINE | ID: mdl-23877789

ABSTRACT

We present a multifunctional nanoparticle platform that has targeting moieties shielded by a matrix metalloproteinase-2 (MMP2) cleavable PEG coating. Upon incubation with MMP2 this surface-switchable coating is removed and the targeting ligands become available for binding. The concept was evaluated in vitro using biotin and αvß3-integrin-specific RGD-peptide functionalized nanoparticles.


Subject(s)
Emulsions/chemistry , Integrin alphaVbeta3 , Matrix Metalloproteinase 2 , Nanoparticles/chemistry , Oligopeptides , Animals , Cell Line, Tumor , Drug Delivery Systems , Flow Cytometry , Humans , Integrin alphaVbeta3/chemistry , Matrix Metalloproteinase 2/chemistry , Mice , Microscopy, Atomic Force , Models, Molecular , Oligopeptides/chemistry , Surface Properties
5.
Neoplasia ; 14(10): 964-73, 2012 Oct.
Article in English | MEDLINE | ID: mdl-23097630

ABSTRACT

One of the challenges of tailored antiangiogenic therapy is the ability to adequately monitor the angiogenic activity of a malignancy in response to treatment. The α(v)ß(3) integrin, highly overexpressed on newly formed tumor vessels, has been successfully used as a target for Arg-Gly-Asp (RGD)-functionalized nanoparticle contrast agents. In the present study, an RGD-functionalized nanocarrier was used to image ongoing angiogenesis in two different xenograft tumor models with varying intensities of angiogenesis (LS174T > EW7). To that end, iron oxide nanocrystals were included in the core of the nanoparticles to provide contrast for T(2)*-weighted magnetic resonance imaging (MRI), whereas the fluorophore Cy7 was attached to the surface to enable near-infrared fluorescence (NIRF) imaging. The mouse tumor models were used to test the potential of the nanoparticle probe in combination with dual modality imaging for in vivo detection of tumor angiogenesis. Pre-contrast and post-contrast images (4 hours) were acquired at a 9.4-T MRI system and revealed significant differences in the nanoparticle accumulation patterns between the two tumor models. In the case of the highly vascularized LS174T tumors, the accumulation was more confined to the periphery of the tumors, where angiogenesis is predominantly occurring. NIRF imaging revealed significant differences in accumulation kinetics between the models. In conclusion, this technology can serve as an in vivo biomarker for antiangiogenesis treatment and angiogenesis phenotyping.


Subject(s)
Bone Neoplasms/diagnosis , Colorectal Neoplasms/diagnosis , Magnetic Resonance Imaging , Molecular Imaging , Nanoparticles , Neovascularization, Pathologic , Sarcoma, Ewing/diagnosis , Spectroscopy, Near-Infrared , Animals , Bone Neoplasms/blood supply , Bone Neoplasms/metabolism , Colorectal Neoplasms/blood supply , Colorectal Neoplasms/metabolism , Contrast Media , Disease Models, Animal , Fluorescence , Humans , Immunoenzyme Techniques , Integrin alphaVbeta3/metabolism , Mice , Oligopeptides/antagonists & inhibitors , Sarcoma, Ewing/blood supply , Sarcoma, Ewing/metabolism
6.
Chem Commun (Camb) ; 48(47): 5835-7, 2012 Jun 14.
Article in English | MEDLINE | ID: mdl-22555311

ABSTRACT

Polylactic-co-glycolic acid (PLGA) based nanoparticles are biocompatible and biodegradable and therefore have been extensively investigated as therapeutic carriers. Here, we engineered diagnostically active PLGA nanoparticles that incorporate high payloads of nanocrystals into their core for tunable bioimaging features. We accomplished this through esterification reactions of PLGA to generate polymers modified with nanocrystals. The PLGA nanoparticles formed from modified PLGA polymers that were functionalized with either gold nanocrystals or quantum dots exhibited favorable features for computed tomography and optical imaging, respectively.


Subject(s)
Fatty Acids/chemistry , Fatty Alcohols/chemistry , Gold/chemistry , Metal Nanoparticles/chemistry , Polyglycolic Acid/chemistry , Quantum Dots , Sulfhydryl Compounds/chemistry , Diagnostic Imaging , Metal Nanoparticles/ultrastructure , Microscopy, Electron, Transmission
7.
ACS Nano ; 5(6): 4422-33, 2011 Jun 28.
Article in English | MEDLINE | ID: mdl-21557611

ABSTRACT

Nanoparticle applications in medicine have seen a tremendous growth in the past decade. In addition to their drug targeting application and their ability to improve bioavailability of drugs, nanoparticles can be designed to allow their detection with a variety of imaging methodologies. In the current study, we developed a multimodal nanoparticle platform to enable imaging guided therapy, which was evaluated in a colon cancer mouse model. This "theranostic" platform is based on oil-in-water nanoemulsions and carries iron oxide nanocrystals for MRI, the fluorescent dye Cy7 for NIRF imaging, and the hydrophobic glucocorticoid prednisolone acetate valerate (PAV) for therapeutic purposes. Angiogenesis-targeted nanoemulsions functionalized with αvß(3)-specific RGD peptides were evaluated, as well. When subcutaneous tumors were palpable, the nanoemulsions were administered at a dose of 30 mg of FeO/kg and 10 mg of PAV/kg. MRI and NIRF imaging showed significant nanoparticle accumulation in the tumors, while tumor growth profiles revealed a potent inhibitory effect in all of the PAV nanoemulsion-treated animals as compared to the ones treated with control nanoemulsions, the free drug, or saline. This study demonstrated that our nanoemulsions, when loaded with PAV, iron oxide nanocrystals, and Cy7, represent a flexible and unique theranostic nanoparticle platform that can be applied for imaging guided therapy of cancer.


Subject(s)
Nanomedicine/methods , Neoplasms, Experimental/therapy , Animals , Colonic Neoplasms/pathology , Drug Carriers , Emulsions , Glucocorticoids/pharmacology , Lipids/chemistry , Magnetic Resonance Imaging/methods , Medical Oncology/methods , Mice , Microscopy, Electron, Transmission/methods , Neoplasm Transplantation , Neovascularization, Pathologic , Oligopeptides/chemistry , Photons , Prednisolone/administration & dosage , Prednisolone/analogs & derivatives
8.
J Pharmacol Exp Ther ; 335(2): 324-31, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20671072

ABSTRACT

A growing body of evidence suggests that chronic kidney disease is a significant risk for cardiovascular events and stroke regardless of traditional risk factors. The aim of this study was to examine the effects of peroxisome proliferator-activated receptor (PPAR) agonists on the tissue damage affecting salt-loaded spontaneously hypertensive stroke-prone rats ( SHRSPs), an animal model that develops a complex pathology characterized by systemic inflammation, hypertension, and proteinuria and leads to end-organ injury (initially renal and subsequently cerebral). Compared with the PPARγ agonist rosiglitazone, the PPARα ligands fenofibrate and clofibrate significantly increased survival (p < 0.001) by delaying the occurrence of brain lesions monitored by magnetic resonance imaging (p < 0.001) and delaying increased proteinuria (p < 0.001). Fenofibrate completely prevented the renal disorder characterized by severe vascular lesions, tubular damage, and glomerular sclerosis, reduced the number of ED-1-positive cells and collagen accumulation, and decreased the renal expression of interleukin-1ß, transforming growth factor ß, and monocyte chemoattractant protein 1. It also prevented the plasma and urine accumulation of acute-phase and oxidized proteins, suggesting that the protection induced by PPARα agonists was at least partially caused by their anti-inflammatory and antioxidative properties. The results of this study demonstrate that PPAR agonism has beneficial effects on spontaneous brain and renal damage in SHRSPs by inhibiting systemic inflammation and oxidative stress, and they support carrying out future studies aimed at evaluating the effect of PPARα agonists on proteinuria and clinical outcomes in hypertensive patients with renal disease at increased risk of stroke.


Subject(s)
Brain/pathology , Inflammation/prevention & control , Kidney Diseases/prevention & control , Oxidative Stress/drug effects , PPAR alpha/agonists , Stroke/complications , Animals , Blotting, Western , Brain/drug effects , Brain/metabolism , Chemokine CCL2/biosynthesis , Clofibrate/pharmacology , Clofibrate/therapeutic use , Disease Models, Animal , Fenofibrate/pharmacology , Fenofibrate/therapeutic use , Hypertension/complications , Hypertension/drug therapy , Hypertension/metabolism , Hypertension/pathology , Inflammation/etiology , Inflammation/metabolism , Inflammation/pathology , Interleukin-1beta/biosynthesis , Kidney Diseases/etiology , Kidney Diseases/metabolism , Kidney Diseases/pathology , Ligands , Male , Rats , Rats, Inbred SHR , Stroke/drug therapy , Stroke/metabolism , Stroke/pathology , Transforming Growth Factor beta/biosynthesis
9.
J Pharmacol Exp Ther ; 334(1): 199-205, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20332187

ABSTRACT

This study investigated the efficacy of terutroban, a specific thromboxane/prostaglandin endoperoxide receptor antagonist, on stroke incidence in spontaneously hypertensive stroke-prone rats (SHRSP). The effects of terutroban were compared with those of aspirin, another antiplatelet agent, and rosuvastatin, known to exert end-organ protection in SHRSP. Salt-loaded male SHRSP were treated orally once a day with vehicle, terutroban (30 mg/kg/day), aspirin (60 mg/kg/day), or rosuvastatin (10 mg/kg/day). Compared with vehicle, and regardless of any effect on blood pressure or serum thromboxane B(2) levels, terutroban significantly increased survival (p < 0.001) as a consequence of a delayed brain lesion occurrence monitored by magnetic resonance imaging (p < 0.001), and a delayed increase of proteinuria (p < 0.001). Terutroban decreased cerebral mRNA transcription of interleukin-1beta, transforming growth factor-beta, and monocyte chemoattractant protein-1 after 6 weeks of dietary treatment. Terutroban also prevented the accumulation of urinary acute-phase proteins at high molecular weight, identified as markers of systemic inflammation, and assessed longitudinally by one-dimensional electrophoresis. Terutroban also has protective effects on the vasculature as suggested by the preservation of endothelial function and endothelial nitric-oxide synthase expression in isolated carotid arteries. These effects are similar to those obtained with rosuvastatin, and superior to those of aspirin. Terutroban increases survival in SHRSP by reducing systemic inflammation as well as preserving endothelial function. These data support clinical development of terutroban in the prevention of cerebrovascular and cardiovascular complications of atherothrombosis.


Subject(s)
Endothelium, Vascular/drug effects , Hypertension/drug therapy , Naphthalenes/therapeutic use , Propionates/therapeutic use , Protective Agents/therapeutic use , Receptors, Prostaglandin/antagonists & inhibitors , Receptors, Thromboxane/antagonists & inhibitors , Stroke/prevention & control , Systemic Inflammatory Response Syndrome/prevention & control , Animals , Aspirin/administration & dosage , Aspirin/pharmacology , Aspirin/therapeutic use , Biomarkers/analysis , Biomarkers/blood , Biomarkers/urine , Blood Pressure/drug effects , Brain/drug effects , Brain/immunology , Brain/pathology , Endothelium, Vascular/immunology , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiopathology , Fluorobenzenes/administration & dosage , Fluorobenzenes/pharmacology , Fluorobenzenes/therapeutic use , Hypertension/complications , Hypertension/immunology , Hypertension/metabolism , Hypertension/pathology , Magnetic Resonance Imaging , Male , Naphthalenes/administration & dosage , Naphthalenes/pharmacology , Propionates/administration & dosage , Propionates/pharmacology , Protective Agents/administration & dosage , Protective Agents/pharmacology , Pyrimidines/administration & dosage , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Rats , Rats, Inbred SHR , Rosuvastatin Calcium , Stroke/etiology , Stroke/immunology , Stroke/metabolism , Stroke/pathology , Sulfonamides/administration & dosage , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Survival Analysis , Systemic Inflammatory Response Syndrome/etiology , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/metabolism
10.
Cardiovasc Res ; 85(3): 503-13, 2010 Feb 01.
Article in English | MEDLINE | ID: mdl-19797426

ABSTRACT

AIMS: The assessment of progenitor cell survival and efficacy after transplantation is one of the major challenges in cardiovascular cell therapy. Translation of currently used imaging techniques to patients is not immediate. Possible options include iron oxide particle loading into cells to be tracked using magnetic resonance (MR) and by MR-based water diffusion anisotropy analysis. The aim of the present study was to assess, using these techniques, the localization and survival of human 'early' endothelial progenitor cells (EPCs) and their effects on vascular and skeletal muscle regeneration in a mouse model of hind limb ischaemia. METHODS AND RESULTS: A paramagnetic iron oxide particle loading protocol of human peripheral blood-derived early EPCs was devised. The iron+ EPCs maintained their phenotype and in vitro functional activity. In addition, the presence of iron+ cells was observed by MR until 7 days after injection into a pharmacologically immunosuppressed mouse model of hind limb ischaemia. Immunohistochemistry with human major histocompatibility complex antibodies revealed the absence of human cells at 7 days post-ischaemia. EPC death was confirmed by staining of iron+ cells with an anti-mouse CD68 antibody and by qPCR performed on DNA extracted from injected ischaemic limbs, at different times following injection. Surprisingly, early EPC injection enhanced arteriogenesis but caused a significant increase in ischaemic tissue inflammation and a retarded muscle regeneration, as evidenced by water diffusion anisotropy analysis and histology. CONCLUSION: In line with recent reports, our results show that the use of iron-based contrast agents does not allow detection of long-term EPC engraftment into ischaemic tissues. They further show that early EPCs exert a potent arteriogenic effect on ischaemic tissues that is not dependent on their prolonged survival. Unexpectedly, injection of these cells elicited a long-term inflammatory response that reflected a delayed muscle healing process.


Subject(s)
Endothelial Cells/cytology , Ischemia/therapy , Magnetic Resonance Imaging/methods , Muscles/physiology , Neovascularization, Physiologic , Regeneration , Stem Cell Transplantation , Animals , Cells, Cultured , Ferric Compounds , Hindlimb/blood supply , Humans , Inflammation/etiology , Male , Mice
11.
Article in English | MEDLINE | ID: mdl-20039335

ABSTRACT

Multifunctional imaging nanoprobes have proven to be of great value in the research of pathological processes, as well as the assessment of the delivery, fate, and therapeutic potential of encapsulated drugs. Moreover, such probes may potentially support therapy schemes by the exploitation of their own physical properties, e.g., through thermal ablation. This review will present four classes of nanoparticulate imaging probes used in this area: multifunctional probes (1) that can be tracked with at least three different and complementary imaging techniques, (2) that carry a drug and have bimodal imaging properties, (3) that are employed for nucleic acid delivery and imaging, and (4) imaging probes with capabilities that can be used for thermal ablation. We will highlight several examples where the suitable combination of different (bio)materials like polymers, inorganic nanocrystals, fluorophores, proteins/peptides, and lipids can be tailored to manufacture multifunctional probes to accomplish nanomaterials of each of the aforementioned classes. Moreover, it will be demonstrated how multimodality imaging approaches improve our understanding of in vivo nanoparticle behavior and efficacy at different levels, ranging from the subcellular level to the whole body.


Subject(s)
Diagnostic Imaging/methods , Molecular Probes/metabolism , Nanoparticles/chemistry , Animals , Drug Delivery Systems , Gene Transfer Techniques , Humans , Temperature
12.
Biomaterials ; 30(36): 6947-54, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19783295

ABSTRACT

Nanoemulsions are increasingly investigated for the delivery of hydrophobic drugs to improve their bioavailability or make their administration possible. In the current study, oil-in-water emulsions with three different mean diameters (30, 60, and 95 nm) were developed as a new multimodality nanoparticle platform for tumor targeting and imaging. To that aim, hydrophobically coated iron oxide particles were included in the soybean oil core of the nanoemulsions to enable their detection with magnetic resonance imaging (MRI), while the conjugation of a near infrared fluorophore allowed optical imaging. The accumulation of this novel nanocomposite in subcutaneous human tumors in nude mice was demonstrated with MRI and fluorescence imaging in vivo, and with Perl's staining of histological tumor sections ex vivo.


Subject(s)
Emulsions/chemistry , Ferric Compounds/chemistry , Nanoparticles/chemistry , Neoplasms , Oils/chemistry , Water/chemistry , Animals , Biocompatible Materials/chemistry , Biocompatible Materials/metabolism , Cell Line, Tumor , Contrast Media/chemistry , Contrast Media/metabolism , Drug Delivery Systems , Emulsions/metabolism , Ferric Compounds/metabolism , Humans , Magnetic Resonance Imaging/methods , Materials Testing , Mice , Mice, Nude , Neoplasm Transplantation , Neoplasms/metabolism , Neoplasms/pathology , Oils/metabolism , Particle Size , Water/metabolism
13.
Eur J Pharmacol ; 604(1-3): 117-24, 2009 Feb 14.
Article in English | MEDLINE | ID: mdl-19135993

ABSTRACT

S 35171 is one of a family of compounds that have been designed to protect mitochondrial function. We tested the hypothesis that S 35171 exerts protective effects in spontaneously hypertensive stroke-prone rats (SHRSPs), an animal model developing spontaneous brain damage preceded by proteinuria and systemic inflammation revealed by the urinary accumulation of acute-phase proteins (APPs) originating in the liver. Male SHRSPs fed a permissive diet received vehicle or S 35171 (10 mg/kg/day) started simultaneously with a high-sodium diet (group A) or after the establishment of proteinuria (group B). The drug delayed urinary APPs accumulation and the appearance of magnetic resonance imaging (MRI)-monitored brain lesions (after 62+/-3 days in group A, and 51+/-2 days in controls, P<0.01). The delay was more pronounced in group B as 30% of the animals survived the entire 90-day experimental period without brain abnormality. Proteomic analysis showed no significant alteration in the expression pattern of brain mitochondrial proteins, but the liver mitochondrial levels of carbamoylphosphate synthase I (CPS-I), an enzyme involved in urea metabolism) and the antioxidant peroxiredoxin-3 spot were affected by hypertension and S 35171. Stress reduces CPS-I and induces the peroxiredoxin-3 spot, whereas S 35171 brought about normal CPS-I expression and a 12-fold higher level of the peroxiredoxin-3 spot. As both enzymes are involved in maintaining mitochondrial functions, their increased expression after S 35171 treatment may be responsible for delaying the pathological condition that leads to the development of brain damage in SHRSPs.


Subject(s)
Antihypertensive Agents/therapeutic use , Hypertension/drug therapy , Mitochondria/drug effects , Stroke/prevention & control , Trimetazidine/analogs & derivatives , Acute-Phase Proteins/biosynthesis , Acute-Phase Proteins/urine , Animals , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/pharmacology , Blood Pressure/drug effects , Blotting, Western , Electrophoresis, Gel, Two-Dimensional , Hypertension/complications , Hypertension/pathology , Liver/drug effects , Liver/metabolism , Magnetic Resonance Imaging , Male , Mitochondria/enzymology , Mitochondria/metabolism , Mitochondria/physiology , Proteinuria/prevention & control , Rats , Rats, Inbred SHR , Sodium, Dietary/administration & dosage , Stroke/etiology , Stroke/pathology , Trimetazidine/administration & dosage , Trimetazidine/pharmacology , Trimetazidine/therapeutic use
14.
Neuroscientist ; 13(3): 208-13, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17519364

ABSTRACT

Although substantial epidemiological studies have failed to find a correlation between cholesterol levels and stroke, clinical trials have shown that HMG-CoA reductase inhibitors (or statins, the most potent hypocholesterolemic drugs available) greatly reduce the incidence of stroke. These clinical observations have opened the way to a number of studies of the non-cholesterol-dependent (or pleiotropic) effects in animal models of stroke, indicating that the neuroprotection is attributable to multiple activities. One of the main protective mechanisms elicited by statin administration is the increase in nitric oxide bioavailability that regulates cerebral perfusion and improves endothelial function, but others include antioxidant properties, the inhibition of inflammatory responses, immunomodulatory actions, the regulation of progenitor cells, and the stabilization of atherosclerotic plaques. Many of these effects are due to the inhibited synthesis of isoprenoid intermediates, which serve as lipid attachments for a variety of intracellular signaling molecules. This article describes the mechanisms involved in the neuroprotective effects of statins.


Subject(s)
Brain Ischemia/prevention & control , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Neuroprotective Agents/therapeutic use , Animals , Humans , Inflammation/drug therapy , Nitric Oxide Synthase Type III/metabolism , Oxidative Stress/drug effects
15.
Am J Pathol ; 170(4): 1165-77, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17392157

ABSTRACT

Salt-loaded, spontaneously hypertensive stroke-prone rats show progressive increases in blood pressure and proteinuria and accumulate acute-phase proteins in body fluids, modeling events during renal damage. The aim of this study was to assess the pathological events occurring in the kidney of spontaneously hypertensive stroke-prone rats over time and evaluate the effects of statin treatment, which is known to improve renal and cardiovascular outcomes. Kidneys of male spontaneously hypertensive stroke-prone rats euthanized at different stages of proteinuria showed progressive inflammatory cell infiltration, the accumulation of alpha-smooth muscle actin-positive cells, degenerative changes in podocytes, and severe fibrosis. These were accompanied by an imbalance in the plasminogen/plasmin and metalloprotease systems characterized by the increased renal expression of plasminogen activator inhibitor-1, tissue plasminogen activator, and urokinase plasminogen activator; the net result was an increase in plasmin and matrix metalloproteinase (MMP)-2 and a reduction in MMP-9 activity. Chronic treatment with the hydrophilic rosuvastatin had renoprotective effects in terms of morphology and inflammation and prevented the changes in plasmin, MMP-2, and MMP-9 activity. These effects were independent of the changes in blood pressure and plasma lipid levels. Treatment with the lipophilic simvastatin was not renoprotective. These data suggest that rosuvastatin may have potential utility as a therapeutic option in renal diseases that are characterized by inflammation and fibrosis.


Subject(s)
Fluorobenzenes/pharmacology , Inflammation/prevention & control , Kidney/drug effects , Pyrimidines/pharmacology , Sulfonamides/pharmacology , Actins/metabolism , Animals , Blood Pressure/drug effects , Blotting, Western , Collagen/metabolism , Disease Progression , Fibrinogen/metabolism , Fibrinolysin/metabolism , Fibrosis , Fluorobenzenes/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Inflammation/metabolism , Inflammation/physiopathology , Kidney/pathology , Kidney/ultrastructure , Male , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Microscopy, Electron , Plasminogen Activator Inhibitor 1/metabolism , Plasminogen Activators/metabolism , Podocytes/drug effects , Podocytes/metabolism , Podocytes/pathology , Proteinuria/prevention & control , Pyrimidines/administration & dosage , Rats , Rats, Inbred SHR , Rosuvastatin Calcium , Simvastatin/administration & dosage , Simvastatin/pharmacology , Stroke/physiopathology , Sulfonamides/administration & dosage
16.
Neurobiol Dis ; 22(2): 445-51, 2006 May.
Article in English | MEDLINE | ID: mdl-16480888

ABSTRACT

We investigated the effects of simvastatin treatment on the expression of IL-1beta and MCP-1, the activity of NF-kB, and the signaling pathways related to NF-kB activation in a rat model of permanent middle cerebral artery occlusion (pMCAO). IL-1beta and MCP-1 expression, determined using RT-PCR, was enhanced by pMCAO; this effect was inhibited by the administration of simvastatin before ischemia. Pre-treatment with simvastatin abolished the ischemia-induced activation of NF-kB observed in vehicle-treated animals. The evaluation of signal transduction pathways, including extracellular signal-regulated kinase (ERK1/2), SAPK/JNK 46/54 and p38, indicated that only ERK1/2 phosphorylation was enhanced by ischemia, and this activation was prevented by simvastatin. ERK1/2-inhibitor, U0126, reduced brain ischemia but not cytokine induction. These results provide evidence that the HMG-CoA reductase inhibitor induces its effect in the protection of ischemic brain damage with a more complex mechanism which also involve anti-inflammatory properties rather than simple inhibition of ERK1/2 signaling pathway.


Subject(s)
Brain Ischemia/drug therapy , Brain/drug effects , Encephalitis/drug therapy , Mitogen-Activated Protein Kinase 3/drug effects , NF-kappa B/drug effects , Simvastatin/pharmacology , Animals , Brain/metabolism , Brain/physiopathology , Brain Ischemia/metabolism , Brain Ischemia/physiopathology , Chemokine CCL2/drug effects , Chemokine CCL2/metabolism , Disease Models, Animal , Down-Regulation/drug effects , Down-Regulation/physiology , Encephalitis/physiopathology , Encephalitis/prevention & control , Enzyme Activation/drug effects , Enzyme Activation/physiology , Enzyme Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/metabolism , Infarction, Middle Cerebral Artery/physiopathology , Interleukin-1/metabolism , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/physiology , Male , Mitogen-Activated Protein Kinase 3/metabolism , NF-kappa B/metabolism , Rats , Rats, Sprague-Dawley , Simvastatin/therapeutic use , Up-Regulation/drug effects , Up-Regulation/physiology
17.
Drugs Today (Barc) ; 41(9): 609-22, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16341292

ABSTRACT

It is now well established that the activation of the renin-angiotensin system (RAS) is involved in the onset and progression of cardiovascular and renal diseases, and that its main effector, angiotensin II (Ang II) has major pro-inflammatory activity that induces the expression of cytokines, chemokines, adhesion molecules, growth factors and reactive oxygen species. By means of these actions, Ang II induces vascular inflammation, endothelial dysfunction and fibrosis, and participates in destabilizing atherosclerotic plaque and establishing chronic kidney diseases. Blocking the RAS by inhibiting Ang II generation or blocking angiotensin receptors reduces the morbidity and mortality associated with cardiovascular and renal disease beyond the levels due to the lowering of blood pressure, and these benefits are at least partially due to the reduction/prevention of both local and systemic inflammatory processes. The aim of this review is to describe the role of the RAS (and particularly Ang II) in initiating and maintaining these processes, and to summarize experimental and clinical evidence supporting the role of drugs acting on the RAS in preventing or modulating inflammation.


Subject(s)
Angiotensin II , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Anti-Inflammatory Agents/pharmacology , Cardiovascular Diseases/etiology , Kidney Diseases/etiology , Renin-Angiotensin System , Angiotensin II/drug effects , Angiotensin II/physiology , Humans , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology
18.
Arterioscler Thromb Vasc Biol ; 25(3): 598-603, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15681303

ABSTRACT

OBJECTIVE: Brain abnormalities, preceded by a systemic inflammation, develop in spontaneously hypertensive stroke-prone rats (SHRSP). In this model, we investigated whether the hydrophilic statin, rosuvastatin, influences the development of inflammation associated with brain abnormalities. Because differences in hydrophilicity/hydrophobicity contribute to the differences in statin pharmacology, we also evaluated the effects of simvastatin, a lipophilic molecule METHODS AND RESULTS: SHRSP, fed a high-salt diet, were treated long-term with vehicle or rosuvastatin (1 and 10 mg/kg per day). Brain abnormalities developed after 40+/-5 days and after 60+/-5 days of salt loading, in vehicle-treated and in rosuvastatin-treated (1 mg/kg per day) SHRSP, respectively. After 100 days of treatment, no damage was detectable in 30% of the rats treated with the highest dose of the drug. In comparison with vehicle-treated SHRSP, rosuvastatin treatment attenuated the transcription of monocyte chemoattractant protein-1, transforming growth factor-beta1, IL-1beta, and tumor necrosis factor-alpha in the kidney, and of P-selectin in brain vessels and increased the transcription of endothelial nitric oxide synthase mRNA in the aorta. Urinary excretion of acute-phase proteins increased with time in vehicle-treated animals but remained negligible in drug-treated animals. These effects are independent of changes in physiological parameters. Treatment of SHRSP with simvastatin (2 to 20 mg/kg per day) did not exert any protective effect. CONCLUSIONS: Rosuvastatin attenuates inflammatory processes associated with cerebrovascular disease.


Subject(s)
Fluorobenzenes/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hypertension/drug therapy , Pyrimidines/pharmacology , Simvastatin/pharmacology , Stroke/drug therapy , Sulfonamides/pharmacology , Vasculitis/drug therapy , Acute-Phase Proteins/immunology , Animals , Cerebral Arteries/drug effects , Cerebral Arteries/immunology , Chemokine CCL2/genetics , Hypertension/immunology , Male , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase Type III , P-Selectin/genetics , Proteinuria/drug therapy , Proteinuria/immunology , RNA, Messenger/metabolism , Rats , Rats, Inbred SHR , Rosuvastatin Calcium , Sodium Chloride, Dietary/pharmacology , Stroke/immunology , Transcription, Genetic , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta1 , Tumor Necrosis Factor-alpha/genetics , Vasculitis/immunology
19.
J Pharmacol Exp Ther ; 311(3): 989-95, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15302895

ABSTRACT

Spontaneously hypertensive stroke-prone rats (SHRSP) develop hypertension and systemic inflammation, with subsequent brain and renal disorders and early death. We tested the hypothesis that valsartan, an angiotensin II type 1 (AT1) receptor antagonist, exerts protective effects in SHRSP through its anti-inflammatory properties, even in the absence of a blood pressure-lowering effect. SHRSP fed a high-salt diet were treated with vehicle or valsartan (1-10 mg/kg/day). The vehicle-treated rats developed hypertension, proteinuria, progressive kidney disease, and, 40 +/- 5 days from the beginning of the treatment, brain damage as visualized by magnetic resonance imaging. Rats treated with 1 mg/kg/day valsartan developed brain damage after 61 +/- 3 days (p <0.01 versus vehicle-treated rats). No damage showed after 100 days in 80% of the rats treated with 10 mg/kg/day. Valsartan treatment preserved renal structure, by preventing the infiltration of inflammatory cells, and lowered renal expression of monocyte chemoattractant protein-1, transforming growth factor-beta1, and interleukin-1beta, compared with vehicle-treated SHRSP. Urinary excretion of acute-phase proteins increased in the latter but remained negligible in the drug-treated animals. Furthermore, valsartan exerted protective effects also when given after established proteinuria. In SHRSP, blockade of AT1 receptor with valsartan prevents the development of proteinuria, delays the appearance of brain damage, preserves renal structure, and increases survival under stressful conditions. Valsartan exerts its beneficial effects independently of any blood pressure fall and by means of broad anti-inflammatory actions both at local and at systemic levels. These observations indicate that the administration of AT1 receptor antagonists may be useful in pathological situations in which an anti-inflammatory effect is required.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/therapeutic use , Anti-Inflammatory Agents , Blood Pressure/physiology , Stroke/drug therapy , Stroke/pathology , Tetrazoles/therapeutic use , Valine/analogs & derivatives , Valine/therapeutic use , Animals , Blood Pressure/drug effects , Body Weight/drug effects , Brain/pathology , Chemokine CCL2/biosynthesis , Immunohistochemistry , Interleukin-1/biosynthesis , Kidney/pathology , Magnetic Resonance Imaging , Male , Proteinuria/chemically induced , RNA, Messenger/biosynthesis , Rats , Rats, Inbred SHR , Stroke/genetics , Survival Analysis , Transforming Growth Factor beta/biosynthesis , Valsartan
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