minocycline and Necrosis

Deep insight into the complex mechanisms of myocardial ischemia-reperfusion injury has been attained in the past years. Minocycline is a second-generation tetracycline with US FDA approval for clinical use in various infections. Lately, several noninfectious cytoprotective activities of minocycline have been discovered as well. There now exists encouraging evidence of its protective role in cardiovascular pathology and its activity against myocardial ischemia-reperfusion injury. In this article, an overview of the major mechanisms involved in myocardial ischemia-reperfusion injury is presented. This is followed by an analysis of the mechanisms by which minocycline exerts its cytoprotective role and of studies that have been conducted in order to analyze minocycline, along with a review of the scope and limitations of its role as a cytoprotective agent.

Topics: Anti-Bacterial Agents; Apoptosis; Calcium; Cytoprotection; HMGB1 Protein; Humans; Hydrogen-Ion Concentration; Inflammation; Ischemic Contracture; Matrix Metalloproteinases; Minocycline; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Myocardial Reperfusion Injury; Myocardium; Necrosis; Reactive Oxygen Species

Minocycline is a second-generation tetracycline and a potential neuroprotective intervention following brain injury. However, despite the recognized beneficial effects of minocycline in a multitude of adult disease states, the clinical application of minocycline in neonates is contentious. Tetracyclines, as a class, are not usually administered to neonates, but there is compelling evidence that minocycline reduces brain injury after neonatal hypoxic-ischemic brain injury. This Review focuses on the evidence for minocycline use in neonates by considering aspects of pharmacology, drug regimens, functional outcomes, and mechanisms of action.

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Blood-Brain Barrier; Brain; Humans; Hypoxia-Ischemia, Brain; Infant Behavior; Infant, Newborn; Matrix Metalloproteinase Inhibitors; Minocycline; Necrosis; Neurons; Neuroprotective Agents

Apoptosis, a genetically programmed form of cell death, contributes to myocyte cell loss in a variety of cardiac pathologies, including cardiac failure and those related to ischemia/reperfusion injury. The apoptotic program is complex, involving both pro- and anti-apoptotic proteins, and apoptosis occurs when the equilibrium between these opposing factors is perturbed. Some of these factors are intrinsic to the apoptotic pathway, such as the pro- and anti-apoptotic members of the Bcl2 family. Other, extrinsic, cellular factors can also modify the outcome of the response to an apoptotic stimulus. In this review, we have focused on some of these extrinsic factors, such as STAT-1 as a pro-apoptotic agent and the urocortins and Bag-1 as anti-apoptotic factors, since these may be potential therapeutic targets. In addition, we discuss the profound cytoprotective effects of the antibiotic, minocycline.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Cardiotonic Agents; Corticotropin-Releasing Hormone; Humans; Ischemic Preconditioning, Myocardial; Minocycline; Mitochondrial Proteins; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Necrosis; STAT Transcription Factors; Urocortins

Evidence from preclinical and clinical studies has demonstrated that myocardial infarction promotes atherosclerosis progression. The impact of focal vascular inflammation on the progression and phenotype of remote atherosclerosis remains unknown. Approach and Results: We used a novel. We show for the first time that focal arterial inflammation in response to vascular injury enhances systemic vascular inflammation, accelerates remote atheroma progression and induces plaques more inflamed, lipid-rich, and collagen-poor in the absence of ischemic myocardial injury. This inflammatory cascade is modulated by pravastatin and minocycline treatments, which have anti-inflammatory effects at both plaque and systemic levels that mitigate atheroma progression.

Topics: Animals; Anti-Inflammatory Agents; Aortitis; Atherosclerosis; Brachiocephalic Trunk; Collagen; Disease Models, Animal; Disease Progression; Inflammation Mediators; Interleukin-6; Lipid Metabolism; Male; Mice, Knockout, ApoE; Minocycline; Necrosis; Plaque, Atherosclerotic; Pravastatin; Time Factors

To better understand the spatiotemporal course of radiation-induced central nervous system (CNS) vascular necrosis and assess the therapeutic potential of approaches for protecting against radiation-induced necrosis, adult female Sprague Dawley rats received 40 Gy surface dose centered on the T9 thoracic spinal cord segment. Locomotor function, blood-spinal cord barrier (BSCB) integrity and histology were evaluated throughout the study. No functional symptoms were observed for several months postirradiation. However, a sudden onset of paralysis was observed at approximately 5.5 months postirradiation. The progression rapidly led to total paralysis and death within less than 48 h of symptom onset. Open-field locomotor scores and rotarod motor coordination testing showed no evidence of neurological impairment prior to the onset of overt paralysis. Histological examination revealed minimal changes to the vasculature prior to symptom onset. However, Evans blue dye (EvB) extravasation revealed a progressive deterioration of BSCB integrity, beginning at one week postirradiation, affecting regions well outside of the irradiated area. Minocycline treatment significantly delayed the onset of paralysis. The results of this study indicate that extensive asymptomatic disruption of the blood-CNS barrier may precede onset of vascular breakdown by several months and suggests that minocycline treatment has a therapeutic effect by delaying radiation-induced necrosis after CNS irradiation.

Topics: Animals; Dose-Response Relationship, Radiation; Female; Microvessels; Minocycline; Necrosis; Radiation Injuries; Radiation-Protective Agents; Rats; Rats, Sprague-Dawley; Spinal Cord; Time Factors

Topics: Anti-Bacterial Agents; Biopsy; Combined Modality Therapy; Drug Hypersensitivity Syndrome; Echocardiography; Eosinophilia; Extracorporeal Membrane Oxygenation; Female; Humans; Immunosuppressive Agents; Minocycline; Myocarditis; Myocardium; Necrosis; Recovery of Function; Treatment Outcome; Ventricular Function, Left; Young Adult

Despite recovery of hemodynamics by fluid resuscitation after hemorrhage, development of the systemic inflammatory response and multiple organ dysfunction syndromes can nonetheless lead to death. Minocycline and doxycycline are tetracycline derivatives that are protective in models of hypoxic, ischemic, and oxidative stress. Our aim was to determine whether minocycline and doxycycline protect liver and kidney and improve survival in a mouse model of hemorrhagic shock and resuscitation.. Mice were hemorrhaged to 30 mmHg for 3 h and then resuscitated with shed blood followed by half the shed volume of lactated Ringer's solution containing tetracycline (10 mg/kg), minocycline (10 mg/kg), doxycycline (5 mg/kg), or vehicle. For pretreatment plus posttreatment, drugs were administered intraperitoneally prior to hemorrhage followed by second equal dose in Ringer's solution after blood resuscitation. Blood and tissue were harvested after 6 h.. Serum alanine aminotransferase (ALT) increased to 1,988 and 1,878 U/L after posttreatment with vehicle and tetracycline, respectively, whereas minocycline and doxycycline posttreatment decreased ALT to 857 and 863 U/L. Pretreatment plus posttreatment with minocycline and doxycycline also decreased ALT to 849 and 834 U/L. After vehicle, blood creatinine increased to 134 µM, which minocycline and doxycycline posttreatment decreased to 59 and 56 µM. Minocycline and doxycycline pretreatment plus posttreatment decreased creatinine similarly. Minocycline and doxycycline also decreased necrosis and apoptosis in liver and apoptosis in both liver and kidney, the latter assessed by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) and caspase 3 activation. Lastly after 4.5 h of hemorrhage followed by resuscitation, minocycline and doxycycline (but not tetracycline) posttreatment improved 1-week survival from 38% (vehicle) to 69% and 67%, respectively.. Minocycline and doxycycline were similarly protective when given before as after blood resuscitation and might therefore have clinical efficacy to mitigate liver and kidney injury after resuscitated hemorrhage.

Topics: Alanine Transaminase; Animals; Apoptosis; Biomarkers; Caspase 3; Creatinine; Cytoprotection; Disease Models, Animal; Doxycycline; Fluid Therapy; Hemodynamics; Kidney; Liver; Male; Mice, Inbred C57BL; Minocycline; Multiple Organ Failure; Necrosis; Protective Agents; Resuscitation; Shock, Hemorrhagic; Tetracycline; Time Factors

The endodontic regenerative procedure (ERP), which is an alternative to calcium hydroxide-induced apexification, involves the use of a triple antibiotic paste (TAP) as a dressing material. The aim of this study was to evaluate the response of rat subcutaneous tissue to implanted polyethylene tubes that were filled with TAP or calcium hydroxide.. Thirty rats received 2 individual implants of polyethylene tubes filled with TAP or calcium hydroxide paste (CHP) and another empty tube as a control. Thirty additional rats received 2 individual implants consisting of polyethylene tubes filled with dressing material carriers (macrogol and propylene glycol) and a sham procedure. After 7, 15, 30, 60, and 90 days, 12 animals were euthanized, and the tubes and surrounding tissue were removed and processed for histology by using glycol methacrylate and stained with hematoxylin and eosin. The histological score ranged from 0 to 3 depending on the content of inflammatory cells; the fibrous capsule was considered thin or thick, and necrosis and calcification were recorded as present or absent. The results were analyzed using the Kruskal-Wallis test.. Both dressing materials induced moderate reactions at 7 and 15 days. These reactions were similar to the control (P > .05) and reduced in intensity (to mild) from day 30 onward (P > .05). The carriers did not interfere with the reaction of the dressing materials.. TAP and CHP were biocompatible over the different experimental periods examined.

Topics: Animals; Anti-Bacterial Agents; Apexification; Biocompatible Materials; Calcinosis; Calcium Hydroxide; Ciprofloxacin; Drug Carriers; Drug Combinations; Fibrosis; Lymphocytes; Macrophages; Male; Materials Testing; Metronidazole; Minocycline; Necrosis; Polyethylene Glycols; Rats; Rats, Wistar; Regeneration; Root Canal Filling Materials; Subcutaneous Tissue; Time Factors; Tooth, Nonvital

Excitotoxicity has been suggested to play an important role in many central nervous system diseases, particularly in bilirubin encephalopathy. Minocycline treatment has been proposed to be one of the most promising potential therapies for excitotoxicity-induced neurological disorders. However, some key questions, such as the electrophysiological effect of minocycline on neuronal excitability and hyperexcitation in pathological conditions, require clarification. In this study, using patch-clamp techniques, we showed that bilirubin increased the frequency of both spontaneous excitatory postsynaptic currents (sEPSCs) and neuronal firing in isolated ventral cochlear nucleus (VCN) neurons at postnatal days 11-14 (P11-14) in rats but it did not affect the amplitude of sEPSCs or glutamate-activated (I(Glu)) currents. However, minocycline had no effect on sEPSC frequency or I(Glu) amplitude. Furthermore, minocycline pretreatment did not abolish bilirubin-induced sEPSC potentiation or neuron firing. These data suggest that minocycline does not affect excitatory synaptic transmission or hyperexcitation induced by bilirubin in VCN neurons. From these results, we propose that the neuroprotective efficacy of minocycline, if it can protect neurons against neurotoxicity induced by substances like bilirubin, is mediated by either an alternative mechanism or downstream events post neuronal hyperexcitation. Certainly, additional investigation of the neuroprotective effects of minocycline is required before embarking on further clinical trials.

Topics: Animals; Apoptosis; Bilirubin; Excitatory Amino Acids; Glutamic Acid; Minocycline; Necrosis; Neurons; Neuroprotective Agents; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Synaptic Transmission; Ventral Thalamic Nuclei

Matrix metalloproteinases (MMPs) are endopeptidases that degrade extracellular matrix and involved in ischemic organ injuries. The present study was designed to determine the role of MMP-2 in the development of ischemic acute kidney injury (AKI). AKI was induced in MMP-2 wild-type (MMP-2(+/+)) mice by 30, 60, 90, and 120 min renal ischemia and reperfusion. Renal histology, expression and activity of MMP-2 and MMP-9, and renal function were examined during the development of AKI. AKI was also induced in MMP-2-deficient (MMP-2(-/-)) mice and MMP-2(+/+) mice treated with inhibitor of MMPs (minocycline and synthetic peptide MMP inhibitor). In MMP-2(+/+) mice, MMP-2 and MMP-9 activities increased significantly at 2 to 24 h, peaked at 6 h, after reperfusion. Immunohistochemical analysis identified MMP-2 in the interstitium around tubules and peritubular capillaries in the outer medulla. Acute tubular injury (ATI), including apoptosis and necrosis, was evident in the outer medulla at 24 h, along with renal dysfunction. As ischemia period increases, MMP-2 and MMP-9 activities at 6 h and severity of AKI at 24 h increased depending on the duration of ischemia between 30 and 120 min. However, the kidneys of MMP-2(-/-) mice showed minimal ATI; serum creatinine 24 h after reperfusion was significantly low in these mice. Inhibitors of MMPs reduced ATI and improved renal dysfunction at 24 h. We conclude that MMPs, especially MMP-2 have a pathogenic role in ischemia-reperfusion AKI, and that inhibitors of MMPs can protect against ischemic AKI.

Topics: Animals; Apoptosis; Creatinine; Immunohistochemistry; Kidney; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Mice; Mice, Knockout; Minocycline; Necrosis; Reperfusion Injury; Time Factors

To reveal the effects of minocycline, an anti-inflammatory and neuroprotective agent, on the viability and physiological properties of retinal pigment epithelial (RPE) cells and to compare the effects with those of triamcinolone acetonide.. The proliferation of human RPE cells in vitro was investigated with a bromodeoxyuridine immunoassay; chemotaxis was examined with a Boyden chamber assay. Cell viability was determined by trypan blue exclusion. The gene expression of growth factors and MMP-9 was determined with real-time RT-PCR, and the secretion of VEGF was examined with ELISA. The phosphorylation of p38 MAPK and ERK1/2 proteins was determined with Western blot analysis.. Minocycline at low concentrations (50 nM-20 microM) stimulated chemotaxis and decreased the proliferation of RPE cells. Minocycline at high concentrations (above 5 microM) decreased the viability of RPE cells through the induction of cell necrosis. The chemotactic effect of minocycline was mediated by the stimulation of autocrine PDGF signaling and the activation of p38 MAPK. Minocycline promoted the expression of PDGF-B, HGF, VEGF, and MMP-9 and increased the amounts of phosphorylated p38 and ERK1/2 proteins in RPE cells. Triamcinolone reduced PDGF-evoked chemotaxis and VEGF expression and secretion and had no significant effects on cell viability and proliferation. Triamcinolone did not reverse the effects of minocycline on cell proliferation, chemotaxis, or viability or the expression of VEGF.. Low-dose minocycline induces the activation of RPE cells, as indicated by the activation of p38 and ERK1/2 and by enhanced chemotaxis mediated by autocrine PDGF signaling. High-dose minocycline induces RPE cell degeneration.

Topics: Blotting, Western; Cell Proliferation; Cell Survival; Cells, Cultured; Chemotaxis; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Glucocorticoids; Humans; Intercellular Signaling Peptides and Proteins; Matrix Metalloproteinase 9; Minocycline; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase 6; Necrosis; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Retinal Pigment Epithelium; Reverse Transcriptase Polymerase Chain Reaction; Triamcinolone Acetonide; Vascular Endothelial Growth Factor A

Graft failure after liver transplantation may involve mitochondrial dysfunction. We examined whether prevention of mitochondrial injury would improve graft function. Orthotopic rat liver transplantation was performed after 18 hours' cold storage in University of Wisconsin solution and treatment with vehicle, minocycline, tetracycline, or N-methyl-4-isoleucine cyclosporin (NIM811) of explants and recipients. Serum alanine aminotransferase (ALT), necrosis, and apoptosis were assessed 6 hours after implantation. Mitochondrial polarization and cell viability were assessed by intravital microscopy. Respiration and the mitochondrial permeability transition (MPT) were assessed in isolated rat liver mitochondria. After transplantation with vehicle or tetracycline, ALT increased to 5242 U/L and 4373 U/L, respectively. Minocycline and NIM811 treatment decreased ALT to 2374 U/L and 2159 U/L, respectively (P < 0.01). Necrosis and terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) also decreased from 21.4% and 21 cells/field, respectively, after vehicle to 10.1% and 6 cells/field after minocycline and to 8.7% and 5.2 cells/field after NIM811 (P < 0.05). Additionally, minocycline decreased caspase-3 activity in graft homogenates (P < 0.05). Long-term graft survival was 27% and 33%, respectively, after vehicle and tetracycline treatment, which increased to 60% and 70% after minocycline and NIM811 (P < 0.05). In isolated mitochondria, minocycline and NIM811 but not tetracycline blocked the MPT. Minocycline blocked the MPT by decreasing mitochondrial Ca(2+) uptake, whereas NIM811 blocks by interaction with cyclophilin D. Intravital microscopy showed that minocycline and NIM811 preserved mitochondrial polarization and cell viability after transplantation (P < 0.05).. Minocycline and NIM811 attenuated graft injury after rat liver transplantation and improved graft survival. Minocycline and/or NIM811 might be useful clinically in hepatic surgery and transplantation.

Topics: Adenosine Diphosphate; Alanine Transaminase; Animals; Anti-Bacterial Agents; Apoptosis; Calcium; Cyclosporine; Graft Survival; Liver; Liver Transplantation; Male; Minocycline; Mitochondria; Mitochondrial Diseases; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Necrosis; Rats; Rats, Inbred Lew; Reperfusion Injury; Tetracycline

Topics: Aged; Anti-Bacterial Agents; Atherosclerosis; Female; Femoral Artery; Humans; Minocycline; Necrosis; Pigmentation; Pigmentation Disorders; Skin Pigmentation; Tibial Arteries; Toes

Topics: Acne Vulgaris; Adolescent; Adult; Female; Hepatic Encephalopathy; Hepatorenal Syndrome; Humans; Liver Transplantation; Minocycline; Necrosis; Pancreatitis

A 47-year-old man with chronic osteomyelitis of the mandible is described. The patient had frequent episodes of acute and subacute exacerbation at varying intervals for a period of six years in spite of extended antibiotic therapy. Intraarterial infusion of antibiotics through the superficial temporal artery also failed to cause any improvement. He was finally treated successfully by surgical intervention.

Topics: Cephalexin; Chronic Disease; Drug Resistance; Humans; Injections, Intra-Arterial; Male; Mandibular Diseases; Middle Aged; Minocycline; Necrosis; Osteomyelitis; Tetracyclines