bimoclomol and Myocardial-Ischemia

Bimoclomol, the recently developed non-toxic heat shock protein (HSP) coinducer, was shown to display multilateral protective activities against various forms of stress or injuries at the level of the cell, tissue or organism. The compound enhanced the transcription, translation and expression of the 70 kD heat shock protein (HSP-70) in myogenic and HeLa cell lines exposed to heat stress, and increased cell survival on exposure to otherwise lethal thermal injury. Bimoclomol increased contractility of the working mammalian heart, this effect was associated with the increased intracellular calcium transients due to increased probability of opening of ryanodine receptors in the sarcoplasmic reticulum (SR). In healthy tissues these cardiac effects were evident only at relatively high concentrations of the drug, while in the ischemic myocardium bimoclomol exerted significant cardioprotective and antiarrhythmic effects at submicromolar concentrations. It decreased ischemia-induced reduction of contractility and of cardiac output, and dramatically decreased the elevation of the ST-segment during ischemia as well as the occurrence of ventricular fibrillation upon reperfusion. Bimoclomol was also active in various pathological animal models subjected to acute or chronic stress. In the spontaneously hypertensive rats chronic pretreatment with bimoclomol restored sensitivity of aortic rings to acetylcholine; this effect was accompanied by accumulation of HSP-70 in the tissues. Bimoclomol pretreatment significantly diminished the consequences of vascular disorders associated with diabetes mellitus. Diabetic neuropathy, retinopathy, and nephropathy were prevented or diminished, while wound healing was enhanced by bimoclomol. Enhancement of wound healing by bimoclomol was observed after thermal injury as well as following ultraviolet (UV) irradiation. In addition to the beneficial effects on peripheral angiopathies, bimoclomol antagonized the increase in permeability of blood-brain barrier induced by subarachnoid hemorrhager or arachidonic acid. A general and very important feature of the above effects of bimoclomol was that the drug failed to cause alterations under physiological conditions (except the enhanced calcium release from cardiac sarcoplasmic reticulum). Bimoclomol was effective only under conditions of stress. Consistent with its HSP-coinducer property, bimoclomol alone had very little effect on HSP production. Its protective activity became apparent only i

Topics: Animals; Blood-Brain Barrier; Cytoprotection; Diabetes Complications; Drug Evaluation, Preclinical; Heat-Shock Proteins; Humans; Imides; Muscle Contraction; Muscle, Smooth, Vascular; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Pyridines; Stimulation, Chemical

The heat shock proteins (hsps) are induced by a variety of stressful stimuli and their overexpression has been shown to protect cells both in vitro and in vivo against such stimuli, as well as against stimuli-inducing apoptosis. The potential therapeutic benefit of elevating hsp levels in individuals with, for example, cerebral or cardiac ischaemia or neurodegenerative diseases has led to the identification of specific methods of inducing hsp expression in a non-stressful manner. These include pharmacological procedures and cytokine treatment to elevate endogenous hsp levels and the development of viral vectors to deliver exogenous hsp genes. The advantages and disadvantages of each of these methods and their ultimate therapeutic potential are discussed.

Topics: Apoptosis; Benzoquinones; Brain Ischemia; Cytokines; Cytoprotection; Genetic Therapy; Heat-Shock Proteins; Humans; Imides; Lactams, Macrocyclic; Myocardial Ischemia; Neurodegenerative Diseases; Pyridines; Rifabutin

Preservation of the chemical architecture of a cell or of an organism under changing and perhaps stressful conditions is termed homeostasis. An integral feature of homeostasis is the rapid expression of genes whose products are specifically dedicated to protect cellular functions against stress. One of the best known mechanisms protecting cells from various stresses is the heat-shock response which results in the induction of the synthesis of heat-shock proteins (HSPs or stress proteins). A large body of information supports that stress proteins--many of them molecular chaperones--are crucial for the maintenance of cell integrity during normal growth as well as during pathophysiological conditions, and thus can be considered "homeostatic proteins." Recently emphasis is being placed on the potential use of these proteins in preventing and/or treating diseases. Therefore, it would be of great therapeutic benefit to discover compounds that are clinically safe yet able to induce the accumulation of HSPs in patients with chronic disorders such as diabetes mellitus, heart disease or kidney failure. Here we show that a novel cytoprotective hydroxylamine derivative, [2-hydroxy-3-(1-piperidinyl) propoxy]-3-pyridinecarboximidoil-chloride maleate, Bimoclomol, facilitates the formation of chaperone molecules in eukaryotic cells by inducing or amplifying expression of heat-shock genes. The cytoprotective effects observed under several experimental conditions, including a murine model of ischemia and wound healing in the diabetic rat, are likely mediated by the coordinate expression of all major HSPs. This nontoxic drug, which is under Phase II clinical trials, has enormous potential therapeutic applications.

Topics: Animals; Cell Line; Cell Survival; Diabetes Mellitus, Experimental; Embryo, Mammalian; Heart; Heat Stress Disorders; Heat-Shock Proteins; HeLa Cells; HSP70 Heat-Shock Proteins; Humans; Imides; In Vitro Techniques; Luciferases; Male; Myocardial Ischemia; Myocardium; Promoter Regions, Genetic; Pyridines; Rats; Rats, Wistar; Recombinant Fusion Proteins; RNA, Messenger; Skin; Transcription, Genetic; Transfection; Wound Healing