title: Multilateral in vivo and in vitro protective effects of the novel heat shock protein coinducer, bimoclomol: results of preclinical studies.
abstract: 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 in the presence of cell damage. Currently, bimoclomol reached the end of the Phase II clinical trial in a group of 410 patients with diabetic complications. Results of this trial will answer the question, whether a compound with promising in vitro and in vivo preclinical findings will produce the anticipated beneficial effects in humans. In the event of a positive outcome of this trial, the indications for bimoclomol will be substantially extended.
authors.affiliation: Department of Physiology, University Medical School of Debrecen, P.O. Box 22, H-4012 Debrecen, Hungary. nanasi@phys.dote.hu
authors.forename: P P
authors.initials: PP
authors.lastname: Nánási
authors.forename: A
authors.initials: A
authors.lastname: Jednákovits
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D019610:Cytoprotection; D048909:Diabetes Complications; D004353:Drug Evaluation, Preclinical; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D006801:Humans; D007094:Imides / Q000493:pharmacokinetics / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D009206:Myocardium / Q000166:cytology; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D013268:Stimulation, Chemical
chemical_list: D006360:Heat-Shock Proteins; D007094:Imides; D011725:Pyridines; C108730:bimoclomol