The applicants have developed a novel class of compounds with potential protective effects in various forms of inflammation. In this proposal, we present evidence that mercaptoalkylguanidine derivatives are (1) inhibitors of the inducible isoform of nitric oxide synthase, an enzyme which is expressed in tissue-infiltrating neutrophils and macrophages and produces cytotoxic amounts of the free radical nitric oxide and (2) scavengers of peroxynitrite, a reactive, toxic oxidant produced in reperfusion injury and (3) protective agents in rodent experimental models of sickle cell disease. The applicants are currently developing MEG for anti-inflammatory indications. Recent preliminary studies indicated that the production of peroxynitrite and the expression of iNOS play an important role in the development of renal dysfunction during sickle cell disease.
The specific aim of the present proposal is to synthesize large quantities of MEG, our lead compound of the mercaptoalkylguanidine class, and perform studies in murine model of sickle cell disease, in order to decide whether the agent may be useful in protecting the kidney in this condition. The results of the current study may unveil an additional indication for the clinical utility of MEG.
Patients with sickle cell anemia, develop a different disturbance in the kidney, as bleeding, infection with the results in dehydration, serious damage to many other organs. These problems occur in all homozygous and many heterozygous patients. The sickle cell gene is estimated to be present in 10% of the African-American population, but is also present in many other parts of the world, including Africa, Mediterranean countries and India, where the repeated hospitalization costs of these patients are very high. As there is no adequate prophylactic therapy for this disease, an effective one could find widespread use in the US as well as in the other countries.
