necrox-5 and Necrosis

Interference with regulated necrosis for clinical purposes carries broad therapeutic relevance and, if successfully achieved, has a potential to revolutionize everyday clinical routine. Necrosis was interpreted as something that no clinician might ever be able to prevent due to the unregulated nature of this form of cell death. However, given our growing understanding of the existence of regulated forms of necrosis and the roles of key enzymes of these pathways, e.g., kinases, peroxidases, etc., the possibility emerges to identify efficient and selective small molecule inhibitors of pathologic necrosis. Here, we review the published literature on small molecule inhibition of regulated necrosis and provide an outlook on how combination therapy may be most effective in treatment of necrosis-associated clinical situations like stroke, myocardial infarction, sepsis, cancer and solid organ transplantation.

Topics: Animals; Apoptosis; Cyclohexylamines; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Mice; Necrosis; Organic Chemicals; Phenylenediamines; Protein Kinases; Pyridazines; Quinoxalines; Receptor-Interacting Protein Serine-Threonine Kinases; Spiro Compounds; Sulfones

Necrosis is a pathological form of cell death that induces an inflammatory response, and immune cell activation contributes to the development and maintenance of hypertension. Necrosis was measured in kidney, spleen, and aorta of 12- to 13-week-old male and female SHRs (spontaneously hypertensive rats); male SHRs had greater renal necrotic cell death than female SHRs. Because male SHRs have a higher blood pressure (BP) and a more proinflammatory T-cell profile than female SHRs, the current studies tested the hypothesis that greater necrotic cell death in male SHRs exacerbates increases in BP and contributes to the proinflammatory T-cell profile. Male and female SHRs were randomized to receive vehicle or Necrox-5-a cell permeable inhibitor of necrosis-from 6 to 12 weeks of age or from 11 to 13 weeks of age. In both studies, Necrox-5 decreased renal necrosis and abolished the sex difference. Treatment with Necrox-5 beginning at 6 weeks of age attenuated maturation-induced increases in BP in male SHR; BP in female SHR was not altered by Necrox-5 treatment. Necrox-5 decreased proinflammatory renal T cells in both sexes, although sex differences were maintained. Administration of Necrox-5 for 2 weeks in SHR with established hypertension resulted in a small but significant decrease in BP in males with no effect in females. These results suggest that greater necrotic cell death in male SHR exacerbates maturation-induced increases in BP with age contributing to sex differences in BP. Moreover, although necrosis is proinflammatory, it is unlikely to explain sex differences in the renal T-cell profile.

Topics: Animals; Aorta; Cell Death; Disease Models, Animal; Female; Heterocyclic Compounds, 4 or More Rings; Hypertension; Kidney; Male; Necrosis; Random Allocation; Rats; Rats, Inbred SHR; Sensitivity and Specificity; Sex Factors; Spleen; Sulfones; Treatment Outcome