Significant Reduction of Total-Body Irradiation-Induced Death in Mice Treated with PrC-210 24 Hours Postirradiation.

The search for radiation countermeasures that can serve as: i. a pre-exposure agent to protect against subsequent irradiation, and/or ii. a post-exposure agent to mitigate the development of Acute Radiation Syndrome after radiation exposure, remains a prominent goal of the U.S. Government. This study was undertaken to determine whether PrC-210, when administered once, 24 h postirradiation, would provide a survival benefit and would mitigate Acute Radiation Syndrome in mice that had received an otherwise 95-100% lethal radiation dose. Our results show that a single intraperitoneal dose of PrC-210 (0.3-0.4 MTD, 151-201 ug/gm body weight) administered 24 h postirradiation, conferred: i. a 45% survival advantage (P = 0.002) in outbred ICR mice and a 25% survival advantage (P = 0.037) in inbred C57Bl/6 mice, ii. a significant increase in body weight in surviving mice (P = 0.012), iii. a discernible protection of intestinal structure by MRI imaging of live mice, iv. visibly denser jejunal villi and surface epithelium and v. visible bone marrow population in PrC-210-treated mice versus saline controls. The ability of PrC-210 to suppress 100% of radiation-induced death when administered minutes before irradiation, or roughly half of this effect (45%) when administered 24 h postirradiation is noteworthy. Determining the multiple paths by which PrC-210 protection is conferred is a process; the results in this report showing protection of two of the major systems central to Acute Radiation Syndrome damage, is a good first step. This was the first study of PrC-210 administered postirradiation; it conferred substantial survival benefit and suppression of Acute Radiation Syndrome. This outcome supports the continued development of PrC-210 to protect humans exposed to ionizing radiation.

Suppression of Inflammation-Associated Kidney Damage Post-Transplant Using the New PrC-210 Free Radical Scavenger in Rats.

Allograft kidney transplantation, which triggers host cellular- and antibody-mediated rejection of the kidney, is a major contributor to kidney damage during transplant. Here, we asked whether PrC-210 would suppress damage seen in allograft kidney transplant. Brown Norway (BN) rat kidneys were perfused in situ (UW Solution) with or without added 30 mM PrC-210, and then immediately transplanted into Lewis (LEW) rats. 20 h later, the transplanted BN kidneys and LEW rat plasma were analyzed. Kidney histology, and kidney/serum levels of several inflammation-associated cytokines, were measured to assess mismatch-related kidney pathology, and PrC-210 protective efficacy. Twenty hours after the allograft transplants: (i) significant histologic kidney tubule damage and mononuclear inflammatory cell infiltration were seen in allograft kidneys; (ii) kidney function metrics (creatinine and BUN) were significantly elevated; (iii) significant changes in key cytokines, i.e., TIMP-1, TNF-alpha and MIP-3A/CCL20, and kidney activated caspase levels were seen. In PrC-210-treated kidneys and recipient rats, (i) kidney histologic damage (Banff Scores) and mononuclear infiltration were reduced to untreated background levels; (ii) creatinine and BUN were significantly reduced; and (iii) activated caspase and cytokine changes were significantly reduced, some to background. In conclusion, the results suggest that PrC-210 could provide broadly applicable organ protection for many allograft transplantation conditions; it could protect transplanted kidneys during and after all stages of the transplantation process-from organ donation, through transportation, re-implantation and the post-operative inflammation-to minimize acute and chronic rejection.