Behavioral toxicity and efficacy of WR-2721 as a radioprotectant

S-2-(3-Aminopropylamino)ethylphosphorothioic acid (WR-2721) is a promising protectant for radiation-induced lethality. However, treatment with WR-2721 also produces nausea, vomiting, diarrhea, and hypotension, which implies severe functional consequences. Three studies were conducted to assess the effects of WR-2721 on rat motor performance and weight and to assess the ability of WR-2721 to mitigate the early performance decrement (PD) produced by ionizing radiation. In the first study, rats trained on the accelerod motor performance task were give 200, 300, or 400 mg/kg WR-2721 intraperitoneally (ip). The highest dose used referenced the maximum tolerated dose in the rat, which is two-thirds the median lethal dose (590 mg/kg). The subjects were tested immediately after treatment, at 30-min intervals for 3 h, and again at 24 h. All groups (N = 6/group) demonstrated a significant decrease in accelerod performance compared to control levels across the eight test trials, which ranged from 24 to 44% in the 200 and 400 mg/kg dose groups, respectively. Performance returned to baseline levels at 24 h. Some deaths occurred at all dose levels. In the second study, motor performance was measured after exposure to radiation alone or a drug/radiation combination (N = 8/group). WR-2721 was administered 30 min before exposure to 130 Gy of gamma radiation from a 60Co source at a dose rate of 20 Gy/min. Rats were tested on the accelerod immediately after WR-2721 treatment and at 10, 15, 30, 60, and 120 min and 24 h following radiation. Performance was significantly depressed compared to control throughout the 24 h following radiation exposure, with and without WR-2721. The decrement produced by WR-2721 and radiation alone appeared to add up to the combined drug/radiation decrement found over the 15- to 120-min test periods. In the third study assessing the effects of WR-2721 on weight, untrained rats treated with 200 or 400 mg/kg WR-2721 exhibited significant weight loss that lasted up to 3 days. Weight returned to pretreatment levels in 15 days, and no deaths occurred. In summary, the data suggest that in the rat (1) WR-2721 is behaviorally toxic at doses relevant to radioprotection, (2) WR-2721 treatment along with the stress of motor performance may combine to lower the level at which lethalities occur, (3) WR-2721 does not protect for radiation-induced PD, and (4) WR-2721 combined with radiation disrupts performance more severely than either radiation or WR-2721 alone.