Modulation of Oxygen Toxicity by Select Anti-Melanogenic Compounds

Abstract

LOCiK 20 (Cont'd) ._,ause selective lysis of parasitized erythrocytes and hence result in a depression in parasitemia. Furthermore, any benefit derived from an effective agent would be noted by the drug's ability to diminish the severity of paras temia decline following HBO exposure.Femalens 1ice (26-30 gin.) were given an intraperitoneal inoculum of 5.Ox W t. berrhe infected erythrocytes.Ten days later, micewere assayed for circulating erythrocyte and pe asitemia levels and were divided into groups representing: (a) controls H (b) 1O-exposed (10 min. compression, 90 min. exposure at 3 atmosphere absolute; 45 min. decompression), (c) drug-treateO and (d) drug-tr ted 1.5 hrs. prior to HBO exposure.Circulating erythrocytes and pa i stemia levels were remonitored 24 hours after treatment.All dat is based as a % of day 11 control parasitemia + I S.E.M...The data clearly indicate that HBO is an effective maneuver to selectively lyse parasitized erythrocytes. In this regard, HBO effected a 20-40% depression in circulating parasitemia relative to non-exposed controls, when monitored 24 hours (on day 11) after exposure.The druZ 2-thiouracil in doses of 20 to 100 mg/kg body weight (but not 10 mg/kg) were effective in combating the HBO-induced decline in parasitemia. Iso-ascorbic acid (500 mg/kg) and reduced glutathione (50 mg/kg) w e likewise effective against HBO exposure. Neither drug (i.e., 2-thi uracil, pso-ascorbi e acid;a.educed glutathione) had any appreciable effect n the course of parasitemia in non-exposed material mice.Our plans for '4.turm tesearch include the following:(a) To complete the dose-response curve for 2-thiouracil at a level of 15 mg/kg body weight, (b) to perform dose-response curves for the drugs, iso-ascorbic acid and reduced glutathione, (c) to assess the efficacy of the remaining 6 anti-melanogenic compounds mentioned herein, as well as others, in our sensitive model malarial system and (d) to test our potentially beneficial agents against other criteria, such as convulsion and survival times in normal non-infected mice exposed to HBO. In sumnary: (a) one of the consequences of 02 toxicity is increased hemolysis and the development of anemia; an occurrence which seems to be mediated by increased availability of melanin or one or more of its immediate precursors; (b) the anemia associated with 0 toxicity ,ars a strong Uli. Research Progress A. General CcementsMany problems and variables were encountered in establishing an effective protocol for studying hyperbaric 0 2 toxicity in malwrl% imice. In brief, our concern was directed toward: (a) construction of a safe, gastight hyperbaric chamber, (b) establishment of appropriate 02 flushing, compression, exposure and decompression procedures, (c) selection of an optimized malarial mouse test system as related to: body weight, level of infection (Plasmodium berghei) inoculum, day of infection on which to expose; level and duration of hyperbaric 02 exposure, and (d) determination of appropriate time intervals at which to assess the consequences ...