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Antioxidant MDL 29,311 prevents diabetes in nonobese diabetic and multiple low-dose STZ-injected mice
E W Heineke1, M B Johnson, J E Dillberger
1Marion Merrell Dow Research Institute, Cincinnati, OH 45215.
Abstract:
Recent investigations suggest a role for antioxidants in preventing IDDM. MDL 29,311 (4,4'-[methylenebis(thio)]bis](1,1- dimethylethyl)]-phenol) is an analogue of the antioxidant probucol. Administered as a 1% dietary admixture to female nonobese diabetic mice from 4 to 24 wk of age, MDL reduced the prevalence of diabetes from 49 to 4% at 24 wk of age (n = 50-61/group). Discontinuation of treatment at 24 wk of age did not result in a rapid onset of diabetes. Probucol (1%) did not prevent diabetes. Initiating MDL treatment at 4 or 8 wk of age was more effective (19 and 17%, respectively, compared with 60% in control mice) than initiating treatment at 12 wk of age (30% diabetic; n = 28-35/group). A lower dose of MDL (0.1%), started at 4 wk of age, decreased the prevalence of diabetes to 36%. Histopathology indicated that MDL did not prevent insulitis. MDL (0.1%) also was evaluated in combination with immunosuppressants. Compared with control mice (65% diabetic), the combination of MDL and deflazacort was more effective (21% diabetic) than either agent alone (39% diabetic for MDL and 59% diabetic for deflazacort), whereas the effectiveness of MDL, cyclosporin, and MDL plus cyclosporin was similar (39, 38, and 34% diabetic, respectively). In another model of IDDM, the multiple-low-dose streptozocin-injected mouse, MDL (1%) also reduced the prevalence of diabetes when administered beginning 8 wk before streptozocin (55% diabetic vs. 100% of control mice; n = 20-25/group). Probucol (1%) was ineffective. MDL appears effective in preventing the onset of disease in two mouse models of IDDM.
Insights
MDL 29,311, an antioxidant, significantly reduced the incidence of insulin-dependent diabetes (IDDM) in mouse models. Early and continuous treatment with MDL 29,311 proved most effective in preventing diabetes onset.
Area of Science:
- Immunology
- Endocrinology
- Pharmacology
Background:
- Recent research indicates antioxidants may play a role in preventing insulin-dependent diabetes mellitus (IDDM).
- MDL 29,311 is a novel antioxidant compound structurally related to probucol.
- Investigating novel therapeutic strategies for IDDM prevention is crucial.
Purpose of the Study:
- To evaluate the efficacy of MDL 29,311 in preventing IDDM in preclinical mouse models.
- To determine the optimal timing and dosage for MDL 29,311 administration.
- To assess the synergistic effects of MDL 29,311 with immunosuppressive agents.
Main Methods:
- Administration of MDL 29,311 as a dietary admixture to female nonobese diabetic mice at various ages and doses.
- Evaluation of probucol as a control antioxidant.
- Assessment of MDL 29,311 in combination with deflazacort and cyclosporin.
- Testing MDL 29,311 in a multiple-low-dose streptozocin-induced mouse model of IDDM.
Main Results:
- MDL 29,311 significantly reduced diabetes prevalence from 49% to 4% in nonobese diabetic mice when administered from 4 to 24 weeks of age.
- Early initiation of MDL 29,311 treatment (4 or 8 weeks) was more effective than later initiation (12 weeks).
- MDL 29,311, in combination with deflazacort, showed enhanced efficacy compared to either agent alone, while its combination with cyclosporin yielded similar results to cyclosporin alone. MDL 29,311 also reduced diabetes incidence in the streptozocin-induced model.
Conclusions:
- MDL 29,311 demonstrates significant potential in preventing the onset of IDDM in multiple mouse models.
- The compound's efficacy is dependent on the timing and duration of administration.
- MDL 29,311 may offer a novel therapeutic avenue for IDDM prevention, potentially in combination with immunosuppressants.