Abstract:
Late stage Human African Trypanosomiasis (HAT) is manifested by brain degeneration following infection by Trypanasoma brucei rhodensiense and Trypanasoma brucei gambiense parasites. This stage can only be treated with melarsoprol (Mel B) which inadvertently induces Post Treatment Reactive Encephalopathy (PTRE) and a mortality of 5% among HAT infected patients. This is an unacceptable mortality for a modern human drug. Investigations were conducted to establish the protective role of Coenzyme Q10 (CoQ10) and endogenous antioxidants (Manganese Superoxide dismutase (MnSOD), Glutathione Reductase (GR), Copper-Zinc Superoxide dismutase (SOD-1) and reduced glutathione (GSH)) against PTRE and putative resultant brain degeneration in a mouse model. This study employed a well characterized mouse model in which female swiss white mice infected with T. b. rhodesiense were manipulated to simulate all phases of HAT, including PTRE. Expressions levels of the endogenous antioxidants in the brain tissues were assessed using imunoblot or spectrophotometric procedures. There were significantly higher expressions of MnSOD (P=0.0014), SOD-1 (P=0.0001), and GR (P=0.0083) in infected than uninfected mice 21 days post infection (dpi), which were two-folds lower than those observed at 57 dpi. Levels of GSH were significantly lower (P=0.0347) in infected 57dpi than uninfected mice 21dpi. Expressions of SOD (P=0.0429), GR (P=0.0001) and GSH (P=0.0001) were significantly higher in infected than in uninfected mice among Mel B treated mice. Mel B treated uninfected mice had significantly lower expressions of GR (P=0.0001) and GSH (P=0.0001) and MnSOD (P=0.0035), than untreated (uninfected) controls. Pre-treatment with CoQ10 significantly increased expression of GSH (P=0.0001) relative to the Mel B treatment alone. This is a significant finding that demonstrates that CoQ10 exposure prior to Mel B could boost GSH and neuroprotect in late stage therapy. The results indicate that the parasites and Mel B suppress the antioxidant system. The resultant time dependent dynamics of antioxidant suppression due to Mel B, and potential ameliorating effects of CoQ10 on the same, shed light on putative mechanism of toxicity of the drug during treatment of late stage HAT and a possible antidote of the toxicity. CoQ10 and endogenous antioxidants can find application in 1) formulation of novel Mel B based drugs against late stage HAT and 2) development of novel markers for staging the disease.
