Coenzyme Q10 and endogenous antioxidants neuro-protect mice brain against deleterious effects of melarsoprol and Trypanasoma brucei rhodesiense

Abstract

Melarsoprol (Mel B) is the only efficacious drug against late stage Human African Trypanosomiasis (HAT), but inadvertently is very toxic and induces Post Treatment Reactive Encephalopathy (PTRE) that is lethal in 5% of the patients. Investigations were conducted to establish the neuro-protective role of Coenzyme Q₁₀ (CoQ₁₀) and other cellular antioxidants ((Manganese Superoxide dismutase (MnSOD), Glutathione Reductase (GR), Copper-Zinc Superoxide dismutase (SOD-1) and glutathione (GSH)) against Mel B toxicity, PTRE and putative resultant brain degeneration in a mouse model. Female Swiss-white mice were infected with Trypanasoma brucei rhodesiense parasite and manipulated to simulate all phases of PTRE and HAT. Expression profiles of the antioxidants in brain tissues were assessed using immunoblots, while GSH was measured spectrophotometrically. Trypanosoma brucei rhodesiense infection resulted in elevation of expression of endogenous antioxidants in the early stage of infection (21dpi), with significant expression (two fold) observed at the terminal stage of the disease (57dpi). CoQ10 assisted in boosting Levels of GSH upon induction of severe late stage of HAT. Similarly CoQ10 administration significantly augmented levels of SOD-1, GR and GSH in infected than in uninfected mice that were treated with Melarsoprol. The time dependent dynamics of antioxidant suppression due to Melarsoprol, and potential ameliorating effects of CoQ₁₀ on the same, indicate putative mechanism underlying and antidote to the toxicity of the drug with potential application in formulation of novel Melarsoprol-based drugs and development of novel markers for staging the disease.

Key Words: Trypanasoma brucei rhodesiense, endogenous antioxidants, late stage HAT; Coenzyme Q₁₀; Melarsoprol;

Abbreviations: GSH, glutathione; CoQ10, Coenzyme Q10; MnSOD, Manganese Superoxide dismutase; GR, Glutathione Reductase; SOD-1, Copper-Zinc Superoxide dismutase; Mel B, melarsoprol; PTRE, Post treatment reactive encephalopathy; HAT, Human African Trypanoomiasis; HEPES, N-2 hydroxyethylpiperazine-N`-2 ethane sulfonic acid; ICDH, isocitrate dehydrogenase; LDH, lactate dehydrogenase; MnSOD, manganese superoxide dismutase; NADP⁺, nicotinamide adenine dinucleotide phosphate, NO, nitric oxide; ONOO^-, peroxynitrite; ROS, reactive oxygen species; SDS, sodium dodecyl sulfate; TCA, tricarboxylic acid; DAB, diaminobenzidine;  PBS, Phosphate buffered saline; dpi, days post infection.