Ginkgo biloba attenuated detrimental inflammatory and oxidative events due to Trypanosoma brucei rhodesiense in mice treated with melarsoprol

Abstract

Background

The severe late stage Human African Trypanosomiasis (HAT) caused by Trypanosoma brucei rhodesiense (T.b.r) is characterized by damage to the blood brain barrier, severe brain inflammation, oxidative stress and organ damage. Melarsoprol (MelB) is currently the only treatment available for this disease. MelB use is limited by its lethal neurotoxicity due to post-treatment reactive encephalopathy. This study sought to assess the potential of Ginkgo biloba (GB), a potent anti-inflammatory and antioxidant, to protect the integrity of the blood brain barrier and ameliorate detrimental inflammatory and oxidative events due to T.b.r in mice treated with MelB.

Methodology

Group one constituted the control; group two was infected with T.b.r; group three was infected with T.b.r and treated with 2.2 mg/kg melarsoprol for 10 days; group four was infected with T.b.r and administered with GB 80 mg/kg for 30 days; group five was given GB 80mg/kg for two weeks before infection with T.b.r, and continued thereafter and group six was infected with T.b.r, administered with GB and treated with MelB.

Results

Co-administration of MelB and GB improved the survival rate of infected mice. When administered separately, MelB and GB protected the integrity of the blood brain barrier and improved neurological function in infected mice. Furthermore, the administration of MelB and GB prevented T.b.r-induced microcytic hypochromic anaemia and thrombocytopenia, as well as T.b.r-driven downregulation of total WBCs. Glutathione analysis showed that co-administration of MelB and GB prevented T.b.r-induced oxidative stress in the brain, spleen, heart and lungs. Notably, GB averted peroxidation and oxidant damage by ameliorating T.b.r and MelB-driven elevation of malondialdehyde (MDA) in the brain, kidney and liver. In fact, the co-administered group for the liver, registered the lowest MDA levels for infected mice. T.b.r-driven elevation of serum TNF-α, IFN-γ, uric acid and urea was abrogated by MelB and GB. Co-administration of MelB and GB was most effective in stabilizing TNFα levels. GB attenuated T.b.r and MelB-driven up-regulation of nitrite.

Conclusion

Utilization of GB as an adjuvant therapy may ameliorate detrimental effects caused by T.b.r infection and MelB toxicity during late stage HAT.

Author summary

Human African Trypanosomiasis (HAT) is a lethal disease caused by Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense (T.b.r) protozoan parasites. The only treatment available for the late, CNS stage due to T.b.r, is melarsoprol (MelB). Notably, MelB has an arsenic moiety, that makes it very neurotoxic, causing fatal post-treatment reactive encephalopathy in about 5% of those treated. This level of drug-induced mortality is unacceptable in this day and age. The question is, how can we block T.b.r-induced organ damage and safely administer MelB? In the late stage HAT, parasites wreak havoc by inducing severe oxidative stress, inflammation and breach of the blood brain barrier (bbb); while on the other hand, MelB is driving lethal encephalopathy. We used a HAT mouse model and sought to elucidate the potential of a standardized GB extract–a potent antioxidant anti-inflammatory, to alleviate T.b.r-driven damage to the bbb, induction of oxidative stress and inflammation; while ameliorating MelB-driven neurotoxic effects. According to the results, GB protected from lethal parasite induced organ damage, as well as MelB toxicity, providing a novel approach for development of an adjuvant therapy.