CEREBELLAR NEUROTOXICITY OF ARTEMETHER‐LUMEFANTRINE IN PROPHYLACTIC, SUPPRESSIVE AND CURATIVE EXPERIMENTAL MALARIA MODELS

Abstract

Artemether‐lumefantrine (AL) is drug of choice for the treatment of uncomplicated malaria in most African and Asian countries, though cases of Plasmodium resistance have been reported. Diagnosis of cerebellar ataxia has been associated in some patients taking artemether‐lumefantrine. Here we report the potential neurotoxicity of this drug on the cerebellar histomorphology and glial pathology of Plasmodium infected mice in prophylactic, suppressive and curative experimental malaria models. All procedures adhered to the guiding principles of care and use of laboratory animals, and institutional ethics committee. 30 Swiss male mice were randomized into 6 groups, 2 groups each for the 3 models representing; the control and test. Prophylactic groups received 0.9% normal saline, and AL 5 mg/kg respectively for 3 days before inoculation with parasite; suppressive groups were inoculated with parasite, and treated immediately; while curative groups were inoculated, and treated 5 days later. Result of routine H&E for prophylactic control showed atrophy and loss of purkinje neurons, but test showed clumping of granule cells and lesions in molecular layer; suppressive control showed widespread lesions in molecular layer, atrophy and loss of purkinje cells, while test showed moderate purkinje neuronal shrinkage with mild lesions, and curative control showed severe distortion of cerebellar cell layers with severe clumping of granule cells, atrophy of purkinje cells and degeneration of neuropil in molecular layer; and test showed less severe distortions. Glial pathology of prophylactic model reveals mildly expressed glial fibrillary acidic protein; suppressive model had moderately expressed GFAP; while reactive astrogliosis was severely expressed in the curative model. In conclusion, severe cerebellar distortion and expression of GFAP in malaria models of artemether‐lumefantrine treated Plasmodium infected mice is dependent mainly on degree of parasite exposure than due to drug toxicity; still caution should be applied in the use of artemether‐lumefantrine.Support or Funding InformationTETFUND, Nigeria