ABSTRACT

Malaria parasite has remained a menace to human immune system as it usually subjects its host to oxidative stress which in turn has an effect on the levels of the antioxidant system due to generation of reactive oxygen species. This study investigated the brain antioxidant activities with six artemisinin-based combination therapies in an experimental malaria model. Forty (40) adult male Swiss albino mice between 20 – 30 g were randomized into 8 groups of 5 animals each. Groups 1 served as the normal control (NC) and were given normal feed and distilled water. Group 2positive control (PC) received 0.2ml of parasitized erythrocyte from a donor mouse. Group 3 was treated with 5.71 mg/kg body weight (ml/kg bw) Artesunate-amodiaquine – AA (CAMOSUNATE®) for 3 days, group 4 received 6.43 mg/kg bw Artesunate-mefloquine – AM (Artequin™) for 3 days, group 5 were given 2.86 mg/kgbw Artesunate-sulfadoxine-pyrimesthamine – ASP (SIMBCURE®) for 3 days, group 6 received 12.5 mg/kg bw Artemisinin-piperaquine – AP(ARTEQUICK®) for 2 days, group 7 received 5.14 mg/kg bw Dihydroartemisinin-piperaquine – DP (P-ALAXIN™) and group 8 received 8 mg/kg bw Artemether-lumefantrine – AL (Coartem®) for 3 days through oral administration after being inoculated with Plasmodium berghei strain intraperitoneally. The mice were then sacrificed by chloroform inhalation after treatment. The mice brain was harvested and the brain homogenates were used for antioxidant assay, also blood sample was obtained through cardiac puncture for parasite estimation. Result for parasitaemia level showed a significant  decreased in groups 3, 4, 6, 7 and 8 in order of decreasing efficacy; AM > DP > AP > AA > AL > ASP. Implying the all the ACTs except ASP were efficacious in parasite clearance. AA, AM, AL and ASP groups had significant depleted levels of GSH, SOD, GPx and GST whereas CAT, MDA levels significantly increased with ASP, AP and DP when compared with NC groups. The vitamins showed variant results with the drugs as there were decreased levels of vitamin C in AP and DP groups while all the artesunate combinations elevated the levels of vitamins E and A. In conclusion the ACTs used suppressed the expression of most of the brain antioxidants even after parasite clearance, possibly due early onset of mice recovery from infection.

Keywords; Antioxidants, Artemisinin-based combination therapy, Brain, Malaria.

TABLE OF CONTENTS

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Cover Page      -           -           -           -           -           -           -           -           -           -           i

Title Page        -           -           -           -           -           -           -           -           -           -           ii

Certification    -           -           -           -           -           -           -           -           -           -           iii

Dedication                  -           -           -           -           -           -           -           -           -           iv

Acknowledgements                -           -           -           -           -           -           -           -           v

Abstract          -           -           -           -           -           -           -           -           -           -           vii

Table of Contents       -           -           -           -           -           -           -           -           -           viii

CHAPTER ONE: INTRODUCTION

 1.1      Background of the Study        -           -           -           -           -           -           -           1

1.2       Statement of the Problem                    -           -           -           -           -           -           4

1.3       Aim and Objective of the Study         -           -           -           -           -           -           5

1.4Justification of the Study                    -           -           -           -           -           -           5

1.5       Scope of the Study                 -           -           -           -           -           -           -           6

CHAPTER TWO: LITERATURE REVIEW

2.1       History and Discovery of Malaria       -           -           -           -           -           -           7

2.2       Malaria in Africa        -           -           -           -           -           -           -           -           8

2.3       Malaria in Nigeria       -           -           -           -           -           -           -           -           8

2.4       Life Cycle of Malaria Parasite            -           -           -           -           -           -           9

2.5       Malaria and the Brain -           -           -           -           -           -           -           -           11

2.5.1    Pathological Mechanisms in Cerebral Malaria           -           -           -           -           11

2.5.2    Neurological Features of Cerebral Malaria    -           -           -           -           -           12

2.6       Malaria and Oxidative Stress  -           -           -           -           -           -           -           12

2.7       Role of Antioxidants in Malaria Pathophysiology    -           -           -           -           14

2.7.1    Classification of Antioxidants Based on their Function        -           -           -           14

2.7.2    Classification of Antioxidants Based on their Sources          -           -           -           14

2.7.3    Ameliorating Effects of Some Non-enzymatic Antioxidants in Malaria       -          16

2.7.4    Lines of Enzymatic Antioxidant Defenses     -           -           -           -           -           19

2.8       Artemisinin-Based Combination Therapy      -           -           -           -           -           24

2.8.1        Artemether-Lumefantrine, AL           -           -           -           -           -           -           27

2.8.2    Artesunate-Amodiaquine, AA            -           -           -           -           -           -           30

2.8.3    Artesunate-Sulfadoxine-pyrimethamine, ASP           -           -           -           -           32

2.8.4    Artesunate-Mefloquine, AM              -           -           -           -           -           -           33

2.8.5    Dihydroartemisinin-Piperaquine, DP             -           -           -           -           -           35

2.8.6    Artemisinin-Piperaquine, AP             -           -           -           -           -           -           36

2.9       Artemisinins and Oxidative Stress     -           -           -           -           -           -           37

2.10     Neurotoxicity of Artemisinin-Based Combination Therapy  -           -           -           39

CHAPTER THREE: MATERIALS AND METHODS

3.1       Materials         -           -           -           -           -           -           -           -           -           41

3.1.1    Experimental Animals            -           -           -           -           -           -           -           41

3.2       Methods          -           -           -           -           -           -           -           -           -           41

3.2.1    Experimental Design  -           -           -           -           -           -           -           -           41

3.3       Acquisition of Donor Mice                 -           -           -           -           -           -           42

3.4       Acquisition of Drugs              -           -           -           -           -           -           -           42

3.5       Parasite Inoculation and Parasite Estimation -           -           -           -           -           43

3.6       Drug Administration               -           -           -           -           -           -           -           43

3.7       Biochemical Analysis -           -           -           -           -           -           -           -           43

CHAPTER FOUR: RESULTS AND DISCUSSION

4.1       Results            -           -           -           -           -           -           -           -           -           49

4.1.1    Effect of six ACTs on parasitemia levels of Plasmodium berghei
-infected Swiss albino mice                -           -           -           -           -           -           49

4.1.2    Effect of six ACTs on the Brain’s Six Enzymatic antioxidant levels of
 Plasmodium berghei-infected Swiss albino mice      -           -           -           -           49

4.1.3Effect of six ACTs on the Brain’s three non-enzymatic
antioxidant levels of Plasmodium berghei-infected Swiss albino mice         -           51

4.2Discussion       -           -           -           -           -           -           -           -           -           52

CHAPTER FIVE: SUMMARY, CONCLUSION AND RECOMMENDATIONS

5.1       Summary         -           -           -           -           -           -           -           -           -           58

5.2       Conclusion      -           -           -           -           -           -           -