EVALUATION OF PROLONGED ADMINISTRATION OF ARTEMETHER-LUMEFANTRINE ON SPERM INDICES AND TESTICULAR BIOMARKERS OF OXIDATIVE STRESS IN MALE WISTAR RATS: AMELIORATIVE EFFECT OF VITAMIN E.

EVALUATION OF PROLONGED ADMINISTRATION OF ARTEMETHER-LUMEFANTRINE ON SPERM INDICES AND TESTICULAR BIOMARKERS OF OXIDATIVE STRESS IN MALE WISTAR RATS: AMELIORATIVE EFFECT OF VITAMIN E.

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ABSTRACT

There is frequent use of artemisinin-based combination therapies (ACTs) due to

recurrence of malaria infection in Nigeria. The ACTs generate free radicals as part of their mode of action. Reactive oxygen species have been implicated in the etiology of male infertility. In this study, the effect of prolonged administration of artemether-lumefantrine (AL) and the ameliorative effect of vitamin E (VE) on testicular functions and biomarkers of oxidative stress was evaluated. Adult male Wistar rats (n = 35) were divided into five (5) groups of seven (7) rats each and treated as follows: Group I (control): 1ml/kg distilled water; group II: 1ml/kg olive oil; group III: 2.29 mg/13.74  mg/kg AL; group IV: 2.29 mg/13.74  mg/kg AL + 100 mg/kg of VE and group V: allowed to recover from treatment with AL for 2 weeks before sampling (2.29 mg/13.74  mg/kg AL + two weeks recovery). Administration was done orally twice daily for a period of two (2) weeks. At the end of the experiment, animals were sacrificed and the testes harvested and sperm indices, testicular testosterone and biomarkers of oxidative stress parameters determined. There was a remarkable but insignificant decrease in all sperm indices and testicular testosterone level in the AL group when compared with the control rats. However, a significantly (P < 0.05) higher percentage of sperm head defects was observed in the recovery than other groups. There was an insignificant increase in testicular malondialdehyde (MDA) level in the AL group when compared with other groups. Similarly, a remarkable but insignificant decrease in the level of testicular antioxidant enzyme, superoxide dismutase, but a significant (P < 0.05) decrease in the levels of catalase and glutathione peroxidase, was equally observed in the AL as compared with other groups. A remarkable but insignificant decrease in malondialdehyde and an increase in antioxidant enzymes, testosterone level, and sperm indices were observed in the vitamin E and recovery groups. It is therefore, concluded that prolonged administration of artemether-lumefantrine: (i) does not significantly affect most sperm indices (except sperm head morphology) and testicular testosterone concentration; (ii) induces significant alterations in testicular antioxidant enzymes activity suggestive of oxidative stress; (iii) and that vitamin E and ceazation of treatment with artemether-lumefantrine causes appreciable amelioration of the alterations in the biomarkers of oxidative stress.

CHAPTER ONE

1.0 INTRODUCTION

1.1 Preamble

Infertility has been a major medical and social predicament, and until recently, most

of the blame for infertility was placed on the female. However, male factor infertility

is now gaining considerable attention. Infertility is defined as the inability to conceive

after one year of regular and unprotected intercourse by couples of reproductive age.

In males it is inability to impregnate a fertile female in a year after unprotected

intercourse. In cases of females, it is inability to conceive in a year after unprotected

intercourse with a fertile male (Agarwal et al., 2007; Badade and Samant, 2011).

Infertility affects approximately 15% of all couples trying to conceive, and male

factor is the sole or contributing factor in roughly half of these cases. It is estimated

that the male factor in couple infertility is between 25% to 50% (Safarinejad, 2008;

Bablok et al., 2011). This occurs when an ―alteration in sperm concentration, motility,

and/or morphology is present in at least one sample of two sperm analyses, collected 1

to 4 weeks apart‖ (Agarwal and Sekhon, 2011). This problem becomes further

compounded when no identifiable reason can be found (Agarwal et al., 2014).

Aside the well documented conventional risk factors of male fertility (male accessory

gland infection, mumps, orchitis, varicocele, and cryptorchidism, etc), poor lifestyle

choices, including prolonged exposure to xenobiotics and other chemical substances

can adversely affect male reproductive system, thereby causing impaired fertility.

Mechanisms of impaired fertility include direct disruption of sperm production and

quality; effects on the delicately balanced hypothalamo-pituitary-testicular axis;

effects on erectile or ejaculatory function, and effects on libido (Sharpe and Irvine,

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2004; Ten et al., 2008). Moreover, oxidative stress mediated by reactive oxygen

species (ROS) is being recognized more commonly as a causative factor in male

infertility (Meeker et al., 2007). This is because mature spermatozoa, encased in a

polyunsaturated lipid membrane, are vulnerable to the effects of ROS, which at high

doses can impair spermatogenesis and decrease sperm quality (Saleh and Agarwal

2002; Mahfouz et al., 2009; Agarwal and Sekhon, 2011).

Malaria is caused by infection of red blood cells with protozoan parasite of the genus

Plasmodium. The parasites are inoculated into the human host by a feeding female

anopheline mosquito. The four Plasmodium species that infect humans are P.

falciparum, P. vivax, P. ovale and P. malariae (WHO, 2010a). Malaria illness

imposes great burden on the society as it has adverse effects on the physical, mental

and social wellbeing of the people as well as on the economic development of the

nation (Peter, 2013). Malaria control requires an integrated approach, including

prevention (primarily vector control) and prompt treatment with effective

antimalarials (WHO, 2010a).

The constant emergence of drug-resistant plamodium parasites to monotherapies have

shored up the use of artemisinin-based combination therapies (ACTs) as the malaria

therapy of choice. Artemether-Lumefantrine is one of the ACTs recommended by the


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