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Abstract
Artesunate (AS) is a class of medication known as artemesinin used in the treatment of
malaria. The occurrence ofPlasmodium falciparum malaria during pregnancy exposes the
mother and foetus to serious risks. The present study was aimed at evaluating the effect of
artesunate during pregnancy with particular reference to the histology and neurochemistry
of the cerebrum and hippocampus. Thirty pregnant Wistar rats were divided into three
groups and were treated intragastrically on gestation day 9 to 15 with safe or high dose
regimen of 4mg/kg/3days + 2mg/kg/4days or 10mg/kg/3days + 4mg/kg/4 days respectively.
Control rats were treated with distilled water. Five pups were sacrificed at each time
intervals of gestation day (GD) 20, postnatal days (PD) 1, 4, 7, 14, 21, and 28 for
morphometrical, histological and immunohistochemical studies on the cerebrum and
hippocampus. The brain tissues were dissected, fixed, processed and examined by light
microscope. Morphometrically, safe dose showed significantly stunted growth of body
particularly in the limbs, tails and brain compared to control. High dose induced marked
teratogenic effects characterized by severe embryo loss indicated as resorptions in most
dams. However, in the dams that littered there was high incidence of craniofacial and other
skeletal malformation. Histologically, the safe dose showed decrease in cell proliferation
with marked difference in the layer stratification of the cerebrum and neuronal degeneration
characterized by pyknosis, vacuolation, and degeneration of the pyramidal cells compared
to the control. High dose showed complete retardation of cerebral and hippocampal
development in the few pups. It also showed a severe form of neurodegeneration
characterize by cytoplasmic vacuolations, distortion of the pyramidal cell layers, central
vii
chromatolysis, aggregation, clumping and scattered cells. Immunolabelling of neurons
specific for the calcium binding protein Calbindin D28k demonstrated fewer primitive cells
characterized by less intensity of the stain in the pyramidal cells in treated groups compared
to control that showed a strong and positive immunoexpression of Calbindin D28k. These
results indicate that artesunate (AS) has a narrow safety margin in rats and could induce
teratogenic and neurotoxicological effects in which the mechanism may involve calcium
homeostasis in the brain.
CHAPTER ONE
1.0 INTRODUCTION
1.1 Background
Malaria remains one of the world‟s most significant health problems despite necessary
research and control efforts (WHO, 2008). It has continued to be the most devastating
human parasitic infection in the world, with about (100 million in Nigeria) at risk of
infection (Giles, 1997). It is said to be responsible for over 2 million deaths each year, and
a leading cause of death in children in those countries where the disease is endemic. This
disease is widespread in tropical and sub-tropical regions (WHO 2010 and Adebisi, 2010).
According to the World Malaria Report, 109 countries were endemic for malaria in 2008,
malaria infects between 350 and 500 million people each year, and kills one million (WHO
2006b; 2008). The occurrence of malaria during pregnancy exposes the mother and infants
to serious risks (WHO, 2010) as pregnancy decreases a woman‟s immunity to malaria,
making her more vulnerable to malaria infection and increasing the possibility of illness,
severe anaemia and death of the mother (WHO, 2010). Regarding the unborn child,
maternal malaria increases the risk of unplanned abortion, stillbirth, premature delivery low
birth weight, infant mortality which is a leading cause of child mortality (WHO, 2003;
2009a, 2010).
Every year at least 30 million pregnancies occur among women in malaria-endemic areas
of Africa. Malaria during pregnancy causes up to 10 000 maternal deaths and 200 000 new
born deaths each year (WHO 2003; WHO 2009a). Artesunate safety during the first
trimester (week 1-12) has not yet been proven (WHO, 2006c). It is therefore imperative that
1
pregnant women be protected against malaria, and the pregnant woman with malaria
receives treatment as soon as possible (WHO, 2002a; 2009a).
Over 40% of the world population lives in endemic areas estimated 500 million clinical
cases, and 1-2 million deaths per year, (WHO, 2010). In Africa it accounts for 90% of cases
of malaria occurring worldwide. One African child dies of malaria every 30 seconds,
responsible for 1 in 4 childhood death and accounts for 10% of Africa‟s diseases burden,
(Agomo et., 2007; WHO, 2010). Nigeria accounts for 25% of malaria cases in WHO
African region. It is responsible for 50% of all clinic attendance affecting mainly children
under the age of 5 years and pregnant women (WHO, 2010). In children an estimated 56
million episodes is under 5 years per year, and is the major causes of poor child
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