Gender differences in the effect of rivastigmine on brain cholinesterase activity and cognitive function in rats
Introduction
Cholinesterase inhibitors are being used increasingly for the treatment of Alzheimer's disease (Giacobini, 1997). A recent study in Alzheimer patients showed that the response to tacrine was associated with gender and ApoE phenotype. The effect of the drug on cognitive function was greater in women with the ApoE2–3 than in the ApoE4 phenotype, but not in men (Farlow et al., 1998). On the other hand, others reported that a greater proportion of men than women with Alzheimer's disease responded to galanthamine or tacrine therapy (MacGowan et al., 1998). This suggested that men were more sensitive than women to the action of these drugs on cognitive function. In contrast to these findings, the response of the hypothalamic–pituitary adrenal (HPA) axis to physostigmine, as measured by increases in plasma ACTH and cortisol, was significantly larger in normal older women and in those with Alzheimer's disease than in men of a similar age (Peskind et al., 1996). Blood levels of physostigmine did not differ in men and women in this study. Pyridostigmine caused a greater release of growth hormone-releasing hormone and severity of cholinergic side effects in normal young women than in men (Barbarino et al., 1991), and physostigmine induced a bigger response to vagal stimulation in female than in male rats (Du et al., 1994). Basal activity of cholinesterase (ChE) in plasma or erythrocytes did not differ significantly in men and women (Singh et al., 1997, Rumenjak, 1998), however, female rats and mice had higher ChE activity than males in plasma, but not in the brain (Tuovinen et al., 1997, Cheng and Tang, 1998).
Although these findings suggest that there is a gender difference in the response to ChE inhibitors, they do not tell us whether this occurs at the level of the enzyme or in other components of the cholinergic system. It may be due to greater activity of choline acetyltransferase (ChAT), higher levels of acetylcholine (Ach) or its receptors in females, which result in an increased response to a ChE inhibitor. Data from rats show that females have more Ach (Hortnagl et al., 1993) and higher ChAT activity (Loy and Sheldon, 1987) in the hippocampus than males, but little is known of any possible gender differences in the inhibitory activity of anticholinesterase drugs on the enzymes in the brain or periphery.
The aim of the present study was to compare the effect of a novel ChE inhibitor, rivastigmine (ENA713), on the activity of the enzyme in different brain regions, heart, skeletal muscle and plasma of age-matched male and female rats and on the cognitive impairment induced by scopolamine. Rivastigmine has recently been shown to improve or delay the decline in cognitive function in subjects with Alzheimer's disease (Corey-Bloom et al., 1998). The role of sex steroids in mediating the differential gender responses to the ChE inhibitor was assessed by measuring the change in enzyme inhibition induced by gonadectomy.
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Animals
The study was performed on male and female Sprague-Dawley rats weighing 200–270 g, purchased from Harlan, Jerusalem, according to the guidelines of the University Committee for Institutional Animal Care, based on those of the National Institutes of Health, USA. The rats were kept in the Animal House prior to testing, 4 per cage for 1 week, at an ambient temperature of 21±1°C and a 12-h diurnal light cycle. Assessment of spatial memory was carried out in a room adjacent to that in which the rats
Effect of gender and gonadectomy on ChE activity ex vivo
There were no significant differences in ChE activity in the cortex, hippocampus, and striatum taken from male and female rats. Enzyme activity was significantly higher in the skeletal muscle of male (P<0.05) and in the plasma of female rats (P<0.01; Table 1). Ovariectomy reduced ChE activity in the heart (P<0.01) and skeletal muscle (P<0.05), but had no effect in any of the brain areas or plasma. Orchidectomy significantly increased ChE activity in the hippocampus (P<0.01), but not in other
Discussion
The present study determined whether there is a difference in the degree of ChE inhibition by rivastigmine in male and female rats. No attempt was made to separate the enzyme into the two major forms, acetyl- and butyrylcholinesterase, since the drug inhibits both forms at similar concentrations (Giacobini, 1997). The results showed a significantly greater effect of the drug in females than in males at different times, and after different doses of the drug in three brain areas, the cerebral
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