Abstract

The cholinesterases, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) (pseudocholinesterase), are abundant in the nervous system and in other tissues. The role of AChE in terminating transmitter action in the peripheral and central nervous system is well understood. However, both knowledge of the function(s) of the cholinesterases in serum, and of their metabolic and endocrine regulation under normal and pathological conditions, is limited. This study investigates AChE and BChE in sera of dystrophin-deficient mdx mutant mice, an animal model for the human Duchenne muscular dystrophy (DMD) and in control healthy mice. The data show systematic and differential variations in the concentrations of both enzymes in the sera, and specific changes dictated by alteration of hormonal balance in both healthy and dystrophic mice. While AChE in mdx-sera is elevated, BChE is markedly diminished, resulting in an overall cholinesterase decrease compared to sera of healthy controls. The androgen testosterone (T) is a negative modulator of BChE, but not of AChE, in male mouse sera. T-removal elevated both BChE activity and the BChE/AChE ratio in mdx male sera to values resembling those in healthy control male mice. Mechanisms of regulation of the circulating cholinesterases and their impairment in the dystrophic mice are suggested, and clinical implications for diagnosis and treatment are considered.

Highlights

  • The presence of cholinesterase activity in serum was already described by Dale in 1914 (Dale, 1914)

  • We further examined whether the systematic differences in the levels of both ChEs in mdx sera were due to impaired endocrine regulation, and if hormonal manipulation can restore the AChE/BChE ratio to that in normal mouse serum

  • Our results demonstrate that testosterone (T) down-regulates the expression of BChE in sera of mice, confirming the early observations on male rat sera that the total ChE content was reduced by circulating T, not as a result of a direct interaction of the steroid with the enzyme but via higher level regulation (Everett and Sawyer, 1946; Sawyer and Everett, 1946, 1947; Illsley and Lamartiniere, 1981)

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Summary

Introduction

The presence of cholinesterase activity in serum was already described by Dale in 1914 (Dale, 1914). Whereas AChE activity in rat muscle increased concomitantly with decrease in BChE, resulting in an inversion in ratio of the amounts of the two enzymes in adult muscle (Berman et al, 1987), an opposite change was observed in mouse serum, leading to a high BChE/AChE ratio post-puberty (Oliver et al, 1992). This was not the case for the serum of the mdx dystrophin-deficient mutant mouse, an animal model for Duchenne muscular dystrophy (DMD). As in DMD patients, a point mutation in the dystrophin gene results in synthesis of a non-functional truncated protein, so that full-length dystrophin is absent from skeletal and cardiac muscles, as well as from certain neural cell populations in the Frontiers in Molecular Neuroscience www.frontiersin.org

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