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Serum cholinesterases are differentially regulated in normal and dystrophin-deficient mutant mice.

Durrant AR, Tamayev L, Anglister L - Front Mol Neurosci (2012)

Bottom Line: 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.While AChE in mdx-sera is elevated, BChE is markedly diminished, resulting in an overall cholinesterase decrease compared to sera of healthy controls.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Neurobiology, Institute for Medical Research - Israel-Canada, IMRIC, Faculty of Medicine, Hebrew University Medical School Jerusalem, Israel.

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.

No MeSH data available.


Related in: MedlinePlus

Circulating ChE activities in wt and mdx mice. ChE activities in the sera of adult male wt (C57Bl/10J)  and mdx □ mice were assayed by: (A,B) Measurement using the Ellman colorimetric method, with ATCh as substrate and the selective inhibitors, iso-OMPA, for measurement of AChE (striped columns), or BW284c51, for measurement of BChE (plain columns) (A); BChE activity was also measured using BTCh (B); (C,D) The radiometric method with 3H-ACh as substrate and with iso-OMPA for AChE (C), or with BW284c51 for BChE (D). (E) CK levels in the sera of wt and mdx mice. Activity values represent the mean ± SEM, of samples from 6 to 8 mice per group for ChEs and of 12 animals per group for CK. Activities in mdx sera differed from wt significantly: The BChE level in mdx sera was reduced compared to wt (*p < 0.01 in B and < 0.05 in D), while AChE in mdx sera was elevated compared with wt (*p < 0.05 in A,C). As expected, CK levels in mdx sera were elevated, compared to those in the wt sera (E, *p < 0.001).
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Figure 2: Circulating ChE activities in wt and mdx mice. ChE activities in the sera of adult male wt (C57Bl/10J) and mdx □ mice were assayed by: (A,B) Measurement using the Ellman colorimetric method, with ATCh as substrate and the selective inhibitors, iso-OMPA, for measurement of AChE (striped columns), or BW284c51, for measurement of BChE (plain columns) (A); BChE activity was also measured using BTCh (B); (C,D) The radiometric method with 3H-ACh as substrate and with iso-OMPA for AChE (C), or with BW284c51 for BChE (D). (E) CK levels in the sera of wt and mdx mice. Activity values represent the mean ± SEM, of samples from 6 to 8 mice per group for ChEs and of 12 animals per group for CK. Activities in mdx sera differed from wt significantly: The BChE level in mdx sera was reduced compared to wt (*p < 0.01 in B and < 0.05 in D), while AChE in mdx sera was elevated compared with wt (*p < 0.05 in A,C). As expected, CK levels in mdx sera were elevated, compared to those in the wt sera (E, *p < 0.001).

Mentions: Mouse serum contains BChE and AChE, both of which hydrolyze ATCh. Total ChE activities in sera of male mdx mice were at least 15% (p < 0.01) below those in normal mice sera (Figure 2A), indicating reduced levels of AChE and/or BChE in the mdx sera. AChE activity, which was found to be very low in sera of normal mice, was significantly elevated in the mdx sera (Figure 2A, detailed below). In contrast, BChE levels, assayed on BTCh, were found to decrease in male mdx-sera to 64–67% of the levels in wt sera (Figure 2B, p < 0.002). Similar results were observed when BChE was assayed on ATCh, with AChE activity being selectively inhibited by BW284c51 (Figure 2A). Since AChE levels in normal mouse serum are very low, the more sensitive radiometric assay was used to confirm the results obtained using the colorimetric Ellman procedure (Figures 2C and D), showing that AChE activity in mdx-sera indeed increased by 50–80% over the level in control wt sera (p < 0.05), confirming an earlier report (Oliver et al., 1992). BChE activity was shown, also by the radiometric assay, to decrease in mdx-sera to 61–76% of wt values (Figure 2D, p < 0.001). Since BChE is the major ChE form in mouse serum (>70%), the large drop in BChE was responsible for the overall reduction in total ChE activity observed in mdx sera. However, the decrease in BChE levels, taken together with the increase in AChE levels, in mdx sera (as shown in Figures 2C and D), reduced the BChE/AChE ratio from 2.3 ± 0.2 in the wt-sera to 1.3 ± 0.5 in mdx-sera. Similar results were found for adult female mdx-mice and are summarized elsewhere (Anglister et al., 2008).


Serum cholinesterases are differentially regulated in normal and dystrophin-deficient mutant mice.

Durrant AR, Tamayev L, Anglister L - Front Mol Neurosci (2012)

Circulating ChE activities in wt and mdx mice. ChE activities in the sera of adult male wt (C57Bl/10J)  and mdx □ mice were assayed by: (A,B) Measurement using the Ellman colorimetric method, with ATCh as substrate and the selective inhibitors, iso-OMPA, for measurement of AChE (striped columns), or BW284c51, for measurement of BChE (plain columns) (A); BChE activity was also measured using BTCh (B); (C,D) The radiometric method with 3H-ACh as substrate and with iso-OMPA for AChE (C), or with BW284c51 for BChE (D). (E) CK levels in the sera of wt and mdx mice. Activity values represent the mean ± SEM, of samples from 6 to 8 mice per group for ChEs and of 12 animals per group for CK. Activities in mdx sera differed from wt significantly: The BChE level in mdx sera was reduced compared to wt (*p < 0.01 in B and < 0.05 in D), while AChE in mdx sera was elevated compared with wt (*p < 0.05 in A,C). As expected, CK levels in mdx sera were elevated, compared to those in the wt sera (E, *p < 0.001).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3378013&req=5

Figure 2: Circulating ChE activities in wt and mdx mice. ChE activities in the sera of adult male wt (C57Bl/10J) and mdx □ mice were assayed by: (A,B) Measurement using the Ellman colorimetric method, with ATCh as substrate and the selective inhibitors, iso-OMPA, for measurement of AChE (striped columns), or BW284c51, for measurement of BChE (plain columns) (A); BChE activity was also measured using BTCh (B); (C,D) The radiometric method with 3H-ACh as substrate and with iso-OMPA for AChE (C), or with BW284c51 for BChE (D). (E) CK levels in the sera of wt and mdx mice. Activity values represent the mean ± SEM, of samples from 6 to 8 mice per group for ChEs and of 12 animals per group for CK. Activities in mdx sera differed from wt significantly: The BChE level in mdx sera was reduced compared to wt (*p < 0.01 in B and < 0.05 in D), while AChE in mdx sera was elevated compared with wt (*p < 0.05 in A,C). As expected, CK levels in mdx sera were elevated, compared to those in the wt sera (E, *p < 0.001).
Mentions: Mouse serum contains BChE and AChE, both of which hydrolyze ATCh. Total ChE activities in sera of male mdx mice were at least 15% (p < 0.01) below those in normal mice sera (Figure 2A), indicating reduced levels of AChE and/or BChE in the mdx sera. AChE activity, which was found to be very low in sera of normal mice, was significantly elevated in the mdx sera (Figure 2A, detailed below). In contrast, BChE levels, assayed on BTCh, were found to decrease in male mdx-sera to 64–67% of the levels in wt sera (Figure 2B, p < 0.002). Similar results were observed when BChE was assayed on ATCh, with AChE activity being selectively inhibited by BW284c51 (Figure 2A). Since AChE levels in normal mouse serum are very low, the more sensitive radiometric assay was used to confirm the results obtained using the colorimetric Ellman procedure (Figures 2C and D), showing that AChE activity in mdx-sera indeed increased by 50–80% over the level in control wt sera (p < 0.05), confirming an earlier report (Oliver et al., 1992). BChE activity was shown, also by the radiometric assay, to decrease in mdx-sera to 61–76% of wt values (Figure 2D, p < 0.001). Since BChE is the major ChE form in mouse serum (>70%), the large drop in BChE was responsible for the overall reduction in total ChE activity observed in mdx sera. However, the decrease in BChE levels, taken together with the increase in AChE levels, in mdx sera (as shown in Figures 2C and D), reduced the BChE/AChE ratio from 2.3 ± 0.2 in the wt-sera to 1.3 ± 0.5 in mdx-sera. Similar results were found for adult female mdx-mice and are summarized elsewhere (Anglister et al., 2008).

Bottom Line: 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.While AChE in mdx-sera is elevated, BChE is markedly diminished, resulting in an overall cholinesterase decrease compared to sera of healthy controls.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Neurobiology, Institute for Medical Research - Israel-Canada, IMRIC, Faculty of Medicine, Hebrew University Medical School Jerusalem, Israel.

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.

No MeSH data available.


Related in: MedlinePlus