Endocrine Abstracts (2003) 6 DP24

Evidence for a cholinergic defect in the brain of the obese-diabetic (ob/ob) mouse

SK Suri1, H Scriven1, MC Lintern1, CJ Bailey2 & ME Smith1

1Department of Physology, Birmingham University, Birmingham, YK; 2Department of Pharmaceutical Sciences, University of Aston, Birmingham, UK.

Central cholinergic defects, as well as cognitive impairments, have been reported in humans with non-insulin-dependent diabetes mellitus (NIDDM). The levels of acetylcholine are partly controlled by the activity of acetylcholinesterase (AChE) which breaks it down. We have previously reported evidence for abnormal AChE activity in the skeletal muscles of the obese diabetic (ob/ob) mouse which provides a model for NIDDM. The aim of the present study was to investigate the levels of AChE in the brains of obese-diabetic mice and their lean littermates. The enzyme activity was measured by the colorimetric method of Ellman et al. (Biochem. Pharmacol. 7, (1961), 88-95) in mice of different ages, and the levels of AChE protein were examined in 12 week-old mice using Western blotting. At 6 weeks of age, before the diabetic condition is manifest, the AChE activity was similar in diabetic and lean mice. However at 12 weeks of age when hyperglycaemia has become evident in the obese-diabetic mice the enzyme activity was significantly lower than in the lean mice. In older diabetic mice, 18 or 34 weeks of age, the enzyme activity had returned to within the normal range of activity exhibited by the lean mice.

Western blots performed on the brains of the12 week old animals showed a major protein band (60 to 65kDa) representing AChE. Paradoxically the AChE protein concentration appeared higher in the obese mice than the leans.

These findings show that the activity of AChE is subnormal in the brain of obese-diabetic mice at an age when the condition is apparent, although the level of AChE protein was higher. It is possible that the latter represented an inactive form of the enzyme. These findings provide evidence for a central cholinergic defect in obese-diabetic mice indicating that this animal model may useful for studying diabetic neuropathy.

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