An Investigation into Gastric Myoelectrical Activity in Response to Drug Treatment during Ageing and in a Mouse Model of Alzheimer's Disease

Interstitial cells of Cajal (ICCs) produce slow waves to facilitate peristalsis by providing an electrical threshold for smooth muscle contractions. The enteric nervous system (ENS) is known to interface with ICCs through excitatory and inhibitory pathways. Altered GI motility may be associated with an activation or inhibition of either or both pathways. A loss or a decrease in neurons and/or ICC is observed in Alzheimer's disease (AD) patients, and it could result in a change in gastric slow wave activity and motility patterns. It is imperative to understand better the pathophysiology of ageing and AD, and studying the GI tract may provide novel insights into ageing and neurodegeneration development. Therefore, the aims of the present study were to first define the characteristics of gastric slow wave activity using mouse models in order to establish criteria for analysis and for the characterisation of the effects of excitatory and inhibitory drugs during ageing and in a mouse model of AD.;The present studies used state-of-the-art radio-telemetry to record gastric slow wave activity in conscious, freely moving mice. Animals were anaesthetised and surgically implanted with telemetry devices (PhysioTelRTMETA-F20, DSI, U.S.A.) with recording wires sutured into the serosal side of the stomach, followed by a 7-day recovery period. Baseline gastric slow wave activity recordings were obtained for 2 h before administering drugs, or vehicle (saline 2 ml/kg, i.p.). The basal gastric slow wave frequency with the highest power (dominant frequency, DF) in 3-month-old ICR mice was 7.1 +/- 0.8 cpm (n=16). The ranges of bradygastria (0 to 5.6 cpm), normogastria (5.6 to 8.6 cpm), tachygastria (8.6 to 15 cpm) were also defined.;Both nicotine and donepezil reduced the DF almost immediately and produced a significant increase in the % power of bradygastria (0 to DF-1.5 cpm) in all age groups. These effects lasted for 2 h before the DF shifted back to pre-nicotine and pre-donepezil levels. During ageing, nicotine, which is known to stimulate ganglia, releases inhibitory mediators that affect ICCs. Donepezil has a more complex action probably via an increase in endogenous ACh levels, stimulating both nicotinic and muscarinic receptors.;The DF and the % power of bradygastria, normogastria, or tachygastria were not affected by bethanechol, metoclopramide, NG-nitro-L-arginine methyl ester (L-NAME), and sodium nitroprusside (P > 0.05); only bethanechol reduced the body temperature. It indicates that NO systems do not involve in the regulation of gastric slow waves.;The baseline DF of Tg2576 did not differ from that of the age-matched wild-type controls (P > 0.05). Nicotine reduced the DF gradually in 6-month-old Tg2576 and their age-matched wild-type controls (P < 0.05). The effects of nicotine lasted for 2 h before the DF shifted back to pre-nicotine levels. Nicotine failed to affect the DF in 12-month-old Tg2576 and their age-matched wild-type controls (P > 0.05) but transiently increased the % power of bradygastric range in 6-month-old wild-type, 12-month-old Tg2576 and their age-matched wild-type controls (P < 0.05). An age-related loss of the effect of nicotine on gastric slow wave activity in wild-type mice was not expected, even though effects on body temperature were maintained.;The information from the present studies provides a novel insight into GI motility dysfunction during ageing and its responsiveness to drug treatment, and it also suggests that the early pathological markers of neurodegeneration may be observed in the gut.