Introduction : Cholinesterase
inhibitors are, so far, the only successful
strategy for the symptornatic treatment of
Alzheimer's disease. Cholinesterase is the
enzyme that is responsible for the hydrolysis of
acetylcholine. Cholinesterase inhibitors both
block this metabolisin of acetylcholine, thus
increasing the level of acetylcholine in the
synaptic cleft, and activate cholinergic
transmission. An important prerequisite for the
use of cholinesterase inhibitors in Alzheimer's
disease therapy is a preferential action in the
central, versus peripheral, nervous system.
Activation of central cholinergic system,
elicits yawning in experimental animals.
Urba-Holmgren described that pilocarpine, a
muscarinic receptor agonist and physostigmine, a
cholinesterase inhibitor, induced yawning in
rats, while neostigimine, which passes the
blood-brain barrier with difficulty, did not
induce yawning. Scopolamine, a centrally acting
muscarinic receptor antagonist, inhibited
yawning induced by cholinergic activation, but
the peripheral muscarinic antagonist,
methylscopolamine, did not. These findings
suggest that the yawning is induced by
central cholinergic activation.
Thus, the elicitation of yawning by
cholinesterase inhibitors can be used as a
useful index for their action within the central
nervous system.
Cholinesterase inhibitors cause a variety of
peripheral cholinergic effects. Fasciculation is
characterized by a fine involuntary movement of
muscles and is a consistent measurement among
peripheral cholinergic signs . Facilitation of
cholinergic transmission at the neuromuscular
junction by cholinesterase inhibitors leads to
fasciculation. We now demonstrated the hight
relationship between induction of fasciculation
by intravenous administration of cholinesterase
inhibitors and in vitro inhibitory activity on
acetylcholinesterase. It was suggested that
fasciculation is a reliable index of peripheral
cholinergic activation by cholinesterase
inhibitors. In addition, we compared the
potencies of several cholinesterase inhibitors
to activate central and peripheral cholinergic
system by concurrent monitoring of yawning and
fasciculation. This experimental design allows
for a clear assessment of the central and
peripheral profiles of cholinesterase
inhibitors. Furthermore, the involvement of
cholinergic and dopaminergic mechanisms in
yawning induced by E2030,
(3-(2-(1-(1,3dioxolan-2-ylmethyl)-4-piperidyl)ethyl)-2
H-3,4-dihydro1,3-benzoxazin-2,4-dione
hydrochloride), a novel centrally acting
cholinesterase inhibitor, was investigated.
[...]
Discussion : In this study, the
proportion of central versus peripheral
cholinergic activity of a number of
cholinesterase inhibitors was clarified. E2030
and donepezil were found to potently and
preferentially activate the central cholinergic
system, as indicated by a marked induction of
yawning in rats, while having relatively
little effect on the intensity of fasciculation,
a peripheral cholinergic marker.
Fasciculation is observed when cholinergic
transmission at the neuromuscular junction is
prompted. The subtype of acetylcholine receptors
in muscles is nicotinic, and it is thus not
surprising that scopolamine did not inhibit the
fasciculation induced by donepezil or E2030, as
shown here, or by physostigmine and distigmine
(data not shown). In this study, fasciculation
produced by intravenous cholinesterase
inhibitors was tightly correlated with the in
vitro activity of acetylcholinesterase
inhibition, but not of butyrylcholinesterase
inhibition. This suggests that the occurrence of
fasciculation depends on the in vitro activity
of cholinesterase inhibitors, as well as their
plasma concentrations, and quite independently
of the brain permeability of each compound. This
evidence supports the use of fasciculation as
a good marker of peripheral cholinergic
activation. Furthermore, it suggests that
acetylcholinesterase, but not
butyrylcholinesterase, is involved in
cholinergic transmission at the neuromuscular
junction.
Results of this study further support the
idea that yawning elicited by cholinesterase
inhibitors is a result of central cholinercic
activation. For example, among several
cholinesterase inhibitors tested, distigmine,
which is a peripherally acting cholinesterase
inhibitor, did not elicit yawning. This
observation was consistent with results of an
early study showing that the peripherally acting
cholinesterase inhibitor, neostigmine, did not
cause yawning. Moreover, the centrally acting
muscarinic receptor antaaonist, scopolamine,
completely blocked E2030-induced yawning, while
the peripherally acting muscarinic receptor
antagonist, methylscopolamine, had no effect on
yawning.
Similar results were obtained in the case of
other cholinesterase inhibitors as well as
muscarinic agonists. It is not clear which
brain sites are involved in yawning induced by
cholinergie activation. Oxytocin was found
to induce yawning when injected into the
hippocampus showed that yawning could be induced
by neuropeptides like a-MSH (et-melanocyte
stimulating hormone) or ACTH
(adrenocorticotropic hormone), and this was
associated with an increase in hippocampal
acetylcholine turnover rate. Some cholinesterase
inhibitors used in the prescrit study have also
been shown to enhance the basal concentration of
extracellular acetylcholine in the hippocampus
of rats. Therefore, it is possible that the
hippocampus is an important site involved in
yawning induced by cholinomimetics.
Putative centrally acting cholinesterase
inhibitors were found to elicit yawning,
suggesting that the study design we used here
meets the criterion of face validity to assess
central cholinergie activity. When comparing the
effective doses to elicit yawning and
fasciculation, E2030 was the only compound that
elicited yawning at a dose (4 mg/kg), which was
less than the dose (16 mg/kg) necessary to
induce fasciculation. Donepezil, tacrine, and
physostigmine elicited both yawning and
fasciculation at the same doses. Ipidacrine
elicited fasciculation more effectively than
yawning (i.e., half the dose). We found,
however, that TAK-147, which is currently in
clinical trials for Alzheimer's disease in
Japan, was not very effective to cause yawning.
We previously reported on the effects of
donepezil, tacrine and TAK-147 on extracellular
acetylcholine concentrations in the cerebral
cortex of rats. The rank order comparing the
values of the ratio of the minimum effective
dose for acetylcholine-increasing action to that
for the fasciculation-producing action was:
donepezil > tacrine > TAK-147. These
results correspond well with the resulis of the
prescrit study.
Analysis of central and peripheral balance
classified cholinesterase inhibitors
approxiinately into three categories. Donepezil
and E2030 are in the first group, and show a
strong preference toward central cholinergie
system activation. Compounds like tacrine,
ipidacrine, and physostiginine are in the second
category and have an equipotent degree of
central and peripheral action. Distigmine can be
classified in a third category of peripherally
acting cholinesterase inhibitors. In this
context, TAK-147 may be in the middle of the
second and third categories. The central and
peripheral balance for each compound depends
mainly on brain permeability and partly on
selectivity for acetylcholinesterase. We
previously showed that donepezil was more potent
than tacrine to improve leaming impairments in
some hypocholinergic models using rats. This
finding, in general, is consistent with the
prescrit results.
It is well known that dopaminergic
systems also are involved in the induction of
yawning. Scopolamine blocks yawning induced
by both cholinomimetics and dopamine receptor
agonists such as apomorphine, while haloperidol,
a dopamine receptor antagonist, inhibits yawning
induced by dopamine receptor agonists, but not
cholinomimetics such as physostigmine, tacrine,
ipidacrine, and pilocarpine. In this study, we
confirmed that E2030-induced yawning was blocked
by scopolamine. Interestingly, haloperidol,
which did not affect donepezil-induced yawning,
partially inhibited E2030-induced yawning. It is
not apparent why haloperidol inhibited yawning
only after the highest dose of E2030, but only
high doses of E2030 may produce additional
dopamie mediated effects on yawning, which can
be blocked by haloperidol. These results suggest
that the doparninergic system might be partially
involved in E2030-induced yawning, and that the
underlying mechanisin is different from that of
donepezil.
This study sheds light on the central and
peripheral balance of action of cholinesterase
inhibitors. Among cholinesterase inhibitors
tested, donepezil and E2030 have a superior
ability to enhance central cholinergic
transmission preferentially. E2030 may have a
suitable balance of central cholinergic action
for symptomatic therapy in the treatment of
Alzheimer's disease as well as donepezil, which
is prescribed worldwide.
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