2013-12-18

. acetylcholinesterase inhibitors reduce #inflammation #Alzheimer's #MetabolicSyndrome

11.9: web.cook/hup/when is it needed?:
intro:
. in studying when huperzine (hup) is needed,
I'm wondering if the reason for it (confusion, forgetful)
was because I was depressed,
or otherwise in some condition that would be
assisted by the cheaper tryptophan .
. hup is an acetycholinesterase inhibitor;
so, is depression related to acetycholinesterase excess
or other causes of acetylcholine deficits ?
12.18: conclusion:
. there needs to be a balance between
dopaminergics and cholinergics;
increasing both equally
leads to good cognitive function;
and, there are several pitfalls
that are degrading one or the other,
including drugs and infections .
. the need for acetylcholinesterase inhibitor
is often due to low-grade infections
within the prostate or teeth,
that are leaking into the blood .

. acetylcholinesterase inhibitor (AChEI)
is inhibiting the breakdown of acetylcholine
 -- an antidote to anticholinergic poisoning .
 . AChEI can treat cognitive impairments from
 not only Alzheimer's and Parkinson's,
but also schizophrenia.
. a large dose of an atypical antidopaminergic,
ziprasidone (geodon, 3 mg/kg, about 200mg),
significantly increased acetylcholine release .
. anticholinergics
are blocking acetylcholine at various receptors:
# Anti-Muscarinic  acetylcholine receptors:
Dimenhydrinate (Dramamine)
Benzatropine (Cogentin)
# Anti-Nicotinic acetylcholine receptors:
Dextromethorphan - ganglion blocker .
. Anticholinergics are used for
gastritis, nausea, prostatitis, asthma, vertigo .
. can cause agitation, confusion, irritable,
urinary retention [yet used for prostatitis?
likely for nausea .]
cholinesterase inhibitors:
cholinesterase-inhibitors
Donepezil (Aricept), rivastigmine (Exelon),
galantamine (Reminyl),
treat mild to moderate cognitive impairment
in dementia of the Alzheimer’s type.
Memantine (Namenda) is not a cholinesterase inhibitor,
and produces its effects through
blockade of N-methyl-D-aspartate (NMDA) receptors.
. cholinesterase inhibitors are for mild stages;
memantine is reserved for the moderate to severe stages .

USMLE` Dopamine Acetylcholine Balance:
Both EPS  (Extra Pyramidal Symptoms)
with its Parkinson like symptoms
and NMS (Neuroleptic Malignant Syndrome)
with all the cholinergic symptoms
can occur because of dopamine antagonists;
because blocking Dopamine
leaves Acetylcholine unopposed.
. by blocking acetylcholine,
acetylcholine goes down (NMS resolves).
and Dopamine goes up (EPS resolves).

12.18: web: neuoleptic effects on acetycholine:
Am J Psychiatry 1998:
. when dopamine receptors were blocked,
there was an excess in acetylcholine
. this acetylcholine/dopamine imbalance resulted in
severe extrapyramidal syndrome .
Karlin 2012:
anticholinergics are enhancing dopamine,
and antidopaminergics are enhancing Acetycholine 
nature 2001:
Antidepressants have been reported to induce
extrapyramidal symptoms, including parkinsonism.
depression often accompanies and contributes to
the morbidity of Parkinson's disease
(a decrease of dopamine in the basal ganglia,
that includes the striatum,
the globus pallidus (GP),
substantia nigra (SN),
subthalamic nucleus (STN) and thalamus).
The substantia nigra pars compacta
provides dopaminergic innervation
to all parts of the striatum
from which both the direct and the indirect
pathways originate.
The direct pathway is modulated by
excitatory D1 dopamine receptors
while the indirect one is modulated by
inhibitory D2 dopamine receptors.
Dopamine, released in the striatum,
is increasing the direct pathway
and decreasing the indirect pathway.
The loss of dopaminergic neurons
observed in Parkinson's disease
results in opposite effects.
The direct pathway to the SNpr and MGP is less active
while there is overactivity of the indirect pathway
through disinhibition of the STN.
Increased output from the SNpr and the MGP
causes inhibition of the thalamus
and reduction of excitatory input to the cortex,
responsible for the expression of parkinsonian symptoms.
Roxindole is a dopaminergic antidepressant,
an agonist at D2/D3 and 5-HT1A receptors,
and an inhibitor of serotonin uptake.
Roxindole is used both in the treatment of
negative schizophrenia and in depressed subjects,
confirming that the dual action on both DA and 5-HT
may be useful in the treatment of
these neuropsychiatric diseases .
Dopamine contributes significantly to the
pathophysiology of depression.
Reduced neurotransmission in the
mesolimbic dopamine system
may sustain symptoms such as
dysthymia and melancholic depression.
Since dopamine plays a crucial role in controlling
incentive, motivation and reward,
its deficiency at the mesolimbic level
induces syndromes characterised by
anhedonia, low energy, lack of motivation
and psychomotor slowing.
. aging markedly decreases dopamine often by
increasing monoamine-oxidase B activity,
that is recycling the dopamine .
 The loss of dopaminergic neurons in the striatum
results in the disinhibition of cholinergic neurons
leading to a predominance of cholinergic function.
. in depression, central cholinergic dominance
may be creating a relative dopamine deficiency .
j neurosci 1983:
. it seems that the [antidopaminergic anti-psychotics]
which can induce extrapyramidal side effects
produce depolarization inactivation of
both A9 and A10 neurons
whereas those without extrapyramidal side effects
inactivate only A10 neurons.
[. so, when antidopaminergism is incomplete
increases in acetycholine are incomplete .]

12.18: web: infection modulating acetylcholine:
. could an infection be increasing
natural levels of acetylcholine recycling ?
acetylcholine reduces inflammatory response,
so perhaps part of a body's immune reaction
could attempt to raise inflammation levels
by doing things to decrease acetylcholine levels
such as increasing acetylcholinesterase .
Geula C, Darvesh S. 2004:
Butyrylcholinesterase is biochemically related to
the cholinergic enzyme acetylcholinesterase.
It is capable of hydrolyzing esters of choline.
Butyrylcholinesterase has unique enzymatic properties
and is widely distributed in the nervous system,
raising the possibility of its involvement in neural function.
In particular, recent evidence indicates that
along with acetylcholinesterase,
butyrylcholinesterase catalyzes the hydrolysis of acetylcholine,
and thus serves as a co-regulator of cholinergic transmission.
Accumulating evidence also indicates that
butyrylcholinesterase is likely to be involved in
neurodegenerative disorders such as Alzheimer's disease.
Therefore, inhibition of butyrylcholinesterase
will not only lead to enhanced cholinergic transmission
but also has the potential to interfere with the disease process
in Alzheimer's disease and other dementing disorders.
Lane RM, Potkin SG, Enz A. 2006:
The cholinesterase inhibitors (ChE-Is)
attenuate the cholinergic deficit underlying the
cognitive and neuropsychiatric dysfunctions in
patients with AD (Alzheimer's disease).
Inhibition of brain acetylcholinesterase (AChE)
has been the major therapeutic target of
ChE-I treatment strategies for AD.
Butyrylcholinesterase (BuChE)-positive neurons
project specifically to the frontal cortex,
and may have roles in attention, executive function,
emotional memory and behaviour.
Furthermore, BuChE activity progressively increases
as the severity of dementia advances,
while AChE activity declines.
Therefore, inhibition of BuChE
may provide additional benefits.
Das 2007:
. in  metabolic syndrome X (insulin resistance,
obesity, hypertension, hyperlipidemias),
type 2 [insulin resistant] diabetes mellitus,
and Alzheimer's disease,
there are high plasma levels of
C-reactive protein, interleukin-6,
tumor necrosis factor-alpha, and lipid peroxides
whereas there are low levels of
endothelial nitric oxide,
suggesting that
these diseases are characterized by
low-grade systemic inflammation.
Recent studies showed that
the plasma and tissue activities of enzymes
butyrylcholinesterase and acetylcholinesterase
are elevated in patients with
Alzheimer's disease, and diabetes mellitus,
hypertension, insulin resistance, and hyperlipidemia.
thereby lowering the plasma and tissue levels
of acetylcholine (ACh).
The "cholinergic anti-inflammatory pathway"
mediated by acetylcholine
acts by inhibiting the production of
tumor necrosis factor, interleukin-1,
macrophage migration inhibitory factor, and
high mobility group box-1
and suppresses the activation of
nuclear factor-kappa B expression.
. ACh is a neurotransmitter and regulates the levels
of serotonin, dopamine and other neuropeptides;
and thus, modulates both immune response
and neurotransmission.
Hence, both acetylcholinesterase and butyrylcholinesterase
by inactivating acetylcholine
may enhance inflammation.
This suggests that increased plasma and tissue activities
of acetylcholinesterase and butyrylcholinesterase
seen in various clinical conditions
could serve as a marker of low-grade systemic inflammation.
[ therefore,
any disease that causes inflammation
may be upregulating AChE (acetylcholinesterase)
in order to reduce acetylcholine
and its anti-inflammatory effects? ]

Bhattacharya ‎1997:
Acetylcholine levels were decreased during infection
perhaps because parasites produce acetylcholinesterase .
Costa 2012:
. acetylcholinesterase levels were
increased during infection
most likely by the host wanting to
mount an inflammatory attack on the parasite .
United Arab Emirates 2013:
. inhibition of the enzyme acetylcholinesterase,
leads to an enhancement of animal survival
following an oral infection with a lethal strain
of S. typhimurium, a Gram-negative, facultative,
intracellular pathogen.
We hypothesized that the resultant
increase in acetylcholine levels
modulates the macrophage's
inflammatory response to infection.
AIDS Research and Human Retroviruses 2009:
. HIV infection is characterized by
persistent immune activation,
increased production of proinflammatory cytokines,
and rapid T cell turnover.
. acetylcholine mediates inflammatory response;
and, use of an acetylcholinesterase inhibitor
for increasing levels of acetylcholine,
led to an increase in the
antiinflammatory cytokine IL-10
and a decrease in T cell proliferation and
production of the proinflammatory cytokine IFN-γ.