Are curcuminoid, which is 5-6.6% of the composition of

Are Bisdemethoxycurcumin and
Caffeine Active Acetylcholinesterase Inhibitors?

Acetylcholinesterase Inhibitors in Alzheimer’s
Disease Therapy

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Acetylcholinesterase (AChE)
is an enzyme located within the autonomic, somatic, and central nervous systems
that catalyzes the hydrolysis of acetylcholine (a neurotransmitter); thereby
causing the termination of an impulse. The enzyme’s active site has an anionic
subsite, and an esteratic subsite. The negative charge on the anionic site
allows for binding with the positive quaternary amine in acetylcholine (Figure
1).1 Once bound, the enzyme catalyzes the
degradation of acetylcholine. However, within patients of Alzheimer’s Disease (AD,
a common form of dementia) there seems to be a loss of cholinergic function
within the cerebral cortex and basal forebrain (which affects memory and
learning). This cholinergic hypothesis indicates that because the dementia
associated with AD may result from a deficiency of cholinergic function, a form
of AD therapy may be to use acetylcholinesterase inhibitors, as compromised
cholingeric pathways could benefit from the hyper-stimulation within nicotinic and
muscarinic receptors caused by the accumulation of acetylcholine.2 Some acetylcholinesterase inhibitors
that have been used within the cholinergic replacement strategy include Tacrine,
Donepezil, Rivastigmine, and Galantamine. These provide symptom therapy for
patients with AD because they enhance acetylcholine function in the brain by
preventing its degradation.3

The Turmeric Plant

The turmeric plant (Curcuma longa), a member of the ginger
family, Zingiberaceae, is typically located in Southeast Asia/India. The dried
powder from its root is composed of over 100 components; mainly curcuminoids,
curcumin, and volatile oils. Turmeric’s applications to modern medicine have
been investigated, revealing that it is an antioxidant, anti-inflammatory, and anticancer
agent.4 It has been shown to reduce symptoms of
AD (eg. curcuminoids may be able to replace the need for the anti-oxidant
vitamin E, and have enhanced the spatial memory of rats with AD).5,6 The component that I propose to extract
and test for effectiveness as an inhibitor of AChE is a type of curcuminoid,
which is 5-6.6% of the composition of turmeric in its standard form.4 The cost of an AChE inhibitor, like
Donepezil tends to be around $185.00 for 300mg, whereas the cost of 45g of
turmeric at Fortinos (McCormick brand) is $4.99 (theoretically contains 2250mg
of curcuminoids). The consumption of turmeric as medicine is therefore cheaper than
comparable inhibitors on the market.7

Caffeine and Bisdemethoxycurcumin as AChE
Inhibitors

            The
component of turmeric to be analyzed is bisdemethoxycurcumin (Figure 2); a
bright yellow diarylheptanoid. This is identical to the potent curcumin within turmeric
(Figure 3), except it does not have methoxy groups (shown to have affected
inhibitory activity against AChE).2,7 Also, the hydroxyl groups that
are ortho to the side chains of various chalcones were proven to be responsible
for their inhibitor activity, and bisdemethoxycurcumin has this functional
group.2 Some known inhibitors of AChE include Neostigmine
(which has a 4° amine that allows it to bind to the
anionic subsite of the active site, Figure 4) and Dyflos (which may bind to the
esteratic subsite, Figure 5). It can be hypothesized that the carbonyl group in
the bisdemethoxycurcumin may bind to the esteratic subsite (like Dyflos) of the
AChE and competitively inhibit the enzyme. Another molecule whose activity
against AChE will be assessed is caffeine (Figure 6), which has been proven to
decrease the incidence of AD when consumed regularly.8,9 Caffeine is
a noncompetitive inhibitor, as it binds to serine and tyrosine residues within
the enzyme (Figure 7) and causes a conformational change that inhibits the
activity of the AChE.10 Consuming turmeric and caffeine in low doses
does not have any major side effects, unlike other AChE inhibitors; hinting at
the possibility of a low cost inhibitor with little to no side effects.