Are Bisdemethoxycurcumin andCaffeine Active Acetylcholinesterase Inhibitors?Acetylcholinesterase Inhibitors in Alzheimer’sDisease TherapyAcetylcholinesterase (AChE)is an enzyme located within the autonomic, somatic, and central nervous systemsthat catalyzes the hydrolysis of acetylcholine (a neurotransmitter); therebycausing the termination of an impulse. The enzyme’s active site has an anionicsubsite, and an esteratic subsite. The negative charge on the anionic siteallows for binding with the positive quaternary amine in acetylcholine (Figure1).1 Once bound, the enzyme catalyzes thedegradation of acetylcholine.
However, within patients of Alzheimer’s Disease (AD,a common form of dementia) there seems to be a loss of cholinergic functionwithin the cerebral cortex and basal forebrain (which affects memory andlearning). This cholinergic hypothesis indicates that because the dementiaassociated with AD may result from a deficiency of cholinergic function, a formof AD therapy may be to use acetylcholinesterase inhibitors, as compromisedcholingeric pathways could benefit from the hyper-stimulation within nicotinic andmuscarinic receptors caused by the accumulation of acetylcholine.2 Some acetylcholinesterase inhibitorsthat have been used within the cholinergic replacement strategy include Tacrine,Donepezil, Rivastigmine, and Galantamine.
These provide symptom therapy forpatients with AD because they enhance acetylcholine function in the brain bypreventing its degradation.3The Turmeric PlantThe turmeric plant (Curcuma longa), a member of the gingerfamily, Zingiberaceae, is typically located in Southeast Asia/India. The driedpowder from its root is composed of over 100 components; mainly curcuminoids,curcumin, and volatile oils.
Turmeric’s applications to modern medicine havebeen investigated, revealing that it is an antioxidant, anti-inflammatory, and anticanceragent.4 It has been shown to reduce symptoms ofAD (eg. curcuminoids may be able to replace the need for the anti-oxidantvitamin E, and have enhanced the spatial memory of rats with AD).5,6 The component that I propose to extractand 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, likeDonepezil tends to be around $185.00 for 300mg, whereas the cost of 45g ofturmeric at Fortinos (McCormick brand) is $4.99 (theoretically contains 2250mgof curcuminoids). The consumption of turmeric as medicine is therefore cheaper thancomparable inhibitors on the market.7Caffeine and Bisdemethoxycurcumin as AChEInhibitors Thecomponent of turmeric to be analyzed is bisdemethoxycurcumin (Figure 2); abright yellow diarylheptanoid. This is identical to the potent curcumin within turmeric(Figure 3), except it does not have methoxy groups (shown to have affectedinhibitory activity against AChE).2,7 Also, the hydroxyl groups thatare ortho to the side chains of various chalcones were proven to be responsiblefor their inhibitor activity, and bisdemethoxycurcumin has this functionalgroup.2 Some known inhibitors of AChE include Neostigmine(which has a 4° amine that allows it to bind to theanionic subsite of the active site, Figure 4) and Dyflos (which may bind to theesteratic subsite, Figure 5).
It can be hypothesized that the carbonyl group inthe bisdemethoxycurcumin may bind to the esteratic subsite (like Dyflos) of theAChE and competitively inhibit the enzyme. Another molecule whose activityagainst AChE will be assessed is caffeine (Figure 6), which has been proven todecrease the incidence of AD when consumed regularly.8,9 Caffeine isa noncompetitive inhibitor, as it binds to serine and tyrosine residues withinthe enzyme (Figure 7) and causes a conformational change that inhibits theactivity of the AChE.10 Consuming turmeric and caffeine in low dosesdoes not have any major side effects, unlike other AChE inhibitors; hinting atthe possibility of a low cost inhibitor with little to no side effects.