In reading over the review of melatonin, this paragraph particularly struck me.
Melatonin has a protective effect on the cholinergic system. It prevents the peroxynitrite-induced
inhibition of choline transport and ChAT activity in synaptosomes and synaptic vesicles [126].
Melatonin treatment of eight-month-old APP695 transgenic mice significantly improved the profound
reduction in ChAT activity in the frontal cortex and the hippocampus [81]. Melatonin also antagonizes
the spatial memory deficit and the decreased ChAT activity found in adult ovariectomized rats [127].
However, in rats perfused intracerebroventricularly with Aβ for 14 days, melatonin was unable to
restore ChAT activity [128]. Melatonin inhibited lipopolysaccharide- and streptozotocin-induced
increase in AChE activity [129]. Recently hybrids of the AChE inhibitor tacrine and melatonin were
synthesized as new drug candidates for treating AD [130,131]. These hybrids showed better
antioxidant and cholinergic-preserving activity than tacrine or melatonin alone. The direct intracerebral
administration of one of these hybrids decreased induced cell death and Aβ load in the APP/PS1
mouse brain parenchyma accompanied by a recovery of cognitive function [131].
My thinking is that many of these compounds (such as melatonin, ferulic acid, and curcumin, for instance)/drugs (pbt2, for instance) show efficacy in certain areas in mice and in human beings, but when applied to humans they seem to fall just a bit short when it comes to cognitive function. There may be great potential for hybrids, natural compounds containing multiple antioxidants, and/or compounds that are highly concentrated and can be inhaled almost directly into the brain (various essential oils via aromatherapy) to get you over that last hump.
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