For the last two de
cades, most efforts on new drug development to treat Alzheimer's disease have been fo
cused to inhibit the synthesis of amyloid beta (A尾), to prevent A尾 deposition, or to
clear up A尾 plaques from the brain of Alzheimer's disease (AD) patients. Other pathogeni
c me
chanisms su
ch as the hyperphosphorylation of the mi
crotubular tau protein (that forms neurofibrillary tangles) have also been addressed as, for instan
ce, with inhibitors of the enzyme gly
cogen synthase-3 kinase beta (GSK3尾). However, in spite of their proven effi
ca
cy in animal models of AD, all these
compounds have so far failed in
clini
cal trials done in AD patients. It seems therefore desirable to explore new
con
cepts and strategies in the field of drug development for AD. We analyze here our hypothesis that a trifun
ctional
chemi
cal entity a
cting on the L subtype of voltage-dependent Ca
2+ channels (VDCCs) and on the mito
chondrial Na
+/Ca
2+ ex
changer (MNCX), and having additional antioxidant properties, may effi
ciently delay or stop the death of vulnerable neurons in the brain of AD patients. In re
cent years, eviden
ce has a
ccumulated indi
cating that enhan
ced neuronal Ca
2+ cy
cling (NCC) and futile mito
chondrial Ca
2+ cy
cling (MCC) are
central stage in a
ctivating
calpain and
cal
cineurin, as well as the intrinsi
c mito
chondrial pathway for apoptosis, leading to death of vulnerable neurons. An additional
contributing fa
ctor to neuronal death is the ex
cess free radi
cal produ
ction linked to distortion of Ca
2+ homeostasis. We propose that an hybrid
compound
containing a dihydropyridine moiety (to blo
ck L
channels and mitigate Ca
2+ entry) and a benzothiazepine moiety (to blo
ck the MNCX and slow down the rate of Ca
2+ efflux from the mito
chondrial matrix into the
cytosol), as well as a polyphenol moiety (to sequester ex
cess free radi
cals)
could break down the pathologi
cal enhan
ced NCC and MCC, thus delaying the initiation of apoptosis and the death of vulnerable neurons. In so doing, su
ch a trifun
ctional
compound
could eventually be
come a neuroprote
ctive medi
cine
capable of delaying disease progression in AD patients.
Keywords:
cs.org/action/doSearch?action=search&searchText=Alzheimer%27s+disease&qsSearchArea=searchText">Alzheimer's disease; cs.org/action/doSearch?action=search&searchText=neuronal+calcium+cycling&qsSearchArea=searchText">neuronal calcium cycling; cs.org/action/doSearch?action=search&searchText=mitochondrial+calcium+cycling&qsSearchArea=searchText">mitochondrial calcium cycling; cs.org/action/doSearch?action=search&searchText=calcium+and+cell+death&qsSearchArea=searchText">calcium and cell death; cs.org/action/doSearch?action=search&searchText=L%5C-type+calcium+channel&qsSearchArea=searchText">L-type calcium channel; cs.org/action/doSearch?action=search&searchText=mitochondrial+sodium%E2%88%92calcium+exchanger&qsSearchArea=searchText">mitochondrial sodium鈭抍alcium exchanger; cs.org/action/doSearch?action=search&searchText=functional+tetrad&qsSearchArea=searchText">functional tetrad; cs.org/action/doSearch?action=search&searchText=multitarget+compounds&qsSearchArea=searchText">multitarget compounds; cs.org/action/doSearch?action=search&searchText=neurotoxicity&qsSearchArea=searchText">neurotoxicity; cs.org/action/doSearch?action=search&searchText=neuroprotection&qsSearchArea=searchText">neuroprotection