title: Stabilizers of neuronal and mitochondrial calcium cycling as a strategy for developing a medicine for Alzheimer's disease.
abstract: For the last two decades, most efforts on new drug development to treat Alzheimer's disease have been focused to inhibit the synthesis of amyloid beta (Aβ), to prevent Aβ deposition, or to clear up Aβ plaques from the brain of Alzheimer's disease (AD) patients. Other pathogenic mechanisms such as the hyperphosphorylation of the microtubular tau protein (that forms neurofibrillary tangles) have also been addressed as, for instance, with inhibitors of the enzyme glycogen synthase-3 kinase beta (GSK3β). However, in spite of their proven efficacy in animal models of AD, all these compounds have so far failed in clinical trials done in AD patients. It seems therefore desirable to explore new concepts and strategies in the field of drug development for AD. We analyze here our hypothesis that a trifunctional chemical entity acting on the L subtype of voltage-dependent Ca(2+) channels (VDCCs) and on the mitochondrial Na(+)/Ca(2+) exchanger (MNCX), and having additional antioxidant properties, may efficiently delay or stop the death of vulnerable neurons in the brain of AD patients. In recent years, evidence has accumulated indicating that enhanced neuronal Ca(2+) cycling (NCC) and futile mitochondrial Ca(2+) cycling (MCC) are central stage in activating calpain and calcineurin, as well as the intrinsic mitochondrial pathway for apoptosis, leading to death of vulnerable neurons. An additional contributing factor to neuronal death is the excess free radical production linked to distortion of Ca(2+) homeostasis. We propose that an hybrid compound containing a dihydropyridine moiety (to block L channels and mitigate Ca(2+) entry) and a benzothiazepine moiety (to block the MNCX and slow down the rate of Ca(2+) efflux from the mitochondrial matrix into the cytosol), as well as a polyphenol moiety (to sequester excess free radicals) could break down the pathological enhanced NCC and MCC, thus delaying the initiation of apoptosis and the death of vulnerable neurons. In so doing, such a trifunctional compound could eventually become a neuroprotective medicine capable of delaying disease progression in AD patients.
authors.affiliation: Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: José-Carlos
authors.initials: JC
authors.lastname: Fernández-Morales
authors.forename: Juan-Alberto
authors.initials: JA
authors.lastname: Arranz-Tagarro
authors.forename: Enrique
authors.initials: E
authors.lastname: Calvo-Gallardo
authors.forename: Marcos
authors.initials: M
authors.lastname: Maroto
authors.forename: Juan-Fernando
authors.initials: JF
authors.lastname: Padín
authors.forename: Antonio G
authors.initials: AG
authors.lastname: García
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000494:pharmacology; D002154:Calpain / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology; D005609:Free Radicals / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D059808:Polyphenols / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D004095:Dihydropyridines; D005609:Free Radicals; D059808:Polyphenols; C062217:benzothiazepine receptor; C038806:1,4-dihydropyridine; D012964:Sodium; D019703:Calcineurin; D002154:Calpain; D002118:Calcium