title: Blocking the Ca(2+)-activated cytotoxic mechanisms of cholinergic neuronal death: a novel treatment strategy for Alzheimer's disease.
abstract: The major neuropathological finding in Alzheimer's disease (AD) is the death of cholinergic cell bodies originating in the nucleus basalis of Mynert. This paper will review the data suggesting that a pharmacologic strategy designed to slow the rate of cholinergic neuronal death (CND) should be of palliative value in the treatment of AD. Recent data on the biology of cell death (CD) show that there are two patterns of CD: necrosis and apoptosis or genetically controlled, programmed cell death. Regardless of whether cells die by necrosis or apoptosis, four Ca(2+)-activated cytotoxic mechanisms are triggered. Cytosolic free [Ca2+]i increases with aging. After 75 years, this rise may lead to the activation of a putative apoptotic gene in AD that results in CND. Since the increase in cytosolic [Ca2+]i may be mediated by the voltage operated L-type Ca2+ channel on the neuronal cell body, chronic treatment with an L-channel blocker, like nimodipine, might palliate the progression of and possibly prevent the majority of cases of AD.
authors.affiliation: Institute for Psychopharmacologie Research, Danvers, MA 01923.
authors.forename: R J
authors.initials: RJ
authors.lastname: Branconnier
authors.forename: M E
authors.initials: ME
authors.lastname: Branconnier
authors.forename: T M
authors.initials: TM
authors.lastname: Walshe
authors.forename: C
authors.initials: C
authors.lastname: McCarthy
authors.forename: P A
authors.initials: PA
authors.lastname: Morse
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D002395:Catecholamines / Q000037:antagonists & inhibitors*; D016923:Cell Death / Q000502:physiology*; D006801:Humans; D009474:Neurons / Q000187:drug effects*; D010275:Parasympathetic Nervous System / Q000166:cytology*
chemical_list: D002395:Catecholamines