title: Inactivation of the human brain muscarinic acetylcholine receptor by oxidative damage catalyzed by a low molecular weight endogenous inhibitor from Alzheimer's brain is prevented by pyrophosphate analogs, bioflavonoids and other antioxidants.
abstract: Oxidative stress has been implicated as a contributing factor to neurodegeneration in Alzheimer's disease. An endogenous, low molecular weight (LMW) inhibitor from Alzheimer's brain inactivates the human brain muscarinic acetylcholine receptor (mAChR). The inhibitor prevents agonist and antagonist binding to the mAChR as assessed by radioligand binding studies. The LMW endogenous inhibitor, which has components with molecular weights between 100 and 1000 Da, requires dissolved oxygen and glutathione. Prevention of inactivation of the mAChR with peroxidase suggests that the LMW endogenous inhibitor generates peroxide. Heme, previously shown to be present in the LMW endogenous inhibitor, also inactivates the mAChR in the presence of peroxide. Free radical damage to the muscarinic receptor by the endogenous inhibitor can be prevented through the use of naturally occurring antioxidants including bilirubin, biliverdin, carnosol, myricetin and quericetin. In addition, pyrophosphate, imidodiphosphate, bisphosphonates and related compounds also protect the muscarinic receptor from free radical damage. Inactivation of the mAChR by the LMW endogenous inhibitor is likely to be a factor in the continual decline of Alzheimer's patients, even those taking acetylcholinesterase inhibitors. Natural antioxidants and pyrophosphate analogs may improve the effectiveness of acetylcholinesterase inhibitors and prove useful in the treatment and prevention of Alzheimer's disease since the muscarinic acetylcholine receptor is required for memory, and decreased cholinergic function is a critical deficit in Alzheimer's disease.
authors.affiliation: The Alzheimer's Research Center, HealthPartners Research Foundation, Regions Hospital, 640 Jackson Street, St. Paul, MN 55101-2595, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Fawcett
authors.forename: Elizabeth Z
authors.initials: EZ
authors.lastname: Bordayo
authors.forename: Kathy
authors.initials: K
authors.lastname: Jackson
authors.forename: Howard
authors.initials: H
authors.lastname: Liu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Peterson
authors.forename: Aleta
authors.initials: A
authors.lastname: Svitak
authors.forename: William H
authors.initials: WH
authors.lastname: Frey
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002384:Catalysis / Q000187:drug effects; D011756:Diphosphates / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use; D006420:Hemeproteins; D006801:Humans; D018727:Muscarinic Antagonists / Q000378:metabolism* / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D011976:Receptors, Muscarinic / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D011756:Diphosphates; D005419:Flavonoids; D006420:Hemeproteins; D018727:Muscarinic Antagonists; D009419:Nerve Tissue Proteins; D011976:Receptors, Muscarinic; C017866:low molecular weight (LMW) inhibitor, Alzheimer's brain, human