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

• Published in: Brain research Vol. 950; no. 1; pp. 10 - 20
• Main Authors: Fawcett, John R, Bordayo, Elizabeth Z, Jackson, Kathy, Liu, Howard, Peterson, Jennifer, Svitak, Aleta, Frey II, William H
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 20.09.2002; Amsterdam Elsevier; New York, NY
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Antioxidant; Antioxidants - pharmacology; Antioxidants - therapeutic use; Bioflavonoid; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Catalysis - drug effects; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Diphosphates - chemistry; Diphosphates - pharmacology; Diphosphates - therapeutic use; Dose-Response Relationship, Drug; Flavonoids - pharmacology; Flavonoids - therapeutic use; Free radical; Heme; Hemeproteins; Humans; Hydrogen peroxide; Inhibitor; Medical sciences; Muscarinic acetylcholine receptor; Muscarinic Antagonists - metabolism; Muscarinic Antagonists - pharmacology; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - pharmacology; Neurology; Oxidative Stress - drug effects; Oxidative Stress - physiology; Pyrophosphate; Receptors, Muscarinic - metabolism; Disorders of the nervous system; Hydrogen peroxide; Bioflavonoid; Heme; Pyrophosphate; Inhibitor; Antioxidant; Free radical; Muscarinic acetylcholine receptor; Human; Oxidative stress; Nervous system diseases; Alzheimer disease; Central nervous system; Cerebral disorder; Cholinergic receptor; Analog; Central nervous system disease; Degenerative disease; Muscarinic receptor; Diphosphates; Brain (vertebrata)
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(02)02981-5

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 assesssed 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.