ENDOGENOUS ALZHEIMERS BRAIN FACTOR AND OXIDIZED GLUTATHIONE INHIBIT ANTAGONIST BINDING TO THE MUSCARINIC RECEPTOR

An endogenous inhibitor (<3,500 Da) of antagonist binding to the musca rinic acetylcholine receptor has been extracted from Alzheimer's disea se (AD) brain with trifluoracetic acid. Oxidized glutathione, (GSSG) h as also been found to inhibit antagonist binding to the receptor. Howe ver, in its reduced form, glutathione (GSH) like other reducing agents , markedly enhances the inhibitory effect of both GSSG and the endogen ous AD inhibitor. EDTA and the free radical scavengers Mn2+ and Trolox , a vitamin E analog, block the action of the endogenous AD inhibitor but not of GSSG in the presence of GSH. Further, while GSSG inhibition is reversible, the action of the endogenous AD inhibitor is irreversi ble, consistent with a free radical mechanism. The enhancement of endo genous AD inhibitor activity by GSH suggested that GSH may be involved in formation of the free radical generated by the inhibitor. The glut athione thiyl radical is shown to inhibit antagonist binding to the re ceptor and is, therefore, a good candidate for the free radical formed by the endogenous AD inhibitor. The ability of Trolox to block the re duction in muscarinic receptor binding caused by the endogenous AD inh ibitor is encouraging and suggests that free radical scavengers, such as vitamin E, may have a potential therapeutic role in AD by protectin g the integrity of the muscarinic receptor.