Multiple effects of tetrahydroaminoacridine on the cholinergic system: biochemical and behavioural aspects.
9-Amino-1,2,3,4-tetrahydroaminoacridine (THA) in combination with lecithin has been reported to improve the memory of Alzheimer's disease patients. We have examined some properties of THA in vitro and in vivo so as to define some of the mechanism(s) by which THA might produce its therapeutic effects. In vitro, THA was more potent at inhibiting human plasma cholinesterase (IC50 = 0.03 microM) than human erythrocyte acetylcholinesterase (IC50 = 0.3 microM) and rat brain acetylcholinesterase (IC50 = 0.32 microM). Radioligand binding studies indicated that THA binds reversibly and competitively to primary M1 and M2 human cortical muscarinic receptors with similar affinities. Moreover, THA showed similar affinity for temporal cortices muscarinic receptors from Alzheimer and non-Alzheimer (control) brains. In vivo, subcutaneous administration of THA (1-8 mg/kg body weight) to adult rats (6 months old) produced a dose dependent decrease in general activity compared to saline-treated rats. However, at a concentration of 0.5 mg/kg body weight, the general activity of the rats was increased compared to saline-treated rats. The cognitive function of the THA-treated adult rats (subcutaneously 2 mg/kg body weight) was not significantly improved compared to saline-treated rats. It is concluded that the mechanisms of action of THA on the cholinergic system involve reversible inhibition of cholinesterases and reversible and competitive interaction with muscarinic acetylcholine receptors. These effects might be of therapeutic value in the treatment of Alzheimer's disease.
Adem
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A
Department of Geriatric Medicine, Karolinska Institute, Huddinge Hospital, Sweden.
Mohammed
A K
AK
Winblad
B
B
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D013619:Tacrine / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
D011976:Receptors, Muscarinic; D013619:Tacrine; D011813:Quinuclidinyl Benzilate