Effect of subchronic treatment with metrifonate and tacrine on brain cholinergic function in aged F344 rats.
The effects of 21-day treatment with the acetylcholinesterase inhibitors metrifonate (80 mg kg(-1) per os (p.o.)) and tacrine (3 mg kg(-1) p.o.), twice daily, on cortical and hippocampal cholinergic systems were investigated in aged rats (24-26 months). Extracellular acetylcholine levels were measured by transversal microdialysis in vivo; choline acetyltransferase and acetylcholinesterase activities were measured ex vivo by means of radiometric methods. Basal cortical and hippocampal extracellular acetylcholine levels, measured 18 h after the last metrifonate treatment, were about 15 and two folds higher, respectively, than in control and tacrine-treated rats. A challenge with metrifonate further increased cortical and hippocampal acetylcholine levels by about three and four times, respectively. Basal extracellular acetylcholine levels, measured 18 h after the last treatment with tacrine were not statistically different from those of the control rats. A challenge with tacrine increased cortical and hippocampal extracellular acetylcholine levels by about four and two times. A 75% inhibition of cholinesterase activity was found 18 h after the last metrifonate administration, while only a 15% inhibition was detectable 18 h after the last tacrine administration. The challenge with metrifonate or tacrine resulted in 90 and 80% cholinesterase inhibition, respectively. These results demonstrate that in aging rats a subchronic treatment with metrifonate results in a long-lasting, cholinesterase inhibition, and a persistent increase in acetylcholine extracellular levels which compensate for the age-associated cholinergic hypofunction. Metrifonate is therefore a potentially useful agent for the cholinergic deficit accompanying Alzheimer's disease.
Giovannini
M G
MG
Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.
Scali
C
C
Bartolini
L
L
Schmidt
B
B
Pepeu
G
G
D000109:Acetylcholine / Q000378:metabolism; D000284:Administration, Oral; D000375:Aging / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000502:physiology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004334:Drug Administration Schedule; D006339:Heart Rate / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013619:Tacrine / Q000494:pharmacology*; D014236:Trichlorfon / Q000494:pharmacology*
D002800:Cholinesterase Inhibitors; D013619:Tacrine; D014236:Trichlorfon; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine