Effect of TAK-147, a novel AChE inhibitor, on cerebral energy metabolism.
Effect of TAK-147, a novel acetylcholinesterase (AChE) inhibitor, on cerebral energy metabolism was investigated using an in vivo 31P-magnetic resonance spectroscopy (31P-MRS) technique and the autoradiographic 2-deoxy-[14C]-D-glucose method in aged Fischer 344 rats. We revealed that high-energy phosphate metabolites, phosphocreatine (PCr) and ATP, in the brain decreased gradually with aging and that significant decrement of cerebral PCr and ATP was observed from 13- and 8.5-month-old in comparison with those of 2.5-month-old rats, respectively. Daily oral administration of TAK-147 (1 mg/kg) for 40 days increased PCr and ATP levels in aged rats (29-month-old). To determine the site at which TAK-147 acts to increase high-energy phosphate metabolism, we investigated the rate of local cerebral glucose utilization (LCGU) in various brain regions. The rate of LCGU decreased in almost all brain regions in aged rats (28 months of age), and the decrease was significant in 29 out of the 35 regions. When TAK-147 was administered orally to the aged rats, the levels were dose dependently increased, especially in the auditory cortex. These results indicate that TAK-147 increases cerebral energy metabolism in aged rats.
Nakayama
T
T
Research on Research, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Takahashi
H
H
Miyamoto
M
M
Goto
G
G
Nagai
Y
Y
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001552:Benzazepines / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D001552:Benzazepines; D002800:Cholinesterase Inhibitors; D010725:Phosphocreatine; C099872:TAK 147; D000255:Adenosine Triphosphate; D005947:Glucose