Zanapezil (
TAK-147 (3-[1benzylpiperdin-4-yl]-1-(2,3,4,5-tetrahydro-1 H-1-benzazepin-8-yl) propan-1-one
fumarate)) is a selective
acetylcholine (ACh)
esterase inhibitor under investigation as a drug for
Alzheimer's disease (AD) treatment. In this study, the effects of
TAK-147 at 2 mg kg(-1) p.o. for 21 days, compared to
donepezil (
E2020), on the levels of ACh, catecolamines and indoleamines were investigated in the ventral hippocampus (VH) of freely moving rats by microdialysis-high-performance liquid chromatography. The results revealed that the VH contains 92.05+/-21.97 fmol 20 microl(-1) ACh and the following monoamines levels (pg 30 microl(-1)),
norepinephrine (NE) 1.92+/-0.39,
epinephrine (Epi) 1.91+/-0.183, 3-methoxy-4-hydroxyphenylglycol (
MHPG) 11.53+/-3.22,
normetanephrine 3.26+/-0.61,
dopamine (DA) 0.77+/-0.23,
3,4-dihydroxyphenylacetic acid (
DOPAC) 3.37+/-1.01,
homovanillic acid (
4-hydroxy-3-methoxyphenylacetic acid; HVA) 4.04+/-0.93,
3-methoxytyramine 0.64+/-0.13,
serotonin (5-HT) 0.73+/-0.16 and 5-hydroxyindoleacetic
acid (5-HIAA) 313.15+/-18.42. On the 21st day and prior to the last dose,
TAK-147 increased ACh, Epi, DA and
5-HT, whereas
E2020 increased
MHPG, Epi and DA. Following the last dose,
TAK-147 increased NE, whereas
E2020 increased NE, ACh and
5-HT in addition to their effects prior to the last dose.
TAK-147 decreased HVA : DA ratio, but only marginally decreased
DOPAC : DA and
5-HIAA :
5-HT ratios. On the other hand,
E2020 decreased ratios of HVA : DA,
DOPAC : DA (prior to the last dose), and
5-HIAA :
5-HT (90-180 min after the last dose). Both drugs decreased
MHPG : NE only at 180 min after the last dose. The results also showed that
TAK-147 increased Epi : NE ratio prior to and for 120 min following the last dose, whereas
E2020 increased the ratio only before the last dose. The present results show that
TAK-147 at a subthreshold dose could differentially increase ACh and
5-HT, compared to
MHPG increased by
E2020. The last dose of each drug could extend their effects to other monoamines. The increase of the monoamines levels, in addition to that on the ACh, and decrease of their oxidation could be of value in the treatment of the AD, other dementic diseases and the cohort
neurological disorders depending on the type of the monoamine underlying the disorder.