Effect of oral administration of zanapezil (TAK-147) for 21 days on acetylcholine and monoamines levels in the ventral hippocampus of freely moving rats

Abstract

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.

Figure 1

Effect of TAK-147 (n=10) and E2020 (n=8) on acetylcholine level (fmol 20 μl⁻¹) in dialysates from the VH. The drugs were injected at 2 mg kg⁻¹ p.o. for 21 days. After establishment of a stable acetylcholine level (pre) on the 21st day, the last dose of either TAK-147 or E2020 was administered (arrow) and acetylcholine was collected and analyzed by HPLC every 20 min thereafter. Values are means±s.e.m. of each group. Data were analyzed by ANOVA-unequal group size with repeated measures followed by Tukey's post hoc test. Each point is compared to MC (n=7) group. ^*P<0.05.

Figure 2

Effect of TAK-147 (n=10) and E2020 (n=8) on NE (a), Epi (b), 3-methoxy-4-hydroxy-phenylglycol (c) and normetanephrine (d) level in dialysates from the VH. The drugs were injected at 2 mg kg⁻¹ p.o. for 21 days. After establishment of a stable level (pre) for each monoamine on the 21st day, the last dose of either TAK-147 or E2020 was administered (arrow) and the monoamines were collected and analyzed by HPLC every 30 min thereafter. The values are means±s.e.m. of each group. Data were analyzed by ANOVA-unequal group size with repeated measures followed by Tukey's post hoc test. Each point is compared to MC (n=7) group. ^*P<0.05.

Figure 3

Effect of TAK-147 (n=10) and E2020 (n=8) on DA (a), DOPAC (b), methoxytyramine (c) and HVA (d) level in dialysates from the VH. ^*P<0.05 compared to MC (n=7). Other details are as in Figure 2.

Figure 4

Effect of TAK-147 (n=10) and E2020 (n=8) on 5-HT (a) and 5-hydroxyindolacetic acid (b) level in dialysates from the VH. ^*P<0.05 compared to MC (n=7). Other details are as in Figure 2.