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

1 Zanapezil -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. 2 In this study, the effects of TAK-147 at 2 mg kg À1 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. 4 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. 5 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.

Cognitive performance of healthy young rats following chronic donepezil administration

“…In addition to its effects on ACh, donepezil is reported to increase levels of norepinephrine, dopamine, and serotonin (Giacobini et al 1996;Zhang et al 2004;Hatip-al-Khatib et al 2005;Liang and Tang 2006;Shearman et al 2006), and to augment the activity of the NMDA system (Moriguchi et al 2005). However, as donepezil interactions with non-cholinergic neurotrasmettitorial systems have only been investigated in a few studies, using heterogeneous methodologies, different drug dosages, and evaluating cortical or subcortical regions, it is difficult to draw any final conclusions.…”

Donepezil, an acetylcholinesterase inhibitor against Alzheimer's dementia, promotes angiogenesis in an ischemic hindlimb model

“…ACh clearly promoted angiogenesis and acceleration of tube formation; however, it is quite difficult to apply ACh directly to an in vivo model, because ACh evokes life threatening side effects, i.e., bronchospasm, enhanced secretion, and diarrhea [27,28]. Therefore, instead of ACh, we selected donepezil, which is globally used in clinical settings without side effects and has been demonstrated to increase tissue ACh levels [9,10,21]. As expected, donepezil promoted angiogenesis in vitro and concomitantly activated the HIF-1 /VEGF pathway.…”

“…To circumvent this, we used donepezil, an acetylcholinesterase inhibitor and anti-Alzheimer's drug, that elevates local levels of ACh without such adverse effects [9,10]. In addition, we tested the effect of donepezil in a murine hindlimb ischemia model.…”

No effect of donepezil on striatal dopamine release in mild to moderate Alzheimer's disease

“…However, evidence suggests that this class of drugs may also enhance dopamine (DA) release by facilitating the desensitisation and subsequent upregulation of nicotinic receptor sites 1 2. Acute exposure to therapeutic doses of donepezil has been shown to significantly increase DA release in the rodent striatum,3 similar to the changes observed following exposure to low dose nicotine,4 and a fourfold increase in DA levels has been observed in the rodent hippocampus following 3 weeks of treatment with oral donepezil 5. This study aimed to test the hypotheses that:…”