title: Comparison of the effect of TAK-147 (zanapezil) and E-2020 (donepezil) on extracellular acetylcholine level and blood flow in the ventral hippocampus of freely moving rats.
abstract: The effects of zanapezil (TAK-147) and donepezil (E2020) on extracellular acetylcholine (ACh) levels were investigated by HPLC-microdialysis of ventral hippocampus (VH) in freely moving intact rats. The results showed that the basal ACh release rate in the VH is 116.7 +/- 12.4 to 158.4 +/- 22.86 fmol/20 microl. At 2, 5 and 10 mg/kg, single p.o., each drug increased ACh level by 9.4%, 106.5%, 50.8% (TAK-147) and 14.8%, 76.1%, 120.94% (E2020), respectively. The ED50 values were 4.52 mg/kg (1.43 - 14.29; R=0.52) and 4.07 mg/kg (1.77 - 9.37; R=0.985) for TAK-147 and E2020, respectively. Analysis of data revealed that the relative TAK-147/E2020 potency ratio is 0.773, but the effect of E2020 was accompanied by more prominent skeletal muscle fasciculation, gnawing, increased defecation and to lesser extent salivation. Moreover, the significant effect of TAK-147 was observed earlier (20 min) than E2020 (60 min). In this study, we also investigated the effect of both drugs at dose of 5 mg/kg p.o. on blood flow in the VH using Laser Doppler Flowmetry. The results showed that the average blood flow rate in the VH is 6.5 +/- 0.9 ml/min/100 g. TAK-147 did not change blood flow, but E2020 increased blood flow in a biphasic manner. The first increment was obtained between 5 and 40 min (11.5 +/- 2.2 to 12.7 +/- 2.2 ml/min/100 g), and the second one 80-105 min (10.7 +/- 1.6 to 13.4 +/- 3.6 ml/min/100 g). In conclusion, the present results indicate that both TAK-147 and E2020 increase ACh level in the VH. E2020 showed greater potency than TAK-147, but it induced more fasciculation and other side effects than TAK-147. Moreover, the blood flow increasing properties of E2020 could be beneficial in some patients with Alzheimer' disease especially those with chronic vascular dementia, but at the same time, it could also indicate less specific ACh increasing activity than TAK-147 and higher risk of cerebral hemorrhage. On the other hand, the fast and specific effect of TAK-147 may be useful for cure of early stages of Alzheimer's disease (AD).
authors.affiliation: Division of Internal Medicine, Department of Pharmacology, Faculty of Medicine, Pamukkale University, Denizli 20070, Turkey.
authors.forename: Izzettin
authors.initials: I
authors.lastname: Hatip-Al-Khatib
authors.forename: Arai
authors.initials: A
authors.lastname: Takashi
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Egashira
authors.forename: Katsunori
authors.initials: K
authors.lastname: Iwasaki
authors.forename: Michihiro
authors.initials: M
authors.lastname: Fujiwara
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism; D007189:Indans / Q000494:pharmacology*; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001552:Benzazepines; D007189:Indans; D010880:Piperidines; C099872:TAK 147; D000077265:Donepezil; D000109:Acetylcholine