Ogura H

References (15)

Title : Serum albumin as a risk factor for death in patients with prolonged sepsis: An observational study - Takegawa_2019_J.Crit.Care_51_139
Author(s) : Takegawa R , Kabata D , Shimizu K , Hisano S , Ogura H , Shintani A , Shimazu T
Ref : J Crit Care , 51 :139 , 2019
Abstract : PURPOSE: The aim of this study was to evaluate an association between nutritional biomarkers and prognosis in septic patients. METHODS: We retrospectively searched the association between nutritional biomarkers including serum albumin (Alb), total protein (TP), total cholesterol (T-chol), and cholinesterase (ChE), and prognosis for septic patients treated in the ICU for >7days. We used time-dependent Cox proportional hazard regression analysis to resolve the difference of the statistical weight of each day's data for all 14 consecutive days among individual sepsis patients. The covariates were based on the minimum moving values determined from 1day, 3days, 7days, and 14days of serial data. The values of these covariates and ICU survival were considered as outcomes. RESULTS: We included 136 septic patients. The decreases in the values of Alb, TP, T-chol, and ChE were significantly associated with the risk of death in the septic patients (p<.05). Especially, the daily changes of Alb were significantly associated with mortality during the ICU stay (p<.05). CONCLUSIONS: We found that the changes in serial data of the nutritional markers of Alb, TP, T-chol, and ChE reflected the higher risk of death in patients with prolonged sepsis.
ESTHER : Takegawa_2019_J.Crit.Care_51_139
PubMedSearch : Takegawa_2019_J.Crit.Care_51_139
PubMedID: 30825787

Title : Low total cholesterol and high total bilirubin are associated with prognosis in patients with prolonged sepsis - Yamano_2016_J.Crit.Care_31_36
Author(s) : Yamano S , Shimizu K , Ogura H , Hirose T , Hamasaki T , Shimazu T , Tasaki O
Ref : J Crit Care , 31 :36 , 2016
Abstract : PURPOSE: Nutritional biochemical indexes are generally used as markers for critically ill patients. However, they are easily influenced by acute phase changes after injury and are difficult to use as common and practical biomarkers. The objective of this study was to determine the most valuable prognostic markers among 15 common laboratory tests in patients with sepsis.
METHODS: We included all sepsis patients who stayed in the intensive care unit for more than 2 weeks. We evaluated 15 biochemistry indexes including serum albumin, total protein, C-reactive protein, cholinesterase, total cholesterol (T-Cho), triglyceride, sodium, potassium, blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, total bilirubin (T-Bil), and prothrombin time. The minimum and maximum values of these indexes during the first 14 days from admission were analyzed by classification and regression tree and multivariate logistic regression analyses.
RESULTS: This study comprised 91 patients with sepsis. The primary split was the minimum value of serum T-Cho (T-Cho (Min)), and the cutoff value was 73.5 mg/dL by classification and regression tree analysis. The second split was the maximum value of T-Bil (T-Bil (Max)), and the cutoff value was 1.35 mg/dL. The rate of mortality was 63% (17/27) in the group with T-Cho (Min) less than 73.5 mg/dL and T-Bil (Max) greater than 1.35 mg/dL. Multivariate logistic regression revealed that T-Cho (Min) and T-Bil (Max) were the biomarkers most closely associated with prognosis.
CONCLUSIONS: Total cholesterol and T-Bil could be associated with prognosis in patients with sepsis.
ESTHER : Yamano_2016_J.Crit.Care_31_36
PubMedSearch : Yamano_2016_J.Crit.Care_31_36
PubMedID: 26596698

Title : Study of neuroprotection of donepezil, a therapy for Alzheimer's disease - Akasofu_2008_Chem.Biol.Interact_175_222
Author(s) : Akasofu S , Kimura M , Kosasa T , Sawada K , Ogura H
Ref : Chemico-Biological Interactions , 175 :222 , 2008
Abstract : Donepezil is a potent acetylcholinesterase inhibitor used for the treatment of Alzheimer's disease. Although acetylcholinesterase inhibitors are thought to be symptomatic treatment of Alzheimer's disease, it is not clear whether they are effective against progressive degeneration of neuronal cells. In this study, we investigated the neuroprotective effects of donepezil against ischemic damage, N-methyl-d-aspartate (NMDA) excitotoxicity, and amyloid-beta (Abeta) toxicity using rat brain primary cultured neurons. Lactate dehydrogenase (LDH) released into the culture medium was measured as a marker of neuronal cell damage. As an ischemic damage model, we used oxygen-glucose deprivation in rat cerebral cortex primary cultured neurons. Pretreatment with donepezil (0.1, 1 and 10 microM) significantly decreased LDH release in a concentration-dependent manner. However, other acetylcholinesterase inhibitors (galantamine, tacrine and rivastigmine) did not significantly decrease LDH release. In a NMDA excitotoxicity model, pretreatment with donepezil (0.1, 1 and 10 microM) decreased the LDH release in a concentration-dependent manner. In binding assay for glutamate receptors, donepezil at 100 microM only slightly inhibited binding to the glycine and polyamine sites on NMDA receptor complex. We further examined the effect of donepezil on Abeta (1-40)- and Abeta (1-42)-induced toxicity in primary cultures of rat septal neurons. Pretreatment with donepezil (0.1, 1 and 10 microM) significantly decreased LDH release induced by Abetas in a concentration-dependent manner. However, other acetylcholinesterase inhibitors (galantamine and tacrine) and NMDA receptor antagonists (memantine and dizocilpine (MK801)) did not significantly decrease LDH release. These results demonstrate that donepezil has protective effects against ischemic damage, glutamate excitotoxicity and Abeta toxicity to rat primary cultured neurons and these effects are not dependent on acetylcholinesterase inhibition and antagonism of NMDA receptors. Thus, donepezil is expected to have a protective effect against progressive degeneration of brain neuronal cells in ischemic cerebrovascular disease and Alzheimer's disease.
ESTHER : Akasofu_2008_Chem.Biol.Interact_175_222
PubMedSearch : Akasofu_2008_Chem.Biol.Interact_175_222
PubMedID: 18571635

Title : Donepezil, an acetylcholinesterase inhibitor, enhances adult hippocampal neurogenesis - Kotani_2008_Chem.Biol.Interact_175_227
Author(s) : Kotani S , Yamauchi T , Teramoto T , Ogura H
Ref : Chemico-Biological Interactions , 175 :227 , 2008
Abstract : Donepezil hydrochloride is a potent and selective acetylcholinesterase inhibitor and has been treated for Alzheimer's disease, in which the cholinergic dysfunction is observed. Recently, the degeneration of medial septal cholinergic nuclei in adult rat suppressed the neurogenesis in hippocampal dentate gyrus (DG) was reported. Then, we determined whether donepezil which activated the brain cholinergic system could modulate hippocampal neurogenesis in normal rats. After the injection of 5'-bromo-2'-deoxyuridine (BrdU) to label dividing cells, we orally treated with donepezil (0.5 or 2mg/kg) once a day for 4 weeks. In the other group, we performed 4-week subcutaneous infusion of scopolamine (0.75 or 3mg/day), a muscarinic acetylcholine receptor blocker. The doses of donepezil and scopolamine we used in this study were reported to activate and inhibit cholinergic activity in rats, respectively. One day after the completion of drug treatment, the animals were sacrificed, and immunohistochemical analysis was performed. Donepezil increased, but scopolamine decreased, the number of BrdU-positive cells in the DG as compared with the vehicle-treated control. Neither drug had any effects on the percentage of BrdU-positive cells that were also positive for a neuronal marker NeuN, nor the number of proliferating cell nuclear antigen-positive cells in the DG. These results indicate that donepezil enhances and scopolamine suppresses the survival of newborn neurons in the DG without affecting the proliferation of neural progenitor cell and the neuronal differentiation. We also found that chronic treatment of donepezil enhanced, and scopolamine suppressed phosphorylation of cAMP response element binding protein (CREB), which was involved in cell survival, in the DG. These results suggest that donepezil activates the central cholinergic transmission and enhances the survival of newborn neurons in the DG via CREB signaling.
ESTHER : Kotani_2008_Chem.Biol.Interact_175_227
PubMedSearch : Kotani_2008_Chem.Biol.Interact_175_227
PubMedID: 18501884

Title : Donepezil attenuates excitotoxic damage induced by membrane depolarization of cortical neurons exposed to veratridine - Akasofu_2008_Eur.J.Pharmacol_588_189
Author(s) : Akasofu S , Sawada K , Kosasa T , Hihara H , Ogura H , Akaike A
Ref : European Journal of Pharmacology , 588 :189 , 2008
Abstract : Long-lasting membrane depolarization in cerebral ischemia causes neurotoxicity via increases of intracellular sodium concentration ([Na+]i) and calcium concentration ([Ca2+]i). Donepezil has been shown to exert neuroprotective effects in an oxygen-glucose deprivation model. In the present study, we examined the effect of donepezil on depolarization-induced neuronal cell injury resulting from prolonged opening of Na+ channels with veratridine in rat primary-cultured cortical neurons. Veratridine (10 microM)-induced neuronal cell damage was completely prevented by 0.1 microM tetrodotoxin. Pretreatment with donepezil (0.1-10 microM) for 1 day significantly decreased cell death in a concentration-dependent manner, and a potent NMDA receptor antagonist, dizocilpine (MK801), showed a neuroprotective effect at the concentration of 10 microM. The neuroprotective effect of donepezil was not affected by nicotinic or muscarinic acetylcholine receptor antagonists. We further characterized the neuroprotective properties of donepezil by measuring the effect on [Na+]i and [Ca2+]i in cells stimulated with veratridine. At 0.1-10 microM, donepezil significantly and concentration-dependently reduced the veratridine-induced increase of [Ca2+]i, whereas MK801 had no effect. At 10 microM, donepezil significantly decreased the veratridine-induced increase of [Na+]i. We also measured the effect on veratridine-induced release of the excitatory amino acids, glutamate and glycine. While donepezil decreased the release of glutamate and glycine, MK801 did not. In conclusion, our results indicate that donepezil has neuroprotective activity against depolarization-induced toxicity in rat cortical neurons via inhibition of the rapid influx of sodium and calcium ions, and via decrease of glutamate and glycine release, and also that this depolarization-induced toxicity is mediated by glutamate receptor activation.
ESTHER : Akasofu_2008_Eur.J.Pharmacol_588_189
PubMedSearch : Akasofu_2008_Eur.J.Pharmacol_588_189
PubMedID: 18508044

Title : Protective effect of donepezil in primary-cultured rat cortical neurons exposed to N-methyl-d-aspartate (NMDA) toxicity - Akasofu_2006_Eur.J.Pharmacol_530_215
Author(s) : Akasofu S , Kimura M , Kosasa T , Ogura H , Sawada K
Ref : European Journal of Pharmacology , 530 :215 , 2006
Abstract : Donepezil has a neuroprotective effect against oxygen-glucose deprivation injury and glutamate toxicity in cultured cortical neurons. In this study, we further characterized the neuroprotective properties of donepezil in rat cortical cell cultures using glutamate receptor-specific agonists (N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazolepropionate (AMPA) and kainate). Pretreatment with donepezil (1 microM) for 12 h significantly decreased the lactate dehydrogenase (LDH) release in response to NMDA (100 microM) by 43.8%, and reduced the LDH release in response to kainate (100 microM) and AMPA (100 microM) by 11.9% and 7.5% (without statistical significance), respectively. Donepezil appeared to inhibit LDH release in a concentration-dependent manner at 0.1-10 microM. Cortical neurons exposed to NMDA retained a normal morphological appearance in the presence of 10 microM donepezil. In binding assay for glutamate receptors, donepezil at 100 microM only slightly inhibited binding to the glycine and polyamine sites on NMDA receptor complex. On the other hand, 12 h pretreatment with donepezil at 10 and 100 microM significantly decreased the NMDA-induced increase of intracellular calcium concentration ([Ca2+]i). In conclusion, our results show that donepezil has protective activity against NMDA toxicity in cortical neurons, and this neuroprotection seems to be partially mediated by inhibition of the increase of [Ca2+]i.
ESTHER : Akasofu_2006_Eur.J.Pharmacol_530_215
PubMedSearch : Akasofu_2006_Eur.J.Pharmacol_530_215
PubMedID: 16406045

Title : Pharmacological evidence of cholinergic involvement in adult hippocampal neurogenesis in rats - Kotani_2006_Neurosci_142_505
Author(s) : Kotani S , Yamauchi T , Teramoto T , Ogura H
Ref : Neuroscience , 142 :505 , 2006
Abstract : In adult hippocampus, neural progenitor cells give rise to neurons throughout life, and the neurogenesis is modulated by various intrinsic and extrinsic factors. Recent reports showed that lesion of septal cholinergic nuclei projecting to hippocampus suppressed the survival of newborn cells in the dentate gyrus (DG) of hippocampus. Here, we studied whether pharmacological treatment to activate or inhibit the cholinergic system could modulate adult hippocampal neurogenesis. 5'-Bromo-2'-deoxyuridine (BrdU) was injected to label dividing cells before the drug treatment. Immunohistochemical analysis was performed in normal rats chronically treated with an acetylcholinesterase inhibitor donepezil or a muscarinic acetylcholine receptor blocker scopolamine for four weeks. Donepezil increased, but scopolamine decreased, the number of BrdU-positive cells in the DG as compared with the control. Neither drug altered the percentage of BrdU-positive cells that were also positive for a neuronal marker neuronal nuclei, nor net population of proliferative cells labeled with proliferating cell nuclear antigen. We also found that donepezil enhanced, and scopolamine suppressed, the expression level of phosphorylated cAMP response element binding protein (CREB), which is related to cell survival, in the DG. These results indicate that donepezil enhances and scopolamine suppresses the survival of newborn cells in the DG via CREB signaling without affecting neural progenitor cell proliferation and the neuronal differentiation. This is the first evidence that pharmacological manipulation of the cholinergic system can modulate adult hippocampal neurogenesis.
ESTHER : Kotani_2006_Neurosci_142_505
PubMedSearch : Kotani_2006_Neurosci_142_505
PubMedID: 16889901

Title : Protective effect of donepezil against Abeta(1-40) neurotoxicity in rat septal neurons - Kimura_2005_Brain.Res_1047_72
Author(s) : Kimura M , Akasofu S , Ogura H , Sawada K
Ref : Brain Research , 1047 :72 , 2005
Abstract : Donepezil, a potent acetylcholinesterase (AChE) inhibitor used for the treatment of Alzheimer's disease (AD), is thought to have a neuroprotective effect in AD patients. Because a deficit in cholinergic neurotransmission is a major feature in AD, and amyloid-beta (Abeta) accumulation has been proposed as a possible causative phenomenon, we were interested to examine the effect of donepezil on Abeta(1-40) induced neurotoxicity in primary cultures of rat septal neurons. Using immunohistochemical staining, almost all the neurons were found to be positive for vesicular acetylcholine transporter (VAChT) in these septal cultures. Septal neuronal cells were cultured for 7 days and then 15 micromol/L of Abeta(1-40) was added to the cell medium for 48 h. The cultured septal neurons were highly susceptible to Abeta toxicity, as shown by morphological examination and lactate dehydrogenase (LDH) assay. Donepezil concentration-dependently reduced the LDH efflux induced by Abeta(1-40), and the effect was significant at 100 nmol/L and above. Donepezil decreased both the negative peak at around 215 nm in the circular dichroism (CD) spectrum and the fluorescence intensity of thioflavin T in the presence of Abeta(1-40). These results suggest that donepezil exerts a neuroprotective effect by reducing the amount of the toxic form of Abeta fibrils in septal neuron cultures. These findings support the idea that the clinical efficacy of donepezil in AD is due to not only activation of cholinergic transmission, but also attenuation of neuronal damage.
ESTHER : Kimura_2005_Brain.Res_1047_72
PubMedSearch : Kimura_2005_Brain.Res_1047_72
PubMedID: 15893738

Title : Comparison of donepezil and memantine for protective effect against amyloid-beta(1-42) toxicity in rat septal neurons - Kimura_2005_Neurosci.Lett_391_17
Author(s) : Kimura M , Komatsu H , Ogura H , Sawada K
Ref : Neuroscience Letters , 391 :17 , 2005
Abstract : Donepezil, a potent acetylcholinesterase (AChE) inhibitor and memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, have been used for the treatment of Alzheimer's disease (AD), and both of them have been shown to have neuroprotective action against glutamate excitotoxicity. However, it is not known whether donepezil and memantine similarly exert neuroprotective effects against amyloid-beta peptide(1-42) [Abeta(1-42)] toxicity in cholinergic neurons. Therefore, in the present study we compared the neuroprotective effects of donepezil and memantine against Abeta(1-42) toxicity in rat cultured septal cholinergic neurons, because deficit in cholinergic neurotransmission is a major feature in AD, and medial septal cholinergic neurons are known to degenerate in AD patients. Septal neuronal cells were cultured for 7 days and then 5 micromol/L of Abeta(1-42) was added to the medium for 48 h. Measurement of the efflux of lactate dehydrogenase (LDH) indicated that septal neuronal cells were highly susceptible to Abeta toxicity and relatively resistant to NMDA toxicity. Donepezil concentration-dependently reduced the LDH efflux induced by Abeta(1-42), and the effect was significant at 1 micromol/L and above. NMDA receptor antagonists, memantine and MK-801, did not show a significant neuroprotective effect against Abeta(1-42) toxicity. It is concluded that the neuroprotective effect of donepezil against Abeta(1-42) toxicity is not mediated by interference with the NMDA-mediated excitotoxic process, and that donepezil may be more effective than memantine against cholinergic neuronal damage induced by Abeta(1-42) exposure.
ESTHER : Kimura_2005_Neurosci.Lett_391_17
PubMedSearch : Kimura_2005_Neurosci.Lett_391_17
PubMedID: 16154269

Title : Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor - Sugimoto_2002_Jpn.J.Pharmacol_89_7
Author(s) : Sugimoto H , Ogura H , Arai Y , Limura Y , Yamanishi Y
Ref : Japanese Journal of Pharmacology , 89 :7 , 2002
Abstract : A wide range of evidence shows that cholinesterase (ChE) inhibitors can interfere with the progression of Alzheimer's disease (AD). The earliest known ChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of AD patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters, while tacrine has hepatotoxic liability. Studies were then focused on finding a new type of acetylcholinesterase (AChE) inhibitor that would overcome the disadvantages of these two compounds. During the study, by chance we found a seed compound. We then conducted a structure-activity relationship study of this compound. After four years of exploratory research, we found donepezil hydrochloride (donepezil). Donepezil showed several positive characteristics including the following: 1) It has a novel structure compared to other conventional ChE inhibitors; 2) It shows strong anti-AChE activity and has long lasting efficacy; 3) The inhibitory characteristic of donepezil shows that it is highly selective for AChE as compared to butyrylcholinesterase (BuChE) and showed reversibility; 4) The results of clinical studies on donepezil show a very high significant difference on ADAS cog and CIBIC plus scores of AD patients. Donepezil is currently marketed in 56 countries all over the world.
ESTHER : Sugimoto_2002_Jpn.J.Pharmacol_89_7
PubMedSearch : Sugimoto_2002_Jpn.J.Pharmacol_89_7
PubMedID: 12083745

Title : Central and peripheral activity of cholinesterase inhibitors as revealed by yawning and fasciculation in rats - Ogura_2001_Eur.J.Pharmacol_415_157
Author(s) : Ogura H , Kosasa T , Kuriya Y , Yamanishi Y
Ref : European Journal of Pharmacology , 415 :157 , 2001
Abstract : This study was designed to investigate the central and peripheral activity profile of cholinesterase inhibitors in rats. Intravenous injection of cholinesterase inhibitors caused fasciculation, a fine involuntary muscular movement. This peripheral cholinergic sign was tightly correlated with in vitro anti-acetylcholinesterase activity by cholinesterase inhibitors, suggesting that fasciculation is a valid index of peripheral cholinergic activation. Yawning, used as a marker of central cholinergic activation, was also monitored. E2030 (3-(2-(1-(1,3-dioxolan-2-ylmethyl)-4-piperidyl)ethyl)-2H-3,4-dihydro-1,3-benzoxazin-2,4-dione hydrochloride) elicited yawning at more than 4 mg/kg, while fasciculation was significantly intensified only at a dose of 16 mg/kg. Donepezil and tacrine induced both yawning and fasciculation at doses greater than 4 mg/kg, whereas physostigmine induced both behaviors at a dose of 8 mg/kg and above. Finally, ipidacrine elicited yawning at a dose of 16 mg/kg and fasciculation at doses greater than 8 mg/kg. Thus, all putative centrally acting cholinesterase inhibitors elicited yawning. TAK-147 (3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-benzazepin-8-yl)-1-propanone fumarate) did not significantly elicit yawning at doses under 16 mg/kg, but elicited fasciculation at a dose of more than 4 mg/kg. Distigmine, a peripherally acting cholinesterase inhibitor, evoked fasciculations, but not yawning. When mild to moderate fasciculation was evoked, donepezil and E2030 elicited more than nine yawns over 30 min, while the other cholinesterase inhibitors elicited approximately five yawns at most during this period. These results indicated that E2030 and donepezil exhibited the most marked preferential central cholinergic activity, relative to peripheral activity, among cholinesterase inhibitors tested. Scopolamine, a centrally acting antimuscarinic drug, completely inhibited E2030-induced yawning, while peripherally acting methylscopolamine did not. Haloperidol, a dopamine receptor antagonist, partially blocked E2030-induced yawning, but did not block donepezil-induced yawning. These results suggest that central cholinergic and, in part, dopaminergic mechanisms are involved in E2030-induced yawning.
ESTHER : Ogura_2001_Eur.J.Pharmacol_415_157
PubMedSearch : Ogura_2001_Eur.J.Pharmacol_415_157
PubMedID: 11274994

Title : [Pharmacological properties of donepezil hydrochloride (Aricept), a drug for Alzheimer's disease] - Ogura_2000_Nihon.Yakurigaku.Zasshi_115_45
Author(s) : Ogura H , Kosasa T , Araki S , Yamanishi Y
Ref : Nihon Yakurigaku Zasshi , 115 :45 , 2000
Abstract : One of the most consistent changes associated with Alzheimer's disease (AD) is a deficit in central cholinergic neurotransmission. Donepezil hydrochloride (DPZ), a novel class of cholinesterase (ChE) inhibitors, inhibits degradation of acetylcholine (ACh) and activates central cholinergic system. In in vitro studies, DPZ more selectively inhibited acetylcholinesterase (IC50: 6.7 nM) than butyrylcholinesterase (IC50: 7400 nM), while tacrine inhibited both acetylcholinesterase (IC50: 77 nM) and butyrylcholinesterase (IC50: 69 nM). After oral dosing, DPZ (ID50: 2.6 mg/kg) inhibited brain ChE dose-dependently without any remarkable effect on ChE in the heart and small intestine, whereas tacrine (ID50: 9.5 mg/kg) inhibited ChE equally in the brain and peripheral tissues. Brain microdialysis revealed that DPZ (2.5 mg/kg) enhanced extracellular ACh concentrations in the cerebral cortex and hippocampus in rats. In behavioral studies, DPZ counteracted both the deficit in passive avoidance induced by lesioning of the nucleus basalis magnocellularis (0.125-1.0 mg/kg) and the impairment in acquisition of a hidden-platform water maze task after lesioning of the medial septum in rats (0.5 mg/kg). DPZ also inhibited the scopolamine-induced impairment of radial maze performance (0.5 mg/kg). Placebo-controlled clinical studies of 12- and 24-week treatments of DPZ (5 mg, 10 mg/day) clearly showed an improvement in cognitive scores of probable AD patients.
ESTHER : Ogura_2000_Nihon.Yakurigaku.Zasshi_115_45
PubMedSearch : Ogura_2000_Nihon.Yakurigaku.Zasshi_115_45
PubMedID: 10876815

Title : Donepezil, a centrally acting acetylcholinesterase inhibitor, alleviates learning deficits in hypocholinergic models in rats - Ogura_2000_Methods.Find.Exp.Clin.Pharmacol_22_89
Author(s) : Ogura H , Kosasa T , Kuriya Y , Yamanishi Y
Ref : Methods Find Exp Clin Pharmacol , 22 :89 , 2000
Abstract : Donepezil is a member of a new class of centrally acting cholinesterase inhibitors which preferentially inhibit acetylcholinesterase rather than butyrylcholinesterase. The effects of donepezil on learning impairments were investigated in some hypocholinergic models in rats. In nucleus basalis magnocellularis (NBM)-lesioned rats, donepezil alleviated deficits in passive avoidance response at a dose of 0.125 mg/kg and higher, while tacrine had only a tendency toward improved performance. Donepezil at 0.5 mg/kg effectively counteracted acquisition impairments in the water maze task induced by lesions of the medial septum; tacrine had no significant effects on impairments in this task. Scopolamine caused an increase of errors in the 8-arm radial maze. Donepezil significantly decreased scopolamine-induced errors in the radial maze at 0.5 mg/kg, whereas tacrine decreased errors at 2 mg/kg. These results suggest that donepezil can clearly minimize learning impairments induced by treatments that cause central cholinergic deficiencies in rats. These findings support the clinical efficacy of donepezil in Alzheimer's disease.
ESTHER : Ogura_2000_Methods.Find.Exp.Clin.Pharmacol_22_89
PubMedSearch : Ogura_2000_Methods.Find.Exp.Clin.Pharmacol_22_89
PubMedID: 10849891

Title : Comparison of inhibitory activities of donepezil and other cholinesterase inhibitors on acetylcholinesterase and butyrylcholinesterase in vitro - Ogura_2000_Methods.Find.Exp.Clin.Pharmacol_22_609
Author(s) : Ogura H , Kosasa T , Kuriya Y , Yamanishi Y
Ref : Methods Find Exp Clin Pharmacol , 22 :609 , 2000
Abstract : This study was designed to compare the in vitro inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) of donepezil and some other cholinesterase (ChE) inhibitors which have been developed for the treatment of Alzheimer's disease. The carbamate derivatives physostigmine and rivastigmine needed preincubation to exhibit appropriate anti-ChE activity. The maximum ChE inhibition by physostigmine developed within 30-60 min, while the inhibitory effect of rivastigmine on AChE and BuChE activities reached its peak after 48 and 6 h, respectively. The order of inhibitory potency (IC50) towards AChE activity under optimal assay conditions for each ChE inhibitor was: physostigmine (0.67 nM) > rivastigmine (4.3 nM) > donepezil (6.7 nM) > TAK-147 (12 nM) > tacrine (77 nM) > ipidacrine (270 nM). The benzylpiperidine derivatives donepezil and TAK-147 showed high selectivity for AChE over BuChE. The carbamate derivatives showed moderate selectivity, while the 4-aminopyridine derivatives tacrine and ipidacrine showed no selectivity. The inhibitory potency of these ChE inhibitors towards AChE activity may illustrate their potential in vivo activity.
ESTHER : Ogura_2000_Methods.Find.Exp.Clin.Pharmacol_22_609
PubMedSearch : Ogura_2000_Methods.Find.Exp.Clin.Pharmacol_22_609
PubMedID: 11256231

Title : [Discovery and development of donepezil hydrochloride for the treatment of Alzheimer's disease] - Sugimoto_1999_Yakugaku.Zasshi_119_101
Author(s) : Sugimoto H , Yamanishi Y , Ogura H , Iimura Y , Yamatsu K
Ref : Yakugaku Zasshi , 119 :101 , 1999
Abstract : The most consistent change of neurotransmitter in the brain of Alzheimer's patients is the dramatic decrease of cholinergic innervation due to the loss of neurons in the basal forebrain. The most widely studied acetylcholinesterase inhibitors (AChEIs) have been physostigmine and tacrine. Physostigmine has very short duration, and tacrine has liability to hepatotoxicity. These are the defects of the inhibitors. Our objective was to find a new type of AChEIs that would overcome the disadvantages of physostigmine and tacrine. Through a random screening, we incidentally found an N-benzylpiperazine derivative which showed positive cholinergic behavior in rats. We replaced the N-benzylpiperazine moiety with N-benzylpiperidine moiety and found a dramatic increase in anti-AChE activity. Even after the replacement of an amide group with a ketone group the activity was held. Furthermore, the cyclic-amide derivative showed enhanced inhibitory activity. On the basis of these results, an indanone derivative was designed. Among these indanone derivatives, donepazil hydrochloride (E2020), brand name ARICEPT was found to be the most balanced compound. The clinical studies of donepezil hydrochloride demonstrated statistically significant effects on ADAS-cog (Alzheimer's Disease Assessment Scale cognitive sub.) and CIBIC Plus (Clinician's Interview-Based Impression of Change plus).
ESTHER : Sugimoto_1999_Yakugaku.Zasshi_119_101
PubMedSearch : Sugimoto_1999_Yakugaku.Zasshi_119_101
PubMedID: 10067428