Okamura T

References (19)

Title : The Impact of Nutritional Markers and Dietary Habits on the Bioimpedance Phase Angle in Older Individuals - Kajiyama_2023_Nutrients_15_
Author(s) : Kajiyama S , Nakanishi N , Yamamoto S , Ichikawa T , Okamura T , Hashimoto Y , Kitagawa N , Hamaguchi M , Fukui M
Ref : Nutrients , 15 : , 2023
Abstract : Low phase angle (PhA), as determined via bioelectrical impedance analysis, reflects unhealthy aging and mortality. In this study, we assessed whether nutritional status, including serum nutritional markers and dietary habits, is related to PhA in older individuals. We recruited 212 participants (aged <= 65 years) who underwent medical health checkups. PhA was measured using a multi-frequency impedance body composition analyzer. Habitual food and nutrient intake was evaluated using a brief, self-administered diet history questionnaire. Low PhA values were defined as >=4.95 in males and >=4.35 in females. Males with low PhA had poor exercise habits (p = 0.0429) and a lower body mass index (p = 0.0024). PhA was significantly correlated with serum cholinesterase levels, a nutritional status marker (r = 0.3313, p = 0.0004 in males; r = 0.3221, p = 0.0070 in females). The low-PhA group had significantly lower total energy and carbohydrate intake per ideal body weight (IBW) than the high-PhA group in males (total energy intake:30.2 +/- 9.8 and 34.5 +/- 9.3 kcal/kg/day, p = 0.0307; carbohydrate intake:15.2 +/- 4.9 and 18.0 +/- 5.8 kcal/kg/day, p = 0.0157). Total energy intake per IBW (adjusted odds ratio [95% confidence interval], 0.94 [0.89-1.00] per 1 kcal/kg/day increase) was independently associated with a low PhA in males. Our study revealed that lower total energy intake independently impacted low PhA in older males.
ESTHER : Kajiyama_2023_Nutrients_15_
PubMedSearch : Kajiyama_2023_Nutrients_15_
PubMedID: 37630789

Title : Acute Respiratory Infection in Human Dipeptidyl Peptidase 4-Transgenic Mice Infected with Middle East Respiratory Syndrome Coronavirus - Iwata-Yoshikawa_2019_J.Virol_93_
Author(s) : Iwata-Yoshikawa N , Okamura T , Shimizu Y , Kotani O , Sato H , Sekimukai H , Fukushi S , Suzuki T , Sato Y , Takeda M , Tashiro M , Hasegawa H , Nagata N
Ref : J Virol , 93 : , 2019
Abstract : Middle East respiratory syndrome coronavirus (MERS-CoV) infection can manifest as a mild illness, acute respiratory distress, organ failure, or death. Several animal models have been established to study disease pathogenesis and to develop vaccines and therapeutic agents. Here, we developed transgenic (Tg) mice on a C57BL/6 background; these mice expressed human CD26/dipeptidyl peptidase 4 (hDPP4), a functional receptor for MERS-CoV, under the control of an endogenous hDPP4 promoter. We then characterized this mouse model of MERS-CoV. The expression profile of hDPP4 in these mice was almost equivalent to that in human tissues, including kidney and lung; however, hDPP4 was overexpressed in murine CD3-positive cells within peripheral blood and lymphoid tissues. Intranasal inoculation of young and adult Tg mice with MERS-CoV led to infection of the lower respiratory tract and pathological evidence of acute multifocal interstitial pneumonia within 7 days, with only transient loss of body weight. However, the immunopathology in young and adult Tg mice was different. On day 5 or 7 postinoculation, lungs of adult Tg mice contained higher levels of proinflammatory cytokines and chemokines associated with migration of macrophages. These results suggest that the immunopathology of MERS-CoV infection in the Tg mouse is age dependent. The mouse model described here will increase our understanding of disease pathogenesis and host mediators that protect against MERS-CoV infection.IMPORTANCE Middle East respiratory syndrome coronavirus (MERS-CoV) infections are endemic in the Middle East and a threat to public health worldwide. Rodents are not susceptible to the virus because they do not express functional receptors; therefore, we generated a new animal model of MERS-CoV infection based on transgenic mice expressing human DPP4 (hDPP4). The pattern of hDPP4 expression in this model was similar to that in human tissues (except lymphoid tissue). In addition, MERS-CoV was limited to the respiratory tract. Here, we focused on host factors involved in immunopathology in MERS-CoV infection and clarified differences in antiviral immune responses between young and adult transgenic mice. This new small-animal model could contribute to more in-depth study of the pathology of MERS-CoV infection and aid development of suitable treatments.
ESTHER : Iwata-Yoshikawa_2019_J.Virol_93_
PubMedSearch : Iwata-Yoshikawa_2019_J.Virol_93_
PubMedID: 30626685

Title : N-3 Polyunsaturated Fatty Acids Decrease the Protein Expression of Soluble Epoxide Hydrolase via Oxidative Stress-Induced P38 Kinase in Rat Endothelial Cells - Okada_2017_Nutrients_9_
Author(s) : Okada T , Morino K , Nakagawa F , Tawa M , Kondo K , Sekine O , Imamura T , Okamura T , Ugi S , Maegawa H
Ref : Nutrients , 9 : , 2017
Abstract : N-3 polyunsaturated fatty acids (PUFAs) improve endothelial function. The arachidonic acid-derived metabolites (epoxyeicosatrienoic acids (EETs)) are part of the endothelial hyperpolarization factor and are vasodilators independent of nitric oxide. However, little is known regarding the regulation of EET concentration by docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in blood vessels. Sprague-Dawley rats were fed either a control or fish oil diet for 3 weeks. Compared with the control, the fish oil diet improved acetylcholine-induced vasodilation and reduced the protein expression of soluble epoxide hydrolase (sEH), a key EET metabolic enzyme, in aortic strips. Both DHA and EPA suppressed sEH protein expression in rat aorta endothelial cells (RAECs). Furthermore, the concentration of 4-hydroxy hexenal (4-HHE), a lipid peroxidation product of n-3 PUFAs, increased in n-3 PUFA-treated RAECs. In addition, 4-HHE treatment suppressed sEH expression in RAECs, suggesting that 4-HHE (derived from n-3 PUFAs) is involved in this phenomenon. The suppression of sEH was attenuated by the p38 kinase inhibitor (SB203580) and by treatment with the antioxidant N-acetyl-L-cysteine. In conclusion, sEH expression decreased after n-3 PUFAs treatment, potentially through oxidative stress and p38 kinase. Mild oxidative stress induced by n-3 PUFAs may contribute to their cardio-protective effect.
ESTHER : Okada_2017_Nutrients_9_
PubMedSearch : Okada_2017_Nutrients_9_
PubMedID: 28672788

Title : Lipoprotein-associated phospholipase A2 is related to risk of subclinical atherosclerosis but is not supported by Mendelian randomization analysis in a general Japanese population - Ueshima_2016_Atherosclerosis_246_141
Author(s) : Ueshima H , Kadowaki T , Hisamatsu T , Fujiyoshi A , Miura K , Ohkubo T , Sekikawa A , Kadota A , Kadowaki S , Nakamura Y , Miyagawa N , Okamura T , Kita Y , Takashima N , Kashiwagi A , Maegawa H , Horie M , Yamamoto T , Kimura T , Kita T
Ref : Atherosclerosis , 246 :141 , 2016
Abstract : OBJECTIVE: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme predominantly bound to low-density lipoprotein (LDL). Lp-PLA2 is recognized as playing a key role in inflammatory processes and the development of atherosclerosis. This study aimed to investigate whether Lp-PLA2 is related to subclinical atherosclerosis, independently from traditional risk factors, in a general Japanese population by analyses of both the observational study and Mendelian randomization using V279F polymorphism. METHODS AND
RESULTS: We cross-sectionally examined community-based sample of 929 Japanese men aged 40-79 years, without statin treatment, who were randomly selected from the resident registration. Multiple regression analyses of Lp-PLA2 activity and concentration were undertaken separately for men aged 40-49 years and 50-79 years, to clarify interactions of age and Lp-PLA2. Lp-PLA2 activity for men aged 50-79 years was significantly and positively related to intima-media thickness (IMT) (P = 0.013) and plaque index (P = 0.008) independent of traditional risk factors including small LDL particles, but not to coronary artery calcification (CAC) score. Associations with Lp-PLA2 concentration were qualitatively similar to those of activity. Corresponding relationships were not observed in men aged 40-49 years. Mendelian randomization analyses based on V279F genotype did not show any significant associations with subclinical atherosclerosis, although the homozygote and heterozygote of V279F showed low Lp-PLA2 activity and concentration.
CONCLUSIONS: Lp-PLA2 activity in Japanese men aged 50-79 years was associated significantly and positively with IMT and plaque in the carotid artery but Mendelian randomization did not support that Lp-PLA2 is a causative factor for subclinical atherosclerosis.
ESTHER : Ueshima_2016_Atherosclerosis_246_141
PubMedSearch : Ueshima_2016_Atherosclerosis_246_141
PubMedID: 26775119

Title : Obesity-induced cerebral hypoperfusion derived from endothelial dysfunction: one of the risk factors for Alzheimer's disease - Toda_2014_Curr.Alzheimer.Res_11_733
Author(s) : Toda N , Ayajiki K , Okamura T
Ref : Curr Alzheimer Res , 11 :733 , 2014
Abstract : Increasing evidence supports the idea that chronic hypoperfusion in the brain is responsible for the pathogenesis underling Alzheimer's disease (AD). Obesity at midlife is associated with the risk of cognitive loss and AD at later life. Obesity decreases cerebral blood flow that is associated with decreased synthesis and actions of nitric oxide (NO) derived from the endothelium and also increases the production of oxidative stress. Increased plasma levels of asymmetric dimethylarginine decreases the production of NO by inhibiting NO synthase activity, leading to cerebral hypoperfusion and cognitive and neurodegenerative changes in AD. Adiponectin has a cerebroprotective action through an eNOSdependent mechanism. Obesity-induced endothelial dysfunction and cerebral hypoperfusion enhance the production of beta-amyloid that in turn impairs endothelial function; this vicious cycle promotes the pathogenic changes leading to AD. Interrupting this cycle by enhancement of NO-mediated cerebral blood flow is expected to promote prophylaxis against AD pathogenesis. This review summarizes recent advances in prophylactic or therapeutic measures, including physical exercise, nutritionally adequate dietary intake, pharmacological treatments such as acetylcholinesterase inhibitors and antioxidants, and bariatric surgery that are efficient in protecting and retarding the progress of cognitive failure and neurodegeneration.
ESTHER : Toda_2014_Curr.Alzheimer.Res_11_733
PubMedSearch : Toda_2014_Curr.Alzheimer.Res_11_733
PubMedID: 25212912

Title : PET probes for imaging brain acetylcholinesterase - Kikuchi_2013_J.Labelled.Comp.Radiopharm_56_172
Author(s) : Kikuchi T , Okamura T , Zhang MR , Irie T
Ref : J Labelled Comp Radiopharm , 56 :172 , 2013
Abstract : Imaging acetylcholinesterase (AChE) is valuable not only for diagnosing and understanding dementia but also for monitoring the effects of cholinesterase inhibitors used as antidementia drugs and for determining the appropriate clinical dosage of newly developed cholinesterase inhibitors. The distribution of AChE in the living brain can be imaged with two different types of radioprobes, including substrate-type and ligand-type probes. The substrate-type positron emission tomography (PET) probes, N-[(11) C]methylpiperidin-4-yl acetate ([(11) C]MP4A), and its propionate, [(11) C]MP4P, have been widely used in clinical studies of dementia, including Alzheimer's disease. [(11) C]MP4A and [(11) C]MP4P have been used to demonstrate a reduction in AChE activity in the brains of dementia patients, as well as the bioavailability of AChE inhibitors, leading to the subsequent development of the widely available (18) F-labeled derivatives of MP4A. In addition, several radiolabeled cholinesterase inhibitors have been developed as PET probes for AChE mapping in the brain. Herein, we have reviewed the development of PET probes for the imaging of AChE in the brain and described the principles of measuring AChE activity in the brain using PET with substrate-type radioprobes. A discussion of the reagents developed from substrate-type PET probes for the specific measurement of AChE activity in vitro has also been provided.
ESTHER : Kikuchi_2013_J.Labelled.Comp.Radiopharm_56_172
PubMedSearch : Kikuchi_2013_J.Labelled.Comp.Radiopharm_56_172
PubMedID: 24285323

Title : Cerebral blood flow regulation by nitric oxide in Alzheimer's disease - Toda_2012_J.Alzheimers.Dis_32_569
Author(s) : Toda N , Okamura T
Ref : J Alzheimers Dis , 32 :569 , 2012
Abstract : Cerebral hypoperfusion due to impaired bioavailability of nitric oxide (NO) synthesized by endothelial nitric oxide synthase and neuronal nitric oxide synthase leads to cognitive decline and neurodegeneration in Alzheimer's disease (AD). Risk factors for endothelial dysfunction, such as inadequate lifestyle, cardiovascular/metabolic diseases, and aging, evokes cerebral hypoperfusion, impaired autoregulation, and increased production of amyloid-beta peptides (Abeta) in association with vasculogenic memory loss and dementia. Decrease in parasympathetic nitrergic nerve activity also plays a role in cerebral hypoperfusion. Abeta is a functional obstacle to NO-mediated vasodilatation; therefore, it decreases cerebral blood flow. Generation of reactive oxygen species by Abeta is a major action in promoting NO degradation. Effective strategies for the prophylaxis or treatment of AD includes acetylcholinesterase inhibitors, drugs acting on the NO-cyclic GMP signaling pathway, antioxidants, peroxisome proliferator-activated receptor gamma-agonists, and hydroxymethylglutaryl-CoA reductase inhibitors. Here our hypothesis about the mechanisms underlying the actions of acetylcholinesterase inhibitors in relation to NO-mediated cerebral blood flow is presented. Future detailed analyses of the relationship between cerebral blood flow regulation by constitutive NO and cognitive decline/neurodegeneration will provide clues for developing novel prophylactic measures and therapeutic means to alleviate AD.
ESTHER : Toda_2012_J.Alzheimers.Dis_32_569
PubMedSearch : Toda_2012_J.Alzheimers.Dis_32_569
PubMedID: 22810094

Title : Effect of radiolabeled metabolite elimination from the brain on the accuracy of cerebral enzyme activity estimation using positron emission tomography with substrate tracers - Ohya_2011_Neuroimage_56_1105
Author(s) : Ohya T , Okamura T , Nagai Y , Fukushi K , Irie T , Suhara T , Zhang MR , Fukumura T , Kikuchi T
Ref : Neuroimage , 56 :1105 , 2011
Abstract : Cerebral enzyme activity can be quantified using positron emission tomography (PET) in conjunction with a radiolabeled enzyme substrate. We investigated the relationship between the elimination rate (k(el)) of tracer metabolites from the brain and the precision of target enzyme activity estimation (k(3)). An initial simulation study indicated that the precision of k(3) estimates was highly dependent on k(el), and was characterized by several kinetic parameters including the ratio of k(el) and the efflux rate (k(2)) of authentic tracer (beta identical withk(el)/k(2)). The optimal tracer condition for high sensitivity was found to be beta<0.1. To verify the simulation results, we performed a PET study with a single monkey using two PET tracers, N-[(18)F]fluoroethylpiperidin-4-ylmethyl acetate ([(18)F]FEP-4MA) and N-[(11)C]methylpiperidin-4-yl acetate ([(11)C]MP4A). Both of these substrate type tracers were developed for measuring cerebral acetylcholinesterase activity. There was good retention of the radioactive metabolite of [(11)C]MP4A in the brain (k(el)=0.0036+/-0.0013 min(-1), beta=0.028), whereas that of [(18)F]FEP-4MA was eliminated from the brain (k(el)=0.012+/-0.0010 min(-1), beta=0.085). A non-linear least square analysis for simultaneous estimation of all parameters showed that the precision of the k(3) estimate for [(18)F]FEP-4MA was as high (7.4%) as that for [(11)C]MP4A (10%). These results indicate that tracers with metabolites that are eliminated from the brain at a slow rate (beta<0.1) may be useful for the quantitative measurement of target enzyme activity.
ESTHER : Ohya_2011_Neuroimage_56_1105
PubMedSearch : Ohya_2011_Neuroimage_56_1105
PubMedID: 21324368

Title : Piperidine-4-methanthiol ester derivatives for a selective acetylcholinesterase assay - Kikuchi_2010_Biol.Pharm.Bull_33_702
Author(s) : Kikuchi T , Okamura T , Fukushi K , Irie T
Ref : Biol Pharm Bull , 33 :702 , 2010
Abstract : The activity of acetylcholinesterase (AChE) is measured to obtain pathological information about the cholinergic system in various disease states and to assess the effect of AChE inhibitors. Using Ellman's method that is commonly used in such examinations, butyrylcholinesterase inhibitors must be added to measure AChE-specific activity because of low selectivity of AChE toward traditional substrates; however, such inhibitors also inhibit AChE. Therefore, it is desirable to obtain an AChE selective substrate that can be used with the Ellman's method. Here, we synthesized novel AChE substrates, 1-methyl-4-acetylthiomethylpiperidine and 1,1-dimethyl-4-acetylthiomethylpiperidine, and evaluated the hydrolysis rate and AChE selectivity by comparison with the results obtained when traditional substrates were used. The hydrolysis rate of the novel compounds by human AChE was one order of magnitude lower than that of the traditional substrates, acetylthiocholine and acetyl-beta-methylthiocholine, whereas the hydrolysis rate using human butyrylcholinesterase was two orders of magnitude lower than that of the traditional substrates. This indicated that AChE showed selectivity towards the novel substrates which was one order of magnitude higher than that of the traditional substrates. The hydrolysis of the novel compounds in a rat cerebral cortical homogenate and a monkey whole blood was completely inhibited by 1 muM of the specific AChE inhibitor, 1,5-bis(4-allyldimethylammoniumphenyl)pentan-3-one, indicating the high specificity of AChE towards the novel substrates in a crude tissue sample. From these results, we conclude that the novel compounds developed would be suitable AChE-selective substrates for Ellman's method.
ESTHER : Kikuchi_2010_Biol.Pharm.Bull_33_702
PubMedSearch : Kikuchi_2010_Biol.Pharm.Bull_33_702
PubMedID: 20410609

Title : Use of a novel radiometric method to assess the inhibitory effect of donepezil on acetylcholinesterase activity in minimally diluted tissue samples - Kikuchi_2010_Br.J.Pharmacol_159_1732
Author(s) : Kikuchi T , Okamura T , Arai T , Obata T , Fukushi K , Irie T , Shiraishi T
Ref : British Journal of Pharmacology , 159 :1732 , 2010
Abstract : BACKGROUND AND PURPOSE: Cholinesterase inhibitors have been widely used for the treatment of patients with dementia. Monitoring of the cholinesterase activity in the blood is used as an indicator of the effect of the cholinesterase inhibitors in the brain. The selective measurement of cholinesterase with low tissue dilution is preferred for accurate monitoring; however, the methods have not been established. Here, we investigated the effect of tissue dilution on the action of cholinesterase inhibitors using a novel radiometric method with selective substrates, N-[(14)C]methylpiperidin-4-yl acetate ([(14)C]MP4A) and (R)-N- [(14)C]methylpiperidin-3-yl butyrate ([(14)C]MP3B_R), for AChE and butyrylcholinesterase (BChE) respectively. EXPERIMENTAL APPROACH: We investigated the kinetics of hydrolysis of [(14)C]-MP4A and [(14)C]-MP3B_R by cholinesterases, and evaluated the selectivity of [(14)C]MP4A and [(14)C]MP3B_R for human AChE and BChE, respectively, compared with traditional substrates. Then, IC(50) values of cholinesterase inhibitors in minimally diluted and highly diluted tissues were measured with [(14)C]MP4A and [(14)C]MP3B_R. KEY RESULTS: AChE and BChE activities were selectively measured as the first-order hydrolysis rates of [(14)C]-MP4A and [(14)C]MP3B_R respectively. The AChE selectivity of [(14)C]MP4A was an order of magnitude higher than traditional substrates used for the AChE assay. The IC(50) values of specific AChE and BChE inhibitors, donepezil and ethopropazine, in 1.2-fold diluted human whole blood were much higher than those in 120-fold diluted blood. In addition, the IC(50) values of donepezil in monkey brain were dramatically decreased as the tissue was diluted. CONCLUSIONS AND IMPLICATIONS: This method would effectively monitor the activity of cholinesterase inhibitors used for therapeutics, pesticides and chemical warfare agents.
ESTHER : Kikuchi_2010_Br.J.Pharmacol_159_1732
PubMedSearch : Kikuchi_2010_Br.J.Pharmacol_159_1732
PubMedID: 20401964

Title : In vivo evaluation of N-[18F]fluoroethylpiperidin-4ylmethyl acetate in rats compared with MP4A as a probe for measuring cerebral acetylcholinesterase activity - Kikuchi_2010_Synapse_64_209
Author(s) : Kikuchi T , Okamura T , Zhang MR , Fukushi K , Irie T
Ref : Synapse , 64 :209 , 2010
Abstract : [(11)C]MP4A is an established radioprobe for quantification of cerebral acetylcholinesterase (AChE) activity by positron emission tomography (PET) based on the kinetics of AChE-mediated metabolism and metabolite trapping. It has been used to assess the deficiency in cholinergic innervation in the brain of patients with dementia. Because (18)F has a longer half-life than (11)C, (18)F-labeled derivatives of [(11)C]MP4A allow delivery of the probe to other PET centers, making AChE measurement more widely applicable. Previously, N-[(18)F]fluoroethylpiperidin-4ylmethyl acetate ([(18)F]FEP-4MA) showed that the (18)F-labeled analog of MP4A possessed desirable properties for the quantification of cerebral AChE activity by PET. Here, we evaluated the in vivo kinetics of [(18)F]FEP-4MA and validated the responsiveness of brain uptake to AChE activity based on a mathematical model derived from the AChE-mediated trapping rationale and compared it with MP4A in rats. Almost all radioactivity in the brain was composed of [(18)F]FEP-4MA and the hydrolyzed metabolite at 0-60-min postinjection. When the authentic radioprobe was not observed in the brain, the regional (18)F uptake in the brain correlated well with regional MP4A uptake, and the elimination rate of (18)F from the brain was higher than that of the metabolite of MP4A. The responsiveness of regional (18)F uptake in the brain was examined by simultaneous assay of (18)F concentration, relative blood flow, and AChE activity. Regional (18)F uptake correlated with regional AChE activity as well as that of MP4A. Therefore, we concluded that [(18)F]FEP-4MA would be applicable to clinical PET study for quantifying cerebral AChE activity.
ESTHER : Kikuchi_2010_Synapse_64_209
PubMedSearch : Kikuchi_2010_Synapse_64_209
PubMedID: 19862687

Title : Cerebral acetylcholinesterase imaging: development of the radioprobes - Kikuchi_2007_Curr.Top.Med.Chem_7_1790
Author(s) : Kikuchi T , Okamura T , Fukushi K , Takahashi K , Toyohara J , Okada M , Zhang MR , Irie T
Ref : Curr Top Med Chem , 7 :1790 , 2007
Abstract : Cerebral acetylcholinesterase (AChE) imaging is not only useful for diagnosis of dementia disorders but also for therapeutic monitoring of the effects of cholinesterase (ChE) inhibitors and for decision of the appropriate clinical dosage of newly developed ChE inhibitors. Several ChE inhibitors or the derivatives such as 1,2,3,4-tetrahydro-9-methylaminoacridine (MTHA), donepezil, physostigmine, CP126,998 and 2-fluoro-CP118,954 have been labeled with positron emitters for mapping cerebral AChE by positron emission tomography (PET). When [(11)C]MTHA or [(11)C]donepezil was injected in animals, the uptake poorly reflect the regional distribution of AChE in the brain because of high non-specific binding and/or less specific to AChE in vivo in the brain tissue. [(11)C]physostigmine, [(11)C]CP126,998 and 2-[(18)F]fluoro-CP118,954 were distributed corresponding well to the regional AChE activity in animals, and also former two probes were successfully applied to clinical PET trial. The other approach is measuring cerebral AChE activity with radiolabeled acetylcholine analogue substrates. We have developed the principle for measuring cerebral enzyme activity by PET and radiolabeled N-methylpiperidinyl esters for quantitative measurement of cerebral AChE activity. N-[(11)C]methylipiperidin-4-yl acetate (MP4A) and N-[(11)C]methylpiperidin-4-yl propionate (MP4P) have been used for clinical studies of other demented disorders including Alzheimer's disease (AD), and the probes have demonstrated not only the reduction of AChE activity in the cerebral cortex of patients with AD but also the inhibitory effects of donepezil and rivastigmine on AChE activity in the brain of AD patients. Following this succession, widely available [(18)F]-labeled derivatives of MP4A and MP4P have been developed based on the structure-activity relationships between AChE and piperidinol esters.
ESTHER : Kikuchi_2007_Curr.Top.Med.Chem_7_1790
PubMedSearch : Kikuchi_2007_Curr.Top.Med.Chem_7_1790
PubMedID: 17979787

Title : N-[18F] fluoroethylpiperidin-4ylmethyl acetate, a novel lipophilic acetylcholine analogue for PET measurement of brain acetylcholinesterase activity - Kikuchi_2005_J.Med.Chem_48_2577
Author(s) : Kikuchi T , Zhang MR , Ikota N , Fukushi K , Okamura T , Suzuki K , Arano Y , Irie T
Ref : Journal of Medicinal Chemistry , 48 :2577 , 2005
Abstract : The reduction of acetylcholinesterase (AChE) activity in the brain has been measured in dementia disorders such as Alzheimer's disease and dementia with Lewy bodies using (11)C-labeled acetylcholine analogues, N-[(11)C]methylpiperidin-4-yl acetate and propionate, and positron emission tomography (PET). Our aim was to develop an (18)F-labeled acetylcholine analogue useful for brain AChE mapping with PET, since (18)F, with a longer half-life, has advantages over (11)C. In a preliminary study, a series of N-[(14)C]ethylpiperidin-3-yl or -4-ylmethanol esters (acetyl and propionyl esters) were newly designed and evaluated in vitro regarding the reactivity with and specificity to AChE using purified human enzymes, leading to a novel (18)F-labeled acetylcholine analogue, N-[(18)F]fluoroethylpiperidin-4-ylmethyl acetate. In rat experiments, the (18)F-labeled candidate showed desirable properties for PET AChE measurement: high brain uptake of the authentic ester, high AChE specificity, a moderate hydrolysis rate, and low membrane permeability (metabolic trapping) of the metabolite.
ESTHER : Kikuchi_2005_J.Med.Chem_48_2577
PubMedSearch : Kikuchi_2005_J.Med.Chem_48_2577
PubMedID: 15801847

Title : N-[18F]fluoroethylpiperidin-4-ylmethyl butyrate: a novel radiotracer for quantifying brain butyrylcholinesterase activity by positron emission tomography - Kikuchi_2004_Bioorg.Med.Chem.Lett_14_1927
Author(s) : Kikuchi T , Zhang MR , Ikota N , Fukushi K , Okamura T , Suzuki K , Arano Y , Irie T
Ref : Bioorganic & Medicinal Chemistry Lett , 14 :1927 , 2004
Abstract : In Alzheimer's disease, cerebral cortical butyrylcholinesterase (BChE) activity is reported to be elevated. Our aim was to develop a novel (18)F-labeled tracer for quantifying cerebral BChE activity by positron emission tomography. With in vitro screening of N-[(14)C]ethylpiperidin-3- and 4-ylmethyl esters, N-[(14)C]ethylpiperidin-4-ylmethyl butyrate was selected as a lead for (18)F-labeling, affording N-[(18)F]fluoroethylpiperidin-4-ylmethyl butyrate. The (18)F-labeled butyrate showed the required properties for in vivo BChE measurement, that is, the lipophilic nature of the authentic ester, high specificity to BChE, a moderate hydrolysis rate, and the hydrophilic nature of the metabolite.
ESTHER : Kikuchi_2004_Bioorg.Med.Chem.Lett_14_1927
PubMedSearch : Kikuchi_2004_Bioorg.Med.Chem.Lett_14_1927
PubMedID: 15050629

Title : Mechanisms underlying the neurogenic relaxation of isolated porcine sphincter pupillae - Toda_1999_Exp.Eye.Res_68_505
Author(s) : Toda M , Okamura T , Fujimiya M , Azuma I , Toda N
Ref : Experimental Eye Research , 68 :505 , 1999
Abstract : Mechanisms of relaxation induced by nerve stimulation were examined in isolated porcine iris sphincter muscle in reference to norepinephrine, nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) and the functional interaction of inhibitory and excitatory nerves. Changes in isometric tension were recorded in strips of the sphincter pupillae, which were stimulated by transmurally applied electrical pulses. The presence of neurons containing acetylcholinesterase and tyrosine hydroxylase (TH) was determined histochemically. Transmural electrical stimulation (0.5-20 Hz) produced a frequency-related contraction, which was reversed to a relaxation by atropine in prostaglandin F2alpha-contracted strips. The relaxant response was abolished by timolol and suppressed by metoprolol, a beta1-adrenoceptor antagonist, but was not influenced by butoxamine, a beta2-receptor antagonist. Norepinephrine-induced relaxations were also attenuated only by timolol and metoprolol. Treatment with NG-nitro-L-arginine, a NO synthase inhibitor, and [D-p-Cl-Phe6,Leu17]VIP, a VIP receptor antagonist, did not inhibit the neurogenic relaxation. Contractions induced by nerve stimulation were potentiated by timolol and physostigmine but not by the NO synthase inhibitor. In the sphincter muscle, cholinesterase- and TH-positive nerve fibers and bundles were histologically detected. It is concluded that porcine iris sphincter is innervated by cholinergic excitatory and adrenergic inhibitory nerves. The neurogenic relaxation is associated solely with activation of beta1 adrenoceptors by norepinephrine but is not mediated by NO or VIP.
ESTHER : Toda_1999_Exp.Eye.Res_68_505
PubMedSearch : Toda_1999_Exp.Eye.Res_68_505
PubMedID: 10192808

Title : Cholinergic nerve function in monkey ciliary arteries innervated by nitroxidergic nerve - Toda_1998_Am.J.Physiol_274_H1582
Author(s) : Toda N , Toda M , Ayajiki K , Okamura T
Ref : American Journal of Physiology , 274 :H1582 , 1998
Abstract : We sought to determine the control of ciliary arterial tone by neurogenic acetylcholine (ACh) acting directly on smooth muscle and in conjunction with vasodilator nerves. Isolated posterior ciliary arteries from monkeys responded to ACh (10(-8)-10(-5) M) with dose-related contractions, which were endothelium independent. The response was not affected by cyclooxygenase inhibitors but was abolished by atropine. Relaxations induced at 10(-4) M ACh in the atropine-treated arterial strips were abolished by hexamethonium and NG-nitro-L-arginine (L-NNA), and L-arginine (L-Arg) reversed the response suppressed by L-NNA. Similar results were also obtained on the nicotine (10(-4) M)-induced relaxation. Contractions due to transmural electrical stimulation in the endothelium-denuded strips treated with L-NNA were potentiated by physostigmine and depressed by atropine; the remaining contraction in the presence of atropine was abolished by prazosin. Relaxations associated with electrical stimulation, sensitive to tetrodotoxin, were abolished or reversed to contractions by L-NNA and restored by L-Arg. Stimulation-induced relaxation was attenuated by exogenous ACh and physostigmine and was potentiated by atropine. ACh did not affect the relaxation caused by nitric oxide (NO). Nerve fibers and bundles containing NADPH diaphorase and acetylcholinesterase were histologically demonstrated in the adventitia of ciliary arteries. We conclude that 1) endogenous and exogenous ACh contracts monkey ciliary arteries by acting on muscarinic receptors in smooth muscle cell membranes, 2) vasodilatation elicited by nerve stimulation with electrical pulses or nicotine is mediated by NO synthesized from L-Arg, 3) neurogenic ACh seems to interfere with the nitroxidergic nerve function by acting on prejunctional muscarinic receptors, and 4) high concentrations of ACh stimulate nicotinic receptors in vasodilator nerve terminals and promote the synthesis and/or release of NO.
ESTHER : Toda_1998_Am.J.Physiol_274_H1582
PubMedSearch : Toda_1998_Am.J.Physiol_274_H1582
PubMedID: 9612367

Title : Cholinergic nerve function in monkey ciliary arteries innervated by nitroxidergic nerve - Toda_1998_Am.J.Physiol.Heart.Circ.Physiol_274_H1582
Author(s) : Toda N , Toda M , Ayajiki K , Okamura T
Ref : American Journal of Physiology Heart Circ Physiol , 274 :H1582 , 1998
Abstract : We sought to determine the control of ciliary arterial tone by neurogenic acetylcholine (ACh) acting directly on smooth muscle and in conjunction with vasodilator nerves. Isolated posterior ciliary arteries from monkeys responded to ACh (10(-8)-10(-5)M) with dose-related contractions, which were endothelium independent. The response was not affected by cyclooxygenase inhibitors but was abolished by atropine. Relaxations induced at 10(-4) M ACh in the atropine-treated arterial strips were abolished by hexamethonium and N (G)-nitro-l-arginine (l-NNA), andl-arginine (l-Arg) reversed the response suppressed by l-NNA. Similar results were also obtained on the nicotine (10(-4) M)-induced relaxation. Contractions due to transmural electrical stimulation in the endothelium-denuded strips treated withl-NNA were potentiated by physostigmine and depressed by atropine; the remaining contraction in the presence of atropine was abolished by prazosin. Relaxations associated with electrical stimulation, sensitive to tetrodotoxin, were abolished or reversed to contractions byl-NNA and restored byl-Arg. Stimulation-induced relaxation was attenuated by exogenous ACh and physostigmine and was potentiated by atropine. ACh did not affect the relaxation caused by nitric oxide (NO). Nerve fibers and bundles containing NADPH diaphorase and acetylcholinesterase were histologically demonstrated in the adventitia of ciliary arteries. We conclude that 1) endogenous and exogenous ACh contracts monkey ciliary arteries by acting on muscarinic receptors in smooth muscle cell membranes, 2) vasodilatation elicited by nerve stimulation with electrical pulses or nicotine is mediated by NO synthesized froml-Arg, 3) neurogenic ACh seems to interfere with the nitroxidergic nerve function by acting on prejunctional muscarinic receptors, and 4) high concentrations of ACh stimulate nicotinic receptors in vasodilator nerve terminals and promote the synthesis and/or release of NO.
ESTHER : Toda_1998_Am.J.Physiol.Heart.Circ.Physiol_274_H1582
PubMedSearch : Toda_1998_Am.J.Physiol.Heart.Circ.Physiol_274_H1582
PubMedID: 29586540

Title : Prejunctional regulation by endogenous and exogenous acetylcholine of adrenergic nerve function in isolated canine mesenteric arteries - Zhang_1997_Hypertens.Res_20_119
Author(s) : Zhang JX , Okamura T , Toda N
Ref : Hypertens Res , 20 :119 , 1997
Abstract : Transmural electrical stimulation (5-30 Hz) produced a frequency-dependent increase in the perfusion pressure of isolated, perfused dog mesenteric artery segments without the endothelium, which was abolished by prazosin or tetrodotoxin. Physostigmine inhibited the pressor response to transmural electrical stimulation, whereas atropine potentiated the response. Treatment with acetylcholine (10(-6) and 10(-5) M) dose-dependently inhibited the response to electrical nerve stimulation. The effect was reversed by the addition of atropine and AF-DX 116 at a concentration (10(-7) M) that selectively blocked the M2 receptor subtype, but not by pirenzepine or 4-DAMP. Acetylcholine did not alter the pressure raised by norepinephrine in perfused arterial segments nor the contraction caused by exogenous norepinephrine in the artery strips. 3H-overflow evoked by transmural electrical stimulation from tissues prelabeled with [3H] norepinephrine was decreased by acetylcholine (10(-6) M) in the superfused dog mesenteric arterial strips. It is concluded that acetylcholine inhibits adrenergic neurogenic contractions by interfering with the release of norepinephrine, which possibly results from activation of the prejunctional M2 receptor subtype.
ESTHER : Zhang_1997_Hypertens.Res_20_119
PubMedSearch : Zhang_1997_Hypertens.Res_20_119
PubMedID: 9220276

Title : Modulation by neurogenic acetylcholine of nitroxidergic nerve function in porcine ciliary arteries - Toda_1997_Invest.Ophthalmol.Vis.Sci_38_2261
Author(s) : Toda M , Okamura T , Azuma I , Toda N
Ref : Invest Ophthalmol Vis Sci , 38 :2261 , 1997
Abstract : PURPOSE:To determine whether nitroxidergic, cholinergic, and vasoactive intestinal polypeptide (VIP)-mediated nerves participate in the regulation of porcine ciliary arterial tone and to analyze the mechanisms underlying the neuronal interaction. METHODS: Changes in isometric tension were recorded in helical strips of the arteries, which were stimulated by transmurally applied electrical pulses or nicotine. The presence of perivascular nerve fibers containing reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase, acetylcholinesterase, and VIP immunoreactivity were determined histologically. RESULTS: Transmural electrical stimulation (2, 5, and 20 Hz) and nicotine produced a relaxation of the arterial strips denuded of the endothelium and contracted with prostaglandin F2alpha. The response was not influenced by timolol but was abolished by oxyhemoglobin and methylene blue. N(G)-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor, abolished the neurogenic relaxation, and L-arginine restored the response. Physostigmine inhibited, but atropine potentiated, the neurogenic response. The relaxation was attenuated by acetylcholine but was not influenced by VIP. There were nerve fibers and bundles containing NADPH diaphorase, acetylcholinesterase, and VIP immunoreactivity in the adventitia of ciliary arteries.
CONCLUSIONS: Porcine ciliary arteries are innervated by NO synthase-containing nerves that liberate NO, possibly as a neurotransmitter on excitation to produce muscular relaxation. Nitroxidergic nerve function is inhibited by acetylcholine released from cholinergic nerve, possibly because of impaired production or release of NO. VIP does not seem to function as a neurotransmitter or a modulator.
ESTHER : Toda_1997_Invest.Ophthalmol.Vis.Sci_38_2261
PubMedSearch : Toda_1997_Invest.Ophthalmol.Vis.Sci_38_2261
PubMedID: 9344349