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Inhibition of acetylcholinesterase by traditional Chinese medical plants: A new source of potential drugs for treating Alzheimer's disease

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Inhibition of acetylcholinesterase by traditional Chinese medical plants: A new source of potential drugs for treating Alzheimer's disease
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  the RA-treated group, but A b  plaque deposition was not significantly de-creased. In the FA-treated group, there was no significant difference in theA b  profile.  Conclusions:  Our results revealed that the phenolic com-pounds inhibited A b  aggregation  in vitro , and prevented the development of AD pathology by affecting different A b  aggregation pathways  in vivo .Clinical trials with these compounds are necessary to confirm the anti-ADeffects and safety in humans. O4-01-04 BENEFICIAL EFFECTS OFANGIOTENSIN IIRECEPTOR BLOCKERS ON METABOLICDISORDER-INDUCED COGNITIVE IMPAIRMENTJun Iwanami , Masaki Mogi, Kana Tsukuda, Li-Juan Min, Akiko Sakata,Fei Jing, Masaru Iwai, Masatsugu Horiuchi,  Ehime University GraduateSchool of Medicine, Tohon, Ehime, Japan. Contact e-mail: iwanami@m.ehime-u.ac.jp Background:  Recent basic and clinical evidence indicate that renin-angio-tensin system (RAS) is involved in metabolic syndrome and diabetes mel-litus (DM) as well as hypertension. Metabolic syndrome and DM havebeen reported to be crucial risk factor for cognitive impairment includingAlzheimer’s disease. Increasing number of patients with metabolic syn-drome and DM suggests that such cognitive decline will become a major worldwide clinical problem in the future. Here, we investigated the rolesof angiotensin II and effect of angiotensin II receptor blockers (ARB) incognitive function.  Methods:  Various mice models were employed.C57BL/6J mice with normal diet (ND), C57BL/6J mice with high-salt and high-cholesterol diet (HCD) as metabolic syndrome-like state, KK-Ay mice as type 2DM, and Tsukuba-Hypertensive-Mice (THM) as humanangiotensin II overproducing model were employed in this study. Thesemice were subjected to passive avoidance task every week with or without ARB.  Results:  1) HCD mice showed a significant reduction of avoidancerate compared with ND mice. This impairment was prevented by treatment with non-hypotensive dose of ARB, olmesartan, partly due to a decreasein superoxide anion production. 2) Learning ability evaluated by an in-crease in avoidance rate was less in KK-Ay mice and significant cognitiveimpairment was observed after 14 weeks-old. Administration of non-hypo-tensive dose of candesartan from 8 weeks-old markedly improved learningability and its administration from 14 weeks-old prevented further cogni-tive decline. Candesartan significantly decreased serum glucose and insu-lin levels and increase glucose-uptake in the brain. 3) THM exhibiteda failure to increase the avoidance rate compared with control mice. Treat-ment with ARB, olmesartan, which decreases blood pressure to the samelevel as C57BL/6J, improved the avoidance rate. However, treatment withhydralazine for the THM did not show an improvement of avoidance ratealthough hydralazine decreased blood pressure to the same level of olme-sartan treatment. Olmesartan attenuated superoxide anion production in thebrain and improved the reduction of cerebral blood flow observed inTHM.  Conclusions:  These results suggest that brain RAS plays an impor-tant role in cognitive function. Regulation of RAS using ARB is expectedto prevent cognitive decline associated with metabolic syndrome, DM andhypertension. O4-01-05 INHIBITION OFACETYLCHOLINESTERASE BYTRADITIONAL CHINESE MEDICAL PLANTS: ANEW SOURCE OF POTENTIAL DRUGS FORTREATING ALZHEIMER’S DISEASEDorothea Kaufmann 1 , Anudeep Kaur Dogra  2 , Ahmed Tahrani 3 ,Florian Herrmann 3 , Michael Wink 3 ,  1  Ruprecht-Karls-University Heidel-berg, Institute of Pharmacy and Molecular Biotechnology, Department of  Biology, Heidelberg, Germany;  2 Centre for Pharmacognosy and Phyto-therapy, The School of Pharmacy, University of London, London, United  Kingdom;  3  Ruprecht-Karls-University Heidelberg, Institute of  Pharmacy and Molecular Biotechnology, Heidelberg, Germany.Contact e-mail: D.Kaufmann@uni-heidelberg.de Background:  Inhibition of acetylcholinesterase (AChE) is a common treat-ment for early stages of the most general form of dementia, Alzheimer’s Dis-ease (AD). When AChE is inhibited, more acetylcholine is available in thesynaptic cleft, resulting in an improvement of cognitive function. Althoughthe therapy with AChE inhibitors (AChEI) is considered to be only symp-tomatic, these medications are still the first choice for treating AD patientsin early stages of the disease.  Methods:  In this study, methanolic, dichloro-methane and aqueous crude extracts from 84 Traditional Chinese Medical(TCM) plants were tested for   in vitro  anti-acetylcholinesterase activity basedon Ellman’s colorimetric assay. Identity of the plants was assured by DNAbarcoding. Thin layer chromatography (TLC) and mass spectrometry (MS)were performed to gain a first insight into the chemical compounds of theTCM plant extracts used.  Results:  Five TCM plants showed a strong inhib-itory activity of AChE. Extracts from  Coptis  spp.,  Capsella bursa-pastoris ,  Mahonia baelei ,  Phellodendron  spp. and  Polygonum multiflorum  exhibiteda distinctive AChE inhibition with  Mahonia bealei  and  Phellodendron  spp.featuring this inhibitory activity in all three extracts. Seven of these TCMplant extracts exhibited EC 50  values ranging from 0.021  m g/ml to 8.7  m g/ ml, therefore showing a stronger AChE inhibition than the already knownAChEI galanthamine (EC 50  ¼  51.1  m g/ml).  Conclusions:  These findingssuggest that Traditional Chinese Medical plants represent an important source of natural compounds that affect the activity of AChE, which might be interesting drug candidates to slow down the progression of AD. O4-01-06 A RANDOMIZED, DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL OF SIMVASTATIN ON CSF,MRI, AND COGNITIVE BIOMARKERS IN MIDDLE-AGED ADULTS AT RISK FOR ALZHEIMER’SDISEASE: THE ESPRIT STUDYCynthia M. Carlsson 1,2 , Carey E. Gleason 1,2 , Sterling C. Johnson 1,2 ,Guofan Xu 1 , Yin Huang 1 , Jodi Barnet  1,2 , Sean Fain 1 , Hanna Blazel 1,2 ,Henrik Zetterberg 3 , Ka  j Blennow 3 , Bruce P. Hermann 1,2 ,N. Maritza Dowling 1,2 , George C. Newman 4 , Luigi Puglielli 1,2 ,Craig S. Atwood 1,2 , Howard Rowley 1,2 , Mark Sager  1,2 , Sanjay Asthana  1,2 , 1 University of Wisconsin School of Medicine and Public Health, Madison,WI, USA;  2 Wisconsin Alzheimer’s Disease Research Center (ADRC), Madison, WI, USA;  3 Sahlgrenska Academy at University of Gothenburg, Molndal, Sweden;  4  Albert Einstein Medical Center, Philadelphia, PA, USA.Contact e-mail: cmc@medicine.wisc.edu Background:  b -amyloid (A b ) dysregulation, cerebral hypoperfusion, andinflammation all contribute to the development of Alzheimer’s disease(AD). Statins beneficially modify these processes in animal models, but it is unclear if these medications favorably alter these mechanisms in asymp-tomatic persons at risk for AD. We investigated whether simvastatin modi-fied CSF A b levels, regional cerebral perfusion, inflammation, and cognitiveperformance in asymptomatic middle-aged adults with parental history of AD. Methods: Onehundredasymptomatic middle-aged adultswithparentalhistoryof ADwere enrolledinto a single-site,9-month,randomized, double-blind, placebo-controlled trial assessing the impact of simvastatin 80 mgdaily vs. placebo on CSF A b  levels, MRI regional perfusion, CSF andplasma inflammation, and cognitive function.The primary outcome measurewas change in CSF A b 42. At baseline and month 9, all participants had CSFcollected for A b 42, A b 40, total tau, phosphorylated tau-181, and interleu-kin-6 (IL-6); blood collected for lipoprotein analysis, high-sensitivity c-reac-tive protein and IL-6; and cognitive measures of memory, language,executive function, and visuospatial skills. Fifty subjects also underwent dy-namic susceptibility contrast MRI at baseline and month 9 (MRI sub-study)to assess regional perfusion. Mixed effects modeling was used to accesstreatment and interaction effects.  Results:  Mean (SD) baseline participant characteristics (n  ¼  100) were: age 53.5 (8.0) years, education 16.2 (2.9)years, MMSE 29.5 (0.7), 70% women, 38%  APOE4  carriers, total choles-terol 190.2 (32.4), LDL 118.6 (28.8), HDL 55.7 (16.4) mg/dL. Ninety-two participants (92%) completed the 9-month trial (47 [94%] in MRI sub-study). Simvastatin reduced mean LDL cholesterol by 40%. Persons ran-domized to simvastatin (n  ¼  51) had similar changes in the primary Oral O4-01: Therapeutics/Therapeutic Strategy Mechanisms and Trials  S151
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