Effects Of Acetylcholinesterase Inhibitors Research Articles

Phytochemical prospecting, vitamins, total phenolics and flavonoids, and antioxidant and acetylcholinesterase activities of Scleroderma citrinum Persoon (Sc) mushroom extract

Scleroderma is a genus of Gasteromycetes and Basidiomycota mushrooms in tropical and subtropical regions. This study aimed to evaluate the ethanolic extract of the mushroom Scleroderma citrinum regarding phytochemical prospecting, vitamin, phenolic, and total flavonoid content, and antioxidant (FRAP and DPPH) and acetylcholinesterase (AChE) inhibition activities. Fruiting bodies of S. citrinum were collected and the ethanolic extract was produced by maceration. Phytochemical prospecting was performed for several phytochemical groups using colorimetric means; the content of vitamins A, B, C, D, and E was obtained qualitatively by colorimetric methods, the content of phenolic and flavonoids by the colorimetric method and quantification by spectrophotometry. The spectrophotometric method performed the antioxidant activity in reducing FRAP and DPPH radicals by spectrophotometry and the acetylcholinesterase inhibition activity. Seventeen positive phytochemical groups were observed, the qualitative presence of vitamins of the A, B, and D complexes, 195.03 mg GAE g-1 of total phenolics, 93.10 mg QE g-1 of total flavonoids, FRAP reduction of 3.941 µM TE g-1, DPPH reduction of 127.78 µg mL-1 and AChE inhibition of 55.6%. The extract of the mushroom Scleroderma citrinum proved to be rich in phytocompounds, vitamins, and important biological antioxidant and acetylcholinesterase inhibition effects.

Effect of acetylcholinesterase inhibition on immune cells in the murine intestinal mucosa

The gastrointestinal tract (GI) is the largest immune organ whose function is controlled by a complex network of neurons from the enteric nervous system (ENS) as well as the sympathetic and parasympathetic system. Evolving evidence indicates that cross-communication between gut-innervating neurons and immune cells regulates many essential physiological functions including protection against mucosal infections. We previously demonstrated that following paraoxon treatment, 70 % of the mice were able to survive an oral infection with S. typhimurium, a virulent strain of Salmonella enterica serovar Typhimurium. The present study aims to investigate the effect that rivastigmine, a reversible AChE inhibitor used for the treatment of neurodegenerative diseases, has on the murine immune defenses of the intestinal mucosa. Our findings show that, similar to what is observed with paraoxon, administration of rivastigmine promoted the release of secretory granules from goblet and Paneth cells, resulting in increased mucin layer. Surprisingly, however, and unlike paraoxon, rivastigmine treatment did not affect overall mortality of infected mice. In order to investigate the mechanistic basis for the differential effects observed between paraoxon and rivastigmine, we used multi-color flowcytometric analysis to characterize the immune cell landscape in the intraepithelial (IE) and lamina propria (LP) compartments of intestinal mucosa. Our data indicate that treatment with paraoxon, but not rivastigmine, led to an increase of resident CD3+CD8+ T lymphocytes in the ileal mucosa (epithelium and lamina propria) and CD11b− CD11c+ dendritic cells in the LP. Our findings indicate the requirement for persistent cholinergic pathway engagement to effect a change in the cellular landscape of the mucosal tissue that is necessary for protection against lethal bacterial infections. Moreover, optimal protection requires a collaboration between innate and adaptive mucosal immune responses in the intestine.

Lathyrane and premyrsinane Euphorbia diterpenes against Alzheimer's disease: Bioinspired synthesis, anti-cholinesterase and neuroprotection bioactivity

The first systematic acylated diversification of naturally scarce premyrsinane diterpenes, together with their biosynthetic precursors lathyrane diterpene were carried out. Two new series of premyrsinane derivates (1a-32a) and lathyrane derivates (1–32) were synthesized from the naturally abundant lathyrane diterpene Euphorbia factor L3 through a bioinspired approach. The cholinesterase inhibitory and neuroprotective activities of these diterpenes were investigated to explore potential anti-Alzheimer's disease (AD) bioactive lead compounds. In general, the lathyrane diterpenes showed the better acetylcholinesterase (AChE) inhibitory activity than that of premyrsinanes. The lathyrane derivative 17 bearing a 3-dimethylaminobenzoyl moiety showed the best AChE inhibition effect with the IC50 value of 7.1 μM. Molecular docking demonstrated that 17 could bond with AChE well (−8 kal/mol). On the other hand, premyrsinanes showed a better neuroprotection profile against H2O2-induced injury in SH-SY5Y cells. Among them, the premyrsinane diterpene 16a had significant neuroprotective effect with the cell viability rate of 113.5 % at 12.5 μM (the model group with 51.2 %). The immunofluorescence, western blot and reactive oxygen species (ROS) analysis were conducted to demonstrate the mechanism of 16a. Furthermore, a preliminary SAR analysis of the two categories of diterpenes was performed to provide the insights for anti-AD drug development.

Safety and efficacy of acetylcholinesterase inhibitors for Alzheimer's disease: A systematic review and meta-analysis.

Alzheimer's disease (AD) affects millions of people worldwide. The most commonly used drugs are acetylcholinesterase inhibitors, i.e., donepezil, galantamine and rivastigmine, which increase levels of acetylcholine. However, the exact efficacy and safety of acetylcholinesterase inhibitors in the treatment of AD is still unclear. The main objective of the current study was to determine the exact safety and efficacy profile of acetylcholinesterase inhibitors in the treatment of AD by conducting a systematic review and meta-analysis of clinical trials according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We conducted a web-based literature search of PubMed and clinical trial websites using relevant keywords. Data were extracted from eligible records and pooled as mean difference (MD) or risk ratio (RR) values with their 95% confidence interval (95% CI) using Review Manager software (v. 5.3 for Windows). Heterogeneity was calculated using χ2 and I2 tests. The standard mean difference (SMD) was -0.33 [-0.52, -0.13] for donepezil, -0.48 [-0.58, -0.38] for galantamine and -0.65 [-1.06, -0.23] for rivastigmine, indicating a significant effect of these drugs on cognitive outcomes. Here we show the significant effects of all available acetylcholinesterase inhibitors on cognitive function in patients with AD. However, further studies are needed to draw valid conclusions about the effects of acetylcholinesterase inhibitors on functional outcomes and adverse events.

Study on the effectiveness of acetylcholinesterase inhibitors in the treatment of primary progressive logopenic aphasia

AbstractBackgroundFor over 25 years, cholinesterase inhibitors (ChEIs) have been the main symptomatic treatment for Alzheimer’s disease (AD). Several meta‐analyses have supported their effectiveness in various neurocognitive aspects of amnestic AD. Over 86% of cases of the logopenic variant of primary progressive aphasia (lvPPA) are caused by a similar pathologic process than AD, yet no study has examined the efficacy of ChEIs in this AD variant. We aimed to explore the efficacy of ChEIs in the treatment of lvPPA by comparing their longitudinal MMSEs to that of treated amnestic AD patients.MethodA retrospective chart review was performed on 48 patients with lvPPA and 52 patients with amnestic AD. Both groups were similar with respect to age, level of education, and onset of symptoms. Drug history and MMSE scores were collected on several time points before and after the introduction of ChEIs.ResultsPatients with lvPPA showed a similar trajectory of decline than amnestic AD patients on serial MMSEs (both WORLD and 100‐7) up to twelve months after the introduction of ChEIs (Figure 1 and 2).ConclusionThis study provides preliminary evidence for efficacy of ChEIs in patients with lvPPA and suggests similar benefits to those seen in amnestic AD patients.

Effects of acetylcholinesterase inhibition with pyridostigmine on cardiovascular system in spontaneously hypertensive rat

Effects of acetylcholinesterase inhibition with pyridostigmine on cardiovascular system in spontaneously hypertensive rat

BIOCHEMICA INVESTIGATION OF THE PHARMACEUTICAL AND COSMETIC USE OF NARCISSUS (Narcissus tazetta L. subsp. tazetta L.) GROWING NATURALLY AROUND IN MUĞLA, TURKEY

Amaryllidaceae is a monocot plant family represented in the world with approximately 85 genera and 1100 species, which has a great economic value as an ornamental plant, as well as plants that are widely used in treatment [1,2]. Narcissus L. species, a member of the Amaryllidaceae family, are perennial, herbaceous plants with bulbs that bear fragrant flowers and up to 30 different species grow naturally in Western Europe, the Mediterranean Region, China and Japan [3,4]. 
 Amaryllidaceous plants have biological activities of medical uses, and their alkaloids have wide applications worldwide [5, 6, 7]. These alkaloids are a group of secondary metabolites on which many studies have been carried out due to their biogenesis, pharmacological and physiological activities. Until today, more than 500 Amaryllidaceae alkaloids have been isolated from different plants of the family, and modern phytochemical studies have shown that these alkaloids are responsible for many pharmacological activities [5, 8, 9, 10]. Due to their similarity to morphine and codeine skeletons, they have high analgesic effects. Among the pharmacological activities, including anti-cholinesterasic, antifungal, anti-inflammatory, cytotoxic, anticancer, antiplatelet, antifeedantan, antiparasitic and antiviral [5, 11]. In the Narcissus genus, the alkaloids found are divided into eight groups according to their skeleton type. These groups, according to the name of the representing alkaloid; It is expressed as norbelladin, lycorine, homolicoline, hemantamine, narciclasin, tazettin, pancracin and galantamine [5]. Among these alkaloids, especially galantamine, analgesic [12], antiviral, cytotoxic [13], antimicrobial and antioxidant [14]. activities have been reported, and it is known to be used in the treatment of Alzheimer's due to its acetylcholinesterase inhibition effect [15]. Apart from these known therapeutic effects of the plant, it is a valuable main product in the cosmetic industry. In ancient times, in the Aegean region, it was grown and essence was obtained from its flowers [4].
 The aim of this work was to perform collect the Narcissus flower, which grows naturally in Muğla and its surroundings in February-April and draws attention with its scent, to determine some of its bioactivities and to conduct research on the purification of the protease enzyme for pharmaceuticals effects, as well as to research the use of the plant in this field by making a perfume design for the cosmetic industry.

Novel Mannich bases with strong carbonic anhydrases and acetylcholinesterase inhibition effects: 3-(aminomethyl)-6-{3-[4-(trifluoromethyl)phenyl]acryloyl}-2(3H)-benzoxazolones.

In this study, a new series of Mannich bases, 3-(aminomethyl)-6-{3-[4-(trifluoromethyl)phenyl]acryloyl}-2( 3H )-benzoxazolones ( 1a–g ), were synthesized by the Mannich reaction. Inhibitory effects of the newly synthesized compounds towards carbonic anhydrases (CAs) and acetylcholinesterase (AChE) enzymes were evaluated to find out new potential drug candidate compounds. According to the inhibitory activity results, Ki values of the compounds 1 and 1a–g were in the range of 12.3 ± 1.2 to 154.0 ± 9.3 nM against hCA I, and they were in the range of 8.6 ± 1.9 to 41.0 ± 5.5 nM against hCA II. Ki values of acetazolamide (AZA) that was used as a reference compound were 84.4 ± 8.4 nM towards hCA I and 59.2 ± 4.8 nM towards hCA II. Ki values of the compounds 1 and 1a–g were in the range of 35.2 ± 2.0 to 158.9 ± 33.5 nM towards AChE. Ki value of Tacrine (TAC), the reference compound, was 68.6 ± 3.8 nM towards AChE. Furthermore, docking studies were done with the most potent compounds 1d , 1g , and 1f (in terms of hCA I, hCA II, and AChE inhibition effects, respectively) to determine the binding profiles of the series with these enzymes. Additionally, the prediction of ADME profiles of the compounds pointed out that the newly synthesized compounds had desirable physicochemical properties as lead compounds for further studies.

Acetylcholinesterase Inhibition Attenuates Lipopolysaccharide‐Induced Hypotension in Unanesthetized Hypertensive Rats

Background Hypertension and sepsis are highly prevalent clinical risk factors for morbidity and mortality. Administration of lipopolysaccharide (LPS) induces systemic inflammation (SI) and phathophysiological changes observed during sepsis, such as exacerbated release of inflammatory markers associated with hypotension, tachycardia, and hypothermia followed by fever. We have previously shown that both LPS-induced hypothesion and hypothermia are enhanced in hypertensive rats. Increased availability of acetylcholine may reduce inflammation. However, whether acetylcholinesterase inhibition modulates SI and its cardiovascular and thermorregulatory consequences in neurogenic hypertension remains unkonwn. Aim This study aimed to investigate the putative anti-inflammatory property of pyridostigmine (PIR), an acetylcholinesterase inhibitor, on cardiovascular and thermoregulatory changes observed during LPS-induced SI (at a septic-like model) in spontaneously hypertensive rats (SHR). Methods Wistar and SHR rats were used in the present study. Forty-eight hours before cardiovascular and deep body temperature (Tb) recordings, the animals underwent the surgery for femoral artery (for direct hemodynamic recordings) and vein catheterization for PIR (0.25 mg kg-1), LPS (1.5mg kg−1), or saline administration. In the same surgical procedure, an intraperitoneal temperature data-logger capsule was inserted for Tb recordings. We combined hemodynamic and thermoregulatory recordings after LPS administration and plasma measurements of interleukin (IL)-1β and IL-6. Results SI in Wistar rats was marked by a drop in blood pressure (2 ± 2 vs. −12 ± 2 mmHg, P < 0.0001). Compared with Wistar, LPS-induced drop in blood pressure was higher in SHR (−44 ± 4 vs. 2 ± 2 mmHg, P < 0.0001). PIR attenuated LPS-induced hypotension in Wistar (-12 ± 2 vs. 4 ± 3 mmHg, P = 0.0048) and SHR rats (-44 ± 4 vs. -23 ± 4 mmHg, P = 0.0016). LPS induced hypothermia followed by fever in Wistar rats (37.5 ± 0.2 vs. 38.9 ± 0.2ºC, P < 0.0001), whereas, in SHR, a maintained hypothermia without fever was observed (36.4 ± 0.2ºC). PIR attenuated fever in Wistar rats (38.9 ± 0.2 vs. 38.0 vs. 0.2ºC, P = 0.0015), but did not affect LPS-induced hypothermia in SHR (36.6 ± 0.1ºC). After LPS administration, Wistar rats showed significant plasma IL-1β (1393 ± 218 vs. 49 ± 12 pg mL−1, P < 0.0001) and IL-6 surges (44732 ± 5870 vs. 144 ± 13, P < 0.0001), and this increase was prevented by PIR pretreatment (1393 ± 218 vs. 430 vs. 98 pg mL−1, P = 0.0018 and 44732 ± 5870 vs. 18280 vs. 4123 pg mL−1, P = 0.0438). This anti-inflammatory effect of PIR was not observed in SHR. Conclusion The findings of the present study are consistent with the notion that pretreatment with an acetylcholinesterase inhibitor (PIR) attenuates the plasma IL-1β and IL-6 surges, hypotension, and fever in Wistar rats. On the other hand, PIR attenuated hypotension without preventing hypothermia, and plasma pro-inflammatory cytokines surges in SHR. We suggest that increased acetylcholine availability reduces LPS-induced SI in Wistar, but not in SHR. These findings reveal a novel effect of acetylcholinesterase inhibition during SI in normotensive and hypertensive rats.

The State of The Art on Acetylcholinesterase Inhibitors in the Treatment of Alzheimer's Disease.

Alzheimer’s disease (AD) is a chronic disabling disease that affects the central nervous system. The main consequences of AD include the decline of cognitive functions and language disorders. One of the causes leading to AD is the decrease of neurotransmitter acetylcholine (ACh) levels in the brain, in part due to a higher activity of acetylcholinesterase (AChE), the enzyme responsible for its degradation. Many acetylcholinesterase inhibitors (AChEIs), both natural and synthetic, have been developed and used through the years to counteract the progression of the disease. The first of such drugs approved for a therapeutic use was tacrine, that binds through a reversible bond to the enzyme. However, tacrine has since been withdrawn because of its adverse effects. Currently, donepezil and galantamine are very promising AChEIs with clinical benefits. Moreover, rivastigmine is considered a pseudo-irreversible compound with anti-AChE action, providing similar effects at the clinical level. The purpose of this review is to provide an overview of what has been published over the last decade on the effectiveness of AChEIs in AD, analysing the most relevant issues under the clinical and methodological profiles and the consequent possible welfare effects for the whole world. Furthermore, novel drugs and possible therapeutic approaches are also discussed.

Evaluation of the effects of acetylcholinesterase inhibitors in the zebrafish touch-evoked response: quantitative vs. qualitative assessment

BackgroundThe difficulty of finding new treatments for neurological diseases with great impact in our society like Alzheimer’s disease can be ascribed in part to the complexity of the nervous system and the lack of quick and cost-effective screening tools. Such tools could not only help to identify potential novel treatments, but could also be used to test environmental contaminants for their potential to cause neurotoxicity. It has been estimated that 5–10% of the anthropogenic chemicals are developmental neurotoxic (DNT) and exposure to DNT compounds has been linked to several neurological diseases. Within this study we were testing the applicability of a quick and cost-effective behavioural test using zebrafish embryos: the touch-evoked response assay, in this case, an assay evaluating the swimming response to a tap in the tail. Two acetylcholinesterase (AChE) inhibitors positive controls (paraoxon and huprine Y), as well as 10 huprine-derivative compounds were tested and the results were evaluated using 2 different methods, a quantitative and a qualitative one.ResultsWe could show that the methodology presented is able to detect behavioural effects of AChE inhibitors. A good correlation between the results obtained with the quantitative and the qualitative method was obtained (R2 = 0.84).ConclusionsOur proposed method enables combination of screening for new drugs with toxicity screening in a whole embryo model alternative to animal experimentation, thereby merging 2 drug development steps into one.

Scopolamine 유발 기억 손상 마우스에서 익모초의 효과

Cognitive impairment is symptoms of dementia, a degenerative brain disease that is drawing attention in a rapidly aging society. This study was conducted to investigate the improvement of cognitive function of Leonurus japonicus on scopolamine-induced memory impairment in mice and the effect and mechanism of memory recovery. In vivo studies were conducted on mice orally pretreated with L. japonicus in doses of 50, 100 and 200 ㎎/㎏ (p.o.) and scopolamine (1 ㎎/㎏, i.p.) were injected 30 min before the behavioral task. Antioxidant activity was assessed by 2,2-diphenyl-1-picryl hydrazyl (DPPH) assay and 2,2-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assay, and acetylcholinesterase (AChE) inhibition activity evaluated by Ellman’s method. In behavior studies showed that L. japonicus has an improved the memory of scopolamine-treated mice in Y-maze, passive avoidance and Morris water maze test. In addition, L. japonicus was also exerted free radical scavenging activity and inhibited acetyl cholinesterase activity. These results suggest that L. japonicus improves short-term and long-term memory in scopolamine-induced memory decline model and prevents scopolamine-induced memory impairments through in reduced oxidative stress and acetyl cholinesterase inhibition effect. Thus, L. japonicus is related to functional medicinal materials for prevention and treatment of human dementia patients.

Novel Cinnamoylated Flavoalkaloids Identified in Tea with Acetylcholinesterase Inhibition Effect.

3-O-Cinnamoylepicatechin (1) was synthesized along with four flavoalkaloids, (-)-6-(5‴S)-N-ethyl-2-pyrrolidinone-3-O-cinnamoylepicatechin (2), (-)-6-(5‴R)-N-ethyl-2-pyrrolidinone-3-O-cinnamoylepicatechin (3), (-)-8-(5‴S)-N-ethyl-2-pyrrolidinone-3-O-cinnamoylepicatechin (4), and (-)-8-(5‴R)-N-ethyl-2-pyrrolidinone-3-O-cinnamoylepicatechin (5) via esterification of epicatechin followed by phenolic Mannich reaction of 1 with theanine in the presence of heat. The new compounds 1-5 were detected in leaves of three tea cultivars, Fuding-Dabai, Huangjingui, and Zimudan with the help of ultra-performance liquid chromatography hyphenated with a photodiode array detector and electrospray ionization high-resolution mass spectrometry (UPLC-PDA-ESI-HRMS), suggesting that they are naturally occurring in tea leaves. The structures of the novel natural products were characterized by one- and two-dimensional nuclear magnetic resonance (1D and 2D NMR) and mass spectroscopy. Compounds 1-5 were then evaluated for their acetylcholinesterase (AChE) inhibitory effect (IC50 = 0.12-1.02 μM). The availability of the synthesized epicatechin derivatives 1-5 via a synthetic route enabled the first unequivocal identification of these derivatives as tea secondary metabolites and made it possible to determine their content in the tea material as well as the diverse bioactivities.

Effect of acetylcholinesterase inhibitors on post-stroke cognitive impairment and vascular dementia: A meta-analysis.

Cognitive impairment is a common complication observed after a stroke. Currently there are no definitively proven pharmacologic therapies for recovery from post-stroke cognitive impairment and vascular dementia. In this meta-analysis, we evaluated the efficacy and safety of cholinesterase inhibitors in their improvement of cognition in patients with post-stroke cognitive impairment and vascular dementia. We conducted a meta-analysis using seven eligible studies from 305 published articles. We investigated the differences in Mini–Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores, before and after cholinergic augmentation in patients with post-stroke cognitive impairment and vascular dementia. MMSE and ADAS-cog scores were also compared during the subsequent follow-up periods. MMSE score of patients with post-stroke cognitive impairment was increased after cholinergic augmentation throughout the 24 weeks with mean differences [MD] of 3.000, 1.732, 1.578 1.516, and 1.222, at 4, 4–8, 8–12, 12–18, and 18–24 weeks, respectively. In addition, ADAS-cog scores decreased at 6, 12, 18, and 24 weeks by pharmaceutical augmentation, but not with placebo with mean differences [MD] of -2.333, -2.913, -2.767, -2.416, and -1.859, respectively. This meta-analysis shows that acetylcholinesterase inhibitors maintain a stable pattern of improved cognitive function in patients with post stroke cognitive impairment and vascular dementia without the increased risk of side effects.

Antitumoral and Anticholinesterasic Activities of the Seven Species from Rubiaceae.

The genus Psychotria and Palicourea are reported as a source of alkaloids and iridoids, which exhibit biological activities. This study aimed to evaluate antiproliferative and anticholinesterase activities and quantification of the alkaloids of seven species among the genus found in Mato Grosso do Sul region in Brazil. Concentrations of alkaloids were measured spectrophotometrically. The extracts were submitted to antiproliferative activity against ten cell lines. The anticholinesterase activity of the extracts was developed using brain structures of male Wistar rats: cerebral cortex, hippocampus, hypothalamus and striatum by the Ellman method. Alkaloids from Psychotria and Palicourea species were quantified which showed values of 47.6 to 21.9 µg/g. Regarding the antiproliferative potential, Palicourea crocea demonstrated selectivity against the 786-0 cell line (GI50: 22.87 µg/mL). Psychotria leiocarpa inhibited cell growth against OVCAR-3 (GI50: 3.28 µg/mL), K-562 (GI50: 5.26 µg/mL), HaCaT (GI50: 27.20 µg/mL), PC-3 (GI50: 34.92 µg/mL), MCF-7 (GI50: 35.80 µg/mL) and P. capillacea showed activity against OVCAR-3 (GI50: 2.33 µg/ml) and U251 (GI50: 16.66 µg/ml). The effect of acetylcholinesterase inhibition was more effective in the hippocampus, demonstrating inhibition for Paliourea crocea, Psychotria deflexa, P. brachybotrya and P. leiocarpa of 70%, 57%, 50% and 40%, respectively, followed by P. poeppigiana and P. capillacea, inhibiting 21%, compared to the control. Herein, the present work showed for the first time, anticholinesterasic and antiproliferative activities of extracts of Palicourea and Psychotria seem to be mainly associated with the levels of alkaloids in the leaves of these species.

Effect of acetylcholinesterase inhibitors in the Alzheimer patients on the daily cardiovascular neurovegetative assessment

Effect of acetylcholinesterase inhibitors in the Alzheimer patients on the daily cardiovascular neurovegetative assessment

Synthesis and characterization of novel substituted thiophene derivatives and discovery of their carbonic anhydrase and acetylcholinesterase inhibition effects.

Novel substituted thiophene derivatives (1, 2a-e, 3, and 4) were synthesized and their structures were characterized by infrared radiation, nuclear magnetic resonance, and mass analysis. These novel substituted thiophene derivatives were effective inhibitor compounds of the carbonic anhydrase I and II isozymes (hCA I and II), and acetylcholinesterase (AChE) enzyme with K i values in the range of 447.28 to 1004.65 nM for hCA I, 309.44 to 935.93 nM for hCA II, and 0.28 to 4.01 nM for AChE, respectively. Novel substituted thiophene derivatives can be good candidate drugs for the treatment of some diseases like neurological disorders, epilepsy, glaucoma, gastric and duodenal ulcers, mountain sickness, or osteoporosis as carbonic anhydrase isozymes inhibitors, and for the treatment of Alzheimer's and Parkinson's diseases as acetylcholinesterase inhibitors.

Graphene-based enzyme-modified field-effect transistor biosensor for monitoring drug effects in Alzheimer’s disease treatment

A reduced graphene oxide-based enzyme-modified field-effect transistor (RGO-EnFET) was fabricated to study the enzymatic kinetics between acetylcholinesterase (AChE) and acetylcholine (ACh), which are related to the progression and treatment of Alzheimer’s disease (AD). The RGO-EnFET exhibited typical ambipolar transfer characteristics with a charge neutrality point (the Dirac point, VDirac) in an aqueous environment, and biological events occurring on the RGO surface were evaluated by observing the Dirac point shift (ΔVDirac) according to reactions. First, the pH sensitivity of the RGO-EnFET was measured to be 24.12 mV pH−1 for a pH range of 4–10 with excellent repeatability. Then, ACh quantification in the concentration range of 1 μM–10 mM was evaluated, with a linear slope of 13.9 mV dec−1 being obtained between ΔVDirac and the ACh concentration on a logarithmic scale. The effects of AChE inhibitors (donepezil and rivastigmine) on the AChE enzymatic activity were also investigated. The distinguishable inhibition rates were acquired for donepezil and rivastigmine at saturation levels of 90% and 75%, respectively. These results indicate that the RGO-EnFET biosensor was successfully exploited as an in vitro analytical tool and has potential of future application in the study of enzymatic kinetics and drug screening for therapeutic purposes.

Cardiovascular Outcomes of Cholinesterase Inhibitors in Individuals with Dementia: A Meta-Analysis and Systematic Review.

To evaluate the cardiovascular (CV) effects of acetylcholinesterase inhibitors (AChEIs) in individuals with dementia DESIGN: Systematic review and meta-analysis. Two authors independently searched major electronic databases from inception until June 17, 2017, for longitudinal (without a control group) and cohort (with a control group) studies reporting CV outcomes in relation to AChEIs. Randomized controlled trials were excluded because they included relatively healthy subjects. Individuals with dementia and controls. Changes in CV parameters were summarized using standardized mean differences (SMDs) with 95% confidence intervals (CIs). Event rates were used to assess incidence of hypertension and bradycardia. Incidence of CV events in demented patients versus in healthy controls were compared using hazard ratios (HRs). Of 4,588 initial hits, 31 studies including 258,540 individuals with dementia and 2,246,592 controls were analyzed. In longitudinal and open-label studies, AChEIs were associated with a significantly greater incidence of hypertension (n=1,573, 4%, 95% CI=2-8%, I2 =47%) and bradycardia (n=13,703, 2%, 95% CI=1-6%, I2 =98%). AChEIs were associated with a decrease in heart rate (SMD=-1.77, 95% CI=-3.58-0.03, I2 =78%) and an increase in PR interval (SMD=0.10, 95% CI=0.008-0.19, I2 =3%) from baseline. During a median follow-up of 116 weeks, AChEIs were associated with a significantly lower risk of CV events (stroke, acute coronary syndrome, CV mortality; HR=0.63, 95% CI=0.45-0.88, I2 =18%), without a significantly greater risk of bradycardic events (HR=1.40, 95% CI=0.76-2.59, I2 =98%). AChEI therapy may be associated with negative chronotropic and hypertensive effects but also with lower risk of CV events.

Adiponectin and sporadic Alzheimer's disease: Clinical and molecular links.

Obesity has been consistently associated with Alzheimer's disease (AD) though the exact mechanisms by which it influences cognition are still elusive and subject of current research. Adiponectin, the most abundant adipokine in circulation, is inversely correlated with adipose tissue dysfunction and seems to be a central player in this association. In fact, different signalling pathways are shared by adiponectin and proteins involved in AD pathophysiology and considerable amount of evidence supports its direct and indirect influence on β-amyloid and tau aggregates formation. In this paper we present a critical review of cellular, animal and clinical studies which have contributed to a more thorough understanding of the extent to which adiponectin influences the risk of developing AD as well as its progression. Finally, the effect of acetylcholinesterase inhibitors on circulating adiponectin levels, possible therapeutic applications and future research strategies are also discussed.