Profiling donepezil template into multipotent hybrids with antioxidant properties

Alzheimer’s disease is debilitating neurodegenerative disorder in the elderly. Current therapy relies on administration of acetylcholinesterase inhibitors (AChEIs) -donepezil, rivastigmine, galantamine, and N-methyl-d-aspartate receptor antagonist memantine. However, their therapeutic effect is only short-term and stabilizes cognitive functions for up to 2 years. Given this drawback together with other pathological hallmarks of the disease taken into consideration, novel approaches have recently emerged to better cope with AD onset or its progression. One such strategy implies broadening the biological profile of AChEIs into so-called multi-target directed ligands (MTDLs). In this review article, we made comprehensive literature survey emphasising on donepezil template which was structurally converted into plethora of MTLDs preserving anti-cholinesterase effect and, at the same time, escalating the anti-oxidant potential, which was reported as a crucial role in the pathogenesis of the Alzheimer’s disease.     

Is Drug Treatment for Dementia Followed Up in Primary Care? A Swedish Study of Dementia Clinics and Referring Primary Care Centres

Purpose

It is largely unknown how the medical treatment of patients diagnosed with dementia is followed up in primary care. Therefore, we studied patient medical records from two dementia clinics and from the referring primary care centres.

Methods

A retrospective study of 241 patients was conducted from April to October 2011 in north west Stockholm, Sweden. Over half (51.5%) of the patients had Alzheimer’s disease (AD), the remainder had mixed AD/vascular dementia (VaD). Eighty-four medical reports from primary care (35% of the study group) were analysed at follow-up 18 months after diagnosis.

Results

All four dementia drugs available on the Swedish market (three cholinesterase inhibitors [donepezil, rivastigmine and galantamine] and memantine) were prescribed at the two dementia clinics. The most commonly used dementia drug was galantamine. There were differences between the two dementia clinics in preference and combination of drugs and of treatment given to male and female patients. At follow-up, 84% were still on dementia medication. Drug use was followed up by the general practitioners (GPs) in two-thirds of the cases. Eighteen per cent of the GPs’ medical records made no reference to the patient’s dementia or treatment even though dementia drugs were included in the list of medications prescribed.

Conclusions

The results indicate that the Swedish guidelines for treatment of cognitive symptoms in AD are being followed in primary care. However, documentation of follow-up of drug treatment was sometimes insufficient, which calls for development of guidelines for complete medical records and medication lists.     

Synthesis and biological activity of derivatives of tetrahydroacridine as acetylcholinesterase inhibitors

Current state of medical sciences does not allow to treatment neurodegenerative diseases such as Alzheimer’s disease (AD). At present treatment of AD is severely restricted. The main class of medicines which are applied in AD is acetylcholinesterase inhibitors (AChEIs) like tacrine, donepezil, galantamine and rivastigmine that do not contribute to significant and long-term improvement in cognitive and behavioural functions.In this work, we report synthesis and biological evaluation of new hybrids of tacrine-6-hydrazinonicotinamide. The synthesis was based on the condensation reaction between tacrine derivatives and the hydrazine nicotinate moiety (HYNIC). All obtained compounds present affinity for both cholinesterases and are characterized by high selectivity in relation to butyrylcholinesterase (BChE).     

Potencies and selectivities of inhibitors of acetylcholinesterase and its molecular forms in normal and Alzheimer's disease brain

Eight inhibitors of acetylcholinesterase (AChE), tacrine, bis-tacrine, donepezil, rivastigmine, galantamine, heptyl-physostigmine, TAK-147 and metrifonate, were compared with regard to their effects on AChE and butyrylcholinesterase (BuChE) in normal human brain cortex. Additionally, the IC50 values of different molecular forms of AChE (monomeric, G1, and tetrameric, G4) were determined in the cerebral cortex in both normal and Alzheimer's human brains. The most selective AChE inhibitors, in decreasing sequence, were in order: TAK-147, donepezil and galantamine. For BuChE, the most specific was rivastigmine. However, none of these inhibitors was absolutely specific for AChE or BuChE. Among these inhibitors, tacrine, bis-tacrine, TAK-147, metrifonate and galantamine inhibited both the G1 and G4 AChE forms equally well. Interestingly, the AChE molecular forms in Alzheimer samples were more sensitive to some of the inhibitors as compared with the normal samples. Only one inhibitor, rivastigmine, displayed preferential inhibition for the G1 form of AChE. We conclude that a molecular form-specific inhibitor may have therapeutic applications in inhibiting the G1 form, which is relatively unchanged in Alzheimer's brain.     

The Acetylcholinesterase Inhibitors Competitively Inhibited an Acetyl l-Carnitine Transport Through the Blood–Brain Barrier

We investigated the interaction of acetylcholinesterase (AChE) inhibitors with acetyl-L-carnitine (ALCAR) transporter at the blood-brain barrier (BBB). ALCAR uptake by conditionally immortalized rat brain capillary endothelial cell lines (TR-BBB cells), as an in vitro model of BBB, were characterized by cellular uptake study using [(3)H]ALCAR. In vivo brain uptake of [(3)H]ALCAR was determined by brain uptake index after carotid artery injection in rats. In results, the transport properties for [(3)H]ALCAR by TR-BBB cell were consistent with those of ALCAR transport by the organic cation/carnitine transporter 2 (OCTN2). Also, OCTN2 was confirmed to be expressed in the cells. The uptake of [(3)H]ALCAR by TR-BBB cells was inhibited by AChE inhibitors such as donepezil, tacrine, galantamine and rivastigmine, which IC(50) values are 45.3, 74.0, 459 and 800 μM, respectively. Especially, donepezil and galantamine inhibited the uptake of [(3)H]ALCAR competitively, but tacrine and rivastigmine inhibited noncompetitively. Furthermore, [(3)H]ALCAR uptake by the rat brain was found to be significantly decreased by quinidine, donepezil and galantamine. Our results suggest that transport of AChE inhibitors such as donepezil and galantamine through the BBB is at least partly mediated by OCTN2 which is involved in transport of ALCAR.     

Study of neuroprotection of donepezil, a therapy for Alzheimer's disease

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 10muM) 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 10muM) decreased the LDH release in a concentration-dependent manner. In binding assay for glutamate receptors, donepezil at 100muM 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 10muM) 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.     

New performance of biosensor technology for Alzheimer's disease drugs: in vitro comparison of tacrine and 7-methoxytacrine

Two drugs were tested using electrochemical biosensor with immobilized acetylcholinesterase (AChE). The first was commercialized drug tacrine (known also as Cognex) used for treatment of cognitive manifestation of Alzheimer\'s disease (AD). The second one was its 7-methoxy derivate (7-MEOTA) that has not been marketed. We determined the IC50 (6.67+/-0.92)x10-7 M for tacrine and (1.66+/-1.43)x10-9 M for 7-MEOTA. In this in vitro study, 7-MEOTA acts as stronger inhibitor of AChE and in this way could be more favorable for treatment of cognitive manifestation of AD. Our study shows that biosensor technology could be used as a quick and cheap tool for testing of promising AChE inhibitors (AD drug candidates).     

No interaction of memantine with acetylcholinesterase inhibitors approved for clinical use

The loss of cholinergic neurons within the basal forebrain of patients with Alzheimer's disease (AD) may underlie aspects of the dementia. Excessive activation of N-methyl-D-aspartate (NMDA) receptors may underlie the degeneration of cholinergic cells. New drug therapies have been designed to either enhance cholinergic function by inhibition acetylcholinesterase (AChE), e.g. galanthamine, tetrahydroaminoacridine or donepezil, or by attenuation of NMDA receptor function, e.g. memantine. A combination of these two therapeutic approaches may be more beneficial at slowing the progression of the AD. The current study investigated whether memantine would attenuate the inhibition of AChE produced by these three drugs. The results indicate that these AChE inhibitors do not lose their therapeutic efficacy in combination with memantine. Our in vitro data suggest that the clinical combination of memantine with a reversible AChE inhibitor should be a valuable pharmacotherapeutic approach to dementia.     

Pharmacological therapy in Alzheimer's disease. Current clinical practice in The Netherlands

Pharmacological therapy in Alzheimer's disease. Current clinical practice in The Netherlands. Dementia affects 195,000 patients of 65 years and older in The Netherlands currently. Rivastigmine and galantamine, both cholinesterase inhibitors, and memantine, an NMDA (N-methyl-D-aspartate) antagonist, are licensed for the treatment of AD. In clinical practice, these drugs have limited effects on cognitive and other symptoms of dementia. We describe the practical care of some patients treated with these drugs and discuss the pros and cons of pharmacotherapy in AD. Extensive knowledge of the drugs, other treatment options and of dementia are necessary for good clinical practice in the treatment of these patients and the counselling of their caregivers.     

Current pharmacologic options for patients with Alzheimer's disease

BACKGROUND: The aim of the current study was to provide general practitioners with an overview of the available treatment options for Alzheimer's disease (AD). Since general practitioners provide the majority of medical care for AD patients, they should be well versed in treatment options that can improve function and slow the progression of symptoms. DESIGN: Biomedical literature related to acetylcholinesterase inhibitors (AChEIs) was surveyed. In the United States, there are four AChEIs approved for the treatment of AD: tacrine, donepezil, rivastigmine, and galantamine. There are other agents under investigation, but at present, AChEIs are the only approved drug category for AD treatment. MEASUREMENTS AND MAIN RESULTS: AD is becoming a major public health concern and underdiagnosis is a significant problem (with only about half of AD patients being diagnosed and only half of those diagnosed actually being treated). Clinical trials have demonstrated that patients with AD who do not receive active treatment decline at more rapid rates than those who do. CONCLUSIONS: Given that untreated AD patients show decline in three major areas (cognition, behavior, and functional ability), if drug treatment is able to improve performance, maintain baseline performance over the long term, or allow for a slower rate of decline in performance, each of these outcomes should be viewed a treatment success.     

In vitro inhibitory profile of NDGA against AChE and its in silico structural modifications based on ADME profile

Acetylcholinesterase (AChE) inhibitors are currently in focus for the pharmacotherapy of Alzheimer’s disease (AD). These inhibitors increase the level of acetylcholine in the brain and facilitate cholinergic neurotransmission. AChE inhibitors such as rivastigmine, galantamine, physostigmine and huperzine are obtained from plants, indicating that plants can serve as a potential source for novel AChE inhibitors. We have performed a virtual screening of diverse natural products with distinct chemical structure against AChE. NDGA was one among the top scored compounds and was selected for enzyme kinetic studies. The IC₅₀ of NDGA on AChE was 46.2 μM. However, NDGA showed very poor central nervous system (CNS) activity and blood–brain barrier (BBB) penetration. In silico structural modification on NDGA was carried out in order to obtain derivatives with better CNS activity as well as BBB penetration. The studies revealed that some of the designed compounds can be used as lead molecules for the development of drugs against AD

针灸联合多奈哌齐和美金刚对重度老年痴呆患者行为能力和认知功能的影响

目的:研究针灸联合多奈哌齐和美金刚对重度老年痴呆患者行为能力和认知功能的影响。方法:选择2015年1月～2018年12月在我院精神科进行诊治的50例重度老年痴呆患者,采用随机数字表法将其平均分为两组,每组25例。对照组患者口服多奈哌齐以及美金刚治疗,初始给药剂量均为每天口服5 mg,逐渐将给药剂量升高至每天口服20 mg,每次1片,每天2次。观察组患者采取针灸联合多奈哌齐和美金刚治疗,每天针灸治疗1次,每治疗6 d后休息1 d。两组患者均连续治疗4周。记录和比较两组患者治疗前后的日常生活能力与认知功能的变化情况。结果:观察组患者治疗4w后的治疗有效率为92.00%(23/25),明显高于对照组[68.00%(17/25)](P0.05);两组治疗4w后的MMSE和BI评分均显著高于治疗前(P0.05),且观察组以上指标均显著高于对照组(P0.05)。结论:针灸联合多奈哌齐和美金刚对重度老年痴呆患者的治疗效果明显优于单纯使用多奈哌齐和美金刚治疗,其可更有效改善患者的行为能力和认知功能。     

Effect of nootropic drugs on the dopamine release and dopamine uptake in structures of the rat striatum

Nootropics increase the overflow of dopamine from rat striatum slices in a concentration dependent manner, but without relation to their clinical effectiveness. The influence of a nootropic drugs and of amphetamine on the stimulus induced dopamine release points to a relationship between nootropic and nooanaleptic activity, on the one hand, and transmitter release, on the other. Dopamine re-uptake is not altered by nootropics like piracetam.     

Antibacterial combination therapy using Co3+, Cu2+, Zn2+ and Pd2+ complexes: Their calf thymus DNA binding studies

Four Co(III)-, Cu(II)-, Zn(II)-, and Pd(II)-based potent antibacterial complexes of formula K₃[Co(ox)₃].3H₂O (I), [Cu(bpy)₂Cl]Cl.5H₂O (II), [Zn(bpy)₃]Cl₂ (III), and [Pd(bpy)₂](NO₃)₂ (IV) (where ox is oxalate and bpy is 2,2′-bipyridine) were synthesized. They were characterized by elemental analyses, molar conductance measurements, UV–Vis, FTIR, ¹H NMR, and ¹³C NMR spectra. These metal complexes were ordered in three combination series of I + II, I + II + III, and I + II + III + IV. Antibacterial activity was tested for each of these four metal complexes and their combinations against Gram-positive and Gram-negative bacteria. All compounds were more potent antibacterial agents against the Gram-negative than those of the Gram-positive bacteria. The four metal complexes showed antibacterial activity in the order I > II > III > IV and the activity of their combinations followed the order of I + II + III + IV > I + II + III > I + II. CT-DNA binding studies of complex I and its three combinations were carried out using UV–vis spectral titration, displacement of ethidium bromide (EB), and electrophoretic mobility assay. The results obtained from UV–vis studies indicated that all series interact effectively with CT-DNA. Fluorescence titration revealed that the complexes quench DNA-EB strongly through the static quenching procedures. The binding constant (K_b), the Stern–Volmer constant (K_sv), and the number of binding sites (n) were determined at different temperatures of 293, 300, and 310 K, respectively. The calculated thermodynamic parameters supported that hydrogen binding and Van der Waals forces play a major role in association of each series of metal complexes with CT-DNA and follow the above-binding affinity order for the series.     

Synthesis and in vitro evaluation of N-alkyl-7-methoxytacrine hydrochlorides as potential cholinesterase inhibitors in Alzheimer disease

All approved drugs for Alzheimer disease (AD) in clinical practice ameliorate the symptoms of the disease. Among them, acetylcholinesterase inhibitors (AChEIs) are used to increase the cholinergic activity. Among new AChEI, tacrine compounds were found to be more toxic compared to 7-MEOTA (9-amino-7-methoxy-1,2,3,4-tetrahydroacridine). In this Letter, series of 7-MEOTA analogues (N-alkyl-7-methoxytacrine) were synthesized. Their inhibitory ability was evaluated on recombinant human acetylcholinesterase (AChE) and plasmatic human butyrylcholinesterase (BChE). Three novel compounds showed promising results towards hAChE better to THA or 7-MEOTA. Three compounds resulted as potent inhibitors of hBChE. The SAR findings highlighted the C₆–C₇ N-alkyl chains for cholinesterase inhibition.     

Uncovering the Molecular Mechanism of Actions between Pharmaceuticals and Proteins on the AD Network

This study begins with constructing the mini metabolic networks (MMNs) of beta amyloid (Aβ) and acetylcholine (ACh) which stimulate the Alzheimer’s Disease (AD). Then we generate the AD network by incorporating MMNs of Aβ and ACh, and other MMNs of stimuli of AD. The panel of proteins contains 49 enzymes/receptors on the AD network which have the 3D-structure in PDB. The panel of drugs is formed by 5 AD drugs and 5 AD nutraceutical drugs, and 20 non-AD drugs. All of these complexes formed by these 30 drugs and 49 proteins are transformed into dyadic arrays. Utilizing the prior knowledge learned from the drug panel, we propose a statistical classification (dry-lab). According to the wet-lab for the complex of amiloride and insulin degrading enzyme, and the complex of amiloride and neutral endopeptidase, we are confident that this dry-lab is reliable. As the consequences of the dry-lab, we discover many interesting implications. Especially, we show that possible causes of Tacrine, donepezil, galantamine and huperzine A cannot improve the level of ACh which is against to their original design purpose but they still prevent AD to be worse as Aβ deposition appeared. On the other hand, we recommend Miglitol and Atenolol as the safe and potent drugs to improve the level of ACh before Aβ deposition appearing. Moreover, some nutrients such as NADH and Vitamin E should be controlled because they may harm health if being used in wrong way and wrong time. Anyway, the insights shown in this study are valuable to be developed further.     

Effects of oxiracetam and piracetam on the electrical activity of neurons of the cerebral cortex

The effect of oxiracetam and piracetam on the spontaneous impulse neuronal activity of the somatosensory cortex of the cat and rabbit was studied. Oxiracetam and piracetam when applied microiontophoretically changed neuronal activity by depressing in the majority of the cases studied or sometimes facilitating the spontaneous firing rate. A small percentage of neurons (about 30%) remains unaffected by the application of the nootropics. In some cases oxiracetam and piracetam diminished the depress effect of morphine and DADLE on the spontaneous impulse neuronal activity.     

In Silico Design of Dual-Binding Site Anti-Cholinesterase Phytochemical Heterodimers as Treatment Options for Alzheimer’s Disease

The number of patients with neurodegenerative diseases, particularly Alzheimer’s disease (AD), continues to grow yearly. Cholinesterase inhibitors (ChEIs) represent the first-line symptomatic drug treatment for mild-to-moderate AD; however, there is an unmet need to produce ChEIs with improved efficacy and reduced side effects. Herein, phytochemicals with reported anti-acetylcholinesterase (AChE) activity were ranked in silico for their anti-AChE potential. Ligands with a similar or higher binding affinity to AChE than galantamine were then selected for the design of novel dual-binding site heterodimeric drugs. In silico molecular docking of heterodimers with the target enzymes, AChE and butyrylcholinesterase (BuChE), were performed, and anti-cholinesterase binding affinities were compared with donepezil. Drug-likeliness properties and toxicity of the heterodimers were assessed using the SwissADME and ProTox-II webservers. Nine phytochemicals displayed similar or higher binding affinities to AChE than galantamine: sanguinarine > huperzine A > chelerythrine > yohimbine > berberine > berberastine > naringenin > akuammicine > carvone. Eleven heterodimeric ligands were designed with phytochemicals separated by four- or five-carbon alkyl-linkers. All heterodimers were theoretically potent AChE and BuChE dual-binding site inhibitors, with the highest affinity achieved with huperzine-4C-naringenin, which displayed 34% and 26% improved affinity to AChE and BuChE, respectively, then the potent ChEI drug, donepezil. Computational pharmacokinetic and pharmacodynamic screening suggested that phytochemical heterodimers would display useful gastrointestinal absorption and with relatively low predicted toxicity. Collectively, the present study suggests that phytochemicals could be garnered for the provision of novel ChEIs with enhanced drug efficacy and low toxicity.     

Evaluating the cost effectiveness of donepezil in the treatment of Alzheimer's disease in Germany using discrete event simulation

Background  

Previous cost-effectiveness studies of cholinesterase inhibitors have modeled Alzheimer's disease (AD) progression and treatment effects through single or global severity measures, or progression to "Full Time Care". This analysis evaluates the cost-effectiveness of donepezil versus memantine or no treatment in Germany by considering correlated changes in cognition, behavior and function.     

The mitochondria-targeted antioxidant MitoQ extends lifespan and improves healthspan of a transgenic Caenorhabditis elegans model of Alzheimer disease

β-Amyloid (Aβ)-induced toxicity and oxidative stress have been postulated to play critical roles in the pathogenic mechanism of Alzheimer disease (AD). We investigated the in vivo ability of a mitochondria-targeted antioxidant, MitoQ, to protect against Aβ-induced toxicity and oxidative stress in a Caenorhabditis elegans model overexpressing human Aβ. Impairment of electron transport chain (ETC) enzymatic activity and mitochondrial dysfunction are early features of AD. We show that MitoQ extends lifespan, delays Aβ-induced paralysis, ameliorates depletion of the mitochondrial lipid cardiolipin, and protects complexes IV and I of the ETC. Despite its protective effects on lifespan, healthspan, and ETC function, we find that MitoQ does not reduce DCFDA fluorescence, protein carbonyl levels or modulate steadystate ATP levels or oxygen consumption rate. Moreover, MitoQ does not attenuate mitochondrial DNA (mtDNA) oxidative damage. In agreement with its design, the protective effects of MitoQ appear to be targeted specifically to the mitochondrial membrane and our findings suggest that MitoQ may have therapeutic potential for Aβ- and oxidative stress-associated neurodegenerative disorders, particularly AD.