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Acetylcholinesterases from Elapidae snake venoms: biochemical, immunological and enzymatic characterization.

We analyzed 45 batches of venom from 20 different species belonging to 11 genera from the 3 main families of venomous snakes (Elapidae, Vipe … also devoid of immunoreactive AChE protein. AChE inhibitors acting at the active site (edrophonium, tacrine) and at the peripheral site (propidium, fasciculin), as well as bis-quaternary ligands (BW284C51, decamethonium), were tested against the venom AChEs from 11 different species. All enzymes had a very similar pattern of reactivity with regard to the …

Structural, metabolic and ionic requirements for the uptake of L-carnitine by primary rat cortical cells.

L-Carnitine (L-C) is involved in the transport of acyl groups into mitochondria for beta-oxidation, although its role in the adult brain is … roM inhibited both L-C (24%) and GABA uptake (17%). Other drugs like the cholinesterase inhibitors, tacrine and eserine, also had a small inhibitory effect on L-C uptake, reducing it at 1 microM by 22 and 21% respectively, although higher concentrations were toxic (> 100 microM). Pretreatment of the cells with neuraminidase (50 U ml-1, 10 min) reduced the …

Providing dental care for patients diagnosed with Alzheimer's disease.

Alzheimer's disease is the most common dementing illness affecting over 4 million Americans. As the population ages, dentists and other health care providers will be faced with the daunting task of managing an increasing number of people with this disease. Currently, there are no definitive medications to treat this disease, although there are a number of recent drugs which may help to alleviate some symptoms. This article reviews the current medical treatment and the dental concerns which face the dentist, patient, and family. Suggestions for dental management are given along with practical r

Tolerability of memantine in combination with cholinesterase inhibitors in dementia therapy.

Memantine, a moderate-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to be effective in dementia, including Alzheimer disease (AD). Therefore, its combination with acetylcholinesterase inhibitors (AChEIs) is anticipated. We report a postmarketing surveillance study conducted among German physicians who, during routine clinical practice, treated demented patients with memantine in combination with an AChEI. Most of the 158 surveyed patients (mean age, 74 years) were diagnosed with AD but other dementias were included. Memantine was prescribed at a wide r

Novel multipotent AChEI-CCB attenuates hyperhomocysteinemia-induced memory deficits and Neuropathologies in rats.

Alzheimer's disease (AD) has multiple etiopathogenic factors, yet the definitive cause remains unclear and the therapeutic strategies have been elusive. Combination therapy, as one of the promising treatments, has been studied for years and may exert synergistic beneficial effects on AD through polytherapeutic targets. In this study, we tested the effects of a synthesized juxtaposition (named SCR1693) composed of an acetylcholinesterase inhibitor (AChEI) and a calcium channel blocker (CCB) on the hyperhomocysteinemia (HHcy)-induced AD rat model, and found that SCR1693 remarkably improved the H

Nose-to-brain drug delivery: An update on clinical challenges and progress towards approval of anti-Alzheimer drugs.

According to the Alzheimer Association Report (2017), Alzheimer's disease (AD) is the 6th primary cause of death in the USA, which affects n … ulations loaded with various anti-Alzheimer agents. These agents include galantamine, deferoxamine, tacrine, tarenflurbil, rivastigmine, risperidone, curcumin, quercetin, piperine, insulin, etc. and various peptides towards the development of a promising IN drug delivery system for the treatment of AD. Through this review article, we want to drag the atte …

A novel acetylcholinesterase inhibitor and calcium channel blocker SCR-1693 improves Aβ25-35-impaired mouse cognitive function.

RATIONALE: The mechanism involved in AD is complex, which has prompted to develop compounds that could simultaneously interact with several potential targets. Here, we report a new synthesized compound SCR-1693 which is designed to target both AChE and calcium channels that are potential for AD therapy. OBJECTIVES: We investigated the effects of SCR-1693 on AChE and calcium channels, the effects of neuroprotection and anti-amnesia in icv-Aβ25-35-injected mice, and the potential mechanisms. METHODS: AChE activity assay, intracellular Ca(2+) content and calcium currents measurement, and Aβ25-3

Regulating autonomic nervous system homeostasis improves pulmonary function in rabbits with acute lung injury.

BACKGROUND: This study aimed to investigate the effects of regulating autonomic nervous system (ANS) homeostasis by inhibiting sympathetic hyperactivity and/or enhancing parasympathetic activity on pulmonary inflammation and functional disturbance. METHODS: An animal model of acute lung injury (ALI) was established in rabbits by an intratracheal injection of hydrochloric acid (HCl) in rabbits. Animals in control groups were received saline or HCl only, and the others received both HCl and followed treatments: vagus nerve stimulation (VNS), intravenous injection of tetrahydroaminoacridine (THA

Cholinergic neurotransmission, REM sleep and depression.

It is known from animal experiments that the regulation of REM and Non-REM sleep is governed by cholinergic and serotonergic/adrenergic neurons in the brain stem. Cholinergic neurons in the gigantocellular field of the tegmentum seem to be responsible for the triggering and maintenance of REM sleep. These findings are of special interest for interpreting abnormalities of REM sleep in depression. Psychiatric sleep research in the last two decades has demonstrated that an early onset of REM sleep and heightened REM density frequently occurs in patients suffering from depression. Extrapolating fr

Donepezil for mild and moderate Alzheimer's disease.

BACKGROUND: Alzheimer's disease is the most common cause of dementia and is a primary degenerative disease of the brain of unknown cause. On … f these abnormalities is to inhibit the breakdown of acetylcholine by blocking the relevant enzyme. Tacrine was the first compound approved as a treatment for AD in the US and worked in this way, but caused severe side effects. E2020 (donepezil, Aricept) is a second generation cholinesterase inhibitor and appears to be highly specific, with relatively few …

[Current therapy of patients with dementia].

In recent years, the efficacy of symptomatic treatment in patients with Alzheimer's disease has repeatedly been demonstrated in a number of multicenter studies. Such treatment aims both to improve the patient's cognitive abilities and to preserve his or her quality of life and ability to cope with the activities of daily life. In this way the burden on relatives and caregivers is reduced, and the need for home or institutionalized care delayed. Causally effective therapeutic strategies resulting in a cure or the delaying of pathophysiological progression are currently not available, but are be

Effects of acute and subchronic administration of dexefaroxan, an alpha(2)-adrenoceptor antagonist, on memory performance in young adult and aged rodents.

The present study examined the influence of dexefaroxan, a potent and selective alpha(2)-adrenoceptor antagonist, on cognitive performance in rodents. In young adult rats, dexefaroxan reversed the deficits induced by UK 14304 [5-bromo-N-(4,5-dihydro-1-H-imidazol-2-yl)-6-quinoxalinamine], scopolamine, and diazepam in a passive avoidance task. In this test, dexefaroxan also attenuated the spontaneous forgetting induced by a 15-week training-testing interval. Moreover, dexefaroxan, given immediately after training, increased the memory performance of rats trained with a weak electric footshock in

Primary Localized Amyloidosis of Larynx: A Case Report.

Psychotic symptoms in Parkinson's disease (PD) are relatively common and, in addition to creating a disturbance in patients' daily lives, ha … se inhibitors currently represent the most promising pharmacological alternative to antipsychotics. Tacrine is rarely tried because of hepatic toxicity, and controlled trials with donepezil have not shown significant reductions in psychotic symptoms, due perhaps to methodological limitations. However, results from an open-label study and a double-blind, p …

Practice guidelines for the diagnosis and treatment of Alzheimer's disease in a managed care setting: Part II--Pharmacologic therapy. Alzheimer's Disease (AD) Managed Care Advisory Council.

The progressive loss of social and physical functioning associated with Alzheimer's disease (AD) results in extensive social and economic costs to society. The early diagnosis and treatment of AD may reduce cognitive and behavioral symptoms of this disease and may slow disease progression, thereby alleviating some of these social and economic costs. The Alzheimer's Disease Managed Care Advisory Council, a panel of experts from managed care, academic medicine, and the Los Angeles chapter of the Alzheimer's Association was convened to synthesize current evidence-based recommendations for AD diag

Cholinergic medication for antipsychotic-induced tardive dyskinesia.

BACKGROUND: Tardive dyskinesia (TD) remains a troublesome adverse effect of conventional antipsychotic (neuroleptic) medication. It has been proposed that TD could have a component of central cholinergic deficiency. Cholinergic drugs have been used to treat TD. OBJECTIVES: To determine the effects of cholinergic drugs (arecoline, choline, deanol, lecithin, meclofenoxate, physostigmine, RS 86, tacrine, metoxytacrine, galantamine, ipidacrine, donepezil, rivastigmine, eptastigmine, metrifonate, xanomeline, cevimeline) for treating antipsychotic-induced TD in people with schizophrenia or other ch…

Olfactory nerve-evoked, metabotropic glutamate receptor-mediated synaptic responses in rat olfactory bulb mitral cells.

The group I metabotropic glutamate receptor (mGluR) subtype, mGluR1, is highly expressed on the apical dendrites of olfactory bulb mitral cells and thus may be activated by glutamate released from olfactory nerve (ON) terminals. Previous studies have shown that mGluR1 agonists directly excite mitral cells. In the present study, we investigated the involvement of mGluR1 in ON-evoked responses in mitral cells in rat olfactory bulb slices using patch-clamp electrophysiology. In voltage-clamp recordings, the average EPSC evoked by single ON shocks or brief trains of ON stimulation (six pulses at 5

Recent Insights in Multi-Target Drugs in Pharmacology and Medicinal Chemistry.

Many of the drugs used in treatment today have been designed based on the "specificity paradigm". Resistance has developed against drugs designed using this approach, leading to a decrease in their effectiveness. In addition, it is well-documented in the literature that diseases with complex etiologies, such as Alzheimer's, Parkinson's, and cancer are influenced by multiple genetic and/or environmental factors. As a result, specificity paradigm is often insufficient for treating these diseases. Therefore, there is a need to develop drugs that interact with multiple targets simultaneously throu

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… They found that IC 50 values to the standard Tacrine ranging from 0.1 to 0.44 μM where 42 with the benzyloxy substitution had the best IC 50 values with 0.1 ± 0.01 μM. [ 173 ] Luo et al. designed, synthesized and evaluated Scutellarein hybrids as multifunctional therapeutic agents for the treatment … Compound 43 with a N(C 2 H 5 ) 2 and a phenyl group exhibited the most potent inhibition of hu AChE enzymes with IC 50 values 8.91 ± 0.08 μM. [ 174 ] Long et al. designed and synthesized series of novel hybrid compounds connecting capsaicin and tacrine moieties as multitarget drugs to treat AD. …

Rivastigmine for Alzheimer's disease.

BACKGROUND: Alzheimer's disease is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer's disease is to enhance cholinergic neurotransmission in the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts. Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. Other cholinesterase inhibitors, including rivastigmine, with …

Epigenetic Dysregulation in Neurodegeneration: The Role of Histone Deacetylases and Emerging Inhibitor Strategies.

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are characterized by complex pathologies with progressive neurodegeneration, protein misfolding, oxidative stress, and persistent inflammation. Recent findings indicate the pivotal involvement of epigenetic disruption, particularly aberrant histone deacetylase (HDAC) activity, in disease initiation and progression. In the current review, we systematically discuss the mechanistic function of HDACs across all classes (I, IIa, IIb, III, and IV) in neurodegenerative disease mechanis

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… Xu et al. (2020) synthesized a diverse library of tacrine-hydroxamate hybrid molecules aimed at addressing multiple pathological mechanisms involved in Alzheimer’s disease, including HDAC activity, acetylcholinesterase (AChE) inhibition, Aβ aggregation, oxidative damage, and metal ion dysregulation [ … By combining structural motifs capable of HDAC inhibition (such as hydroxamic acids), AChE inhibition (such as carbamate or tacrine-like scaffolds), and anti-amyloid activity, these triple-action compounds aim to restore acetylation balance, enhance cholinergic signaling, and reduce amyloid burden, offering …

Advances in MALDI Mass Spectrometry Imaging Single Cell and Tissues.

Compared with conventional optical microscopy techniques, mass spectrometry imaging (MSI) or imaging mass spectrometry (IMS) is a powerful, label-free analytical technique, which can sensitively and simultaneously detect, quantify, and map hundreds of biomolecules, such as peptides, proteins, lipid, and other organic compounds in cells and tissues. So far, although several soft ionization techniques, such as desorption electrospray ionization (DESI) and secondary ion mass spectrometry (SIMS) have been used for imaging biomolecules, matrix-assisted laser desorption/ionization (MALDI) is still t

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… A study revealed age-related changes in acetylcholine levels in normal mice treated with the acetylcholinesterase inhibitor drug tacrine. Using MALDI-MSI, tacrine was found to significantly increase acetylcholine levels in most brain regions of mice. … The distribution of tacrine and its hydroxylated metabolites in the brain was also observed, and the metabolite levels decreased significantly in 14-month-old mice. …