Acetylcholinesterase Enzyme Inhibitor Molecules with Therapeutic Potential
for Alzheimer's Disease

Sivaraman, Bhuvaneswari; R, Vijaykumar; VELMURUGAN, BALA AAKASH; Natarajan, Ramalakshmi

doi:10.2174/1871527320666210928160159

Cited by 7 publications

(3 citation statements)

References 69 publications

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“…By re-testing these in control (slo loxP/+ , see Methods) and non-balanced BK GOF (slo E366G/+ ) male flies, we identified rivastigmine as a specific and dose-dependent suppressor of motor defects caused by BK GOF in Drosophila (Figure 1B-E). Rivastigmine is a reversible non-competitive inhibitor of AChE, elevating synaptic ACh by preventing its hydrolysis in synaptic clefts (Figure 1C) 18 .…”

Section: Pharmacological Suppression Of Motor Defects In Bk Gof Fliesmentioning

confidence: 99%

Pharmacological rescue of motor circuit dysfunction in aDrosophilamodel of paroxysmal dyskinesia

Wilson,

Jiang,

Desai

et al. 2024

Preprint

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BackgroundParoxysmal dyskinesias (PxDs) are characterised by bouts of involuntary dystonic and choreiform movements. The patho-mechanisms underlying these debilitating disorders remain poorly understood, and drug treatments are often limited. We recently generated aDrosophilamodel of a PxD-linked mutation causing BK potassium channel gain- of-function (BK GOF), and showed that BK GOF perturbs movement inDrosophilaby disrupting neurodevelopment. However, whether locomotor capacity in BK GOF flies can be pharmacologically restored following neurodevelopmental insults has remained unclear.ObjectiveTo identify pharmacological suppressors of motor defects caused by BK GOF.MethodsUsing adult BK GOF flies, we performed an unbiased, in vivo, locomotion-based screen of 370 FDA-approved drugs. To test the impact of positive hits from this screen on motor circuit activity, we used optical imaging to record the intrinsic rhythmic activity ofDrosophilalarval motor circuits driving peristalsis and turning behaviors.ResultsWe found that inhibitors of acetylcholinesterase – a protein that degrades acetylcholine in cholinergic synapses – partially rescued movement defects caused by BK GOF. Inhibition of acetylcholinesterase also partially restored intrinsic activity of motor circuits controlling forward movement and turning in BK GOF larvae.ConclusionsOur findings indicate that elevating cholinergic tone can reverse motor circuit dysfunction in an animal model of PxD caused by BK GOF. Furthermore, our study provides proof-of-principle thatDrosophilacan be utilised for screens to uncover putative drug treatments for involuntary movement disorders.

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Section: Pharmacological Suppression Of Motor Defects In Bk Gof Fliesmentioning

confidence: 99%

Pharmacological rescue of motor circuit dysfunction in aDrosophilamodel of paroxysmal dyskinesia

Wilson,

Jiang,

Desai

et al. 2024

Preprint

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“…Studies have shown that marker genes of AD are generally APP gene on chromosome 21, the presenilin 1 (PS1) gene on chromosome 14 and presenilin 2 (PS2) gene on chromosome 1, and the susceptibility genes of sporadic AD are mainly apolipoprotein E (ApoE) gene on chromosome 19 (Prince et al, 2015; Qazi et al, 2018). Cholinergic theory believes that most of the cognitive impairments suffered by AD patients are caused by the increased activity of acetylcholinesterase (AChE) in the brain and the lack of acetylcholine (ACh), which leads to the lack of cholinergic neurotransmitters (Friedli & Inestrosa, 2021; Sivaraman et al, 2022). The oxidative stress theory is based on mitochondrial dysfunction.…”

Section: Etiological Mechanism Of Admentioning

confidence: 99%

Update on new trends and progress of natural active ingredients in the intervention of Alzheimer's disease, based on understanding of traditional Chinese and Western relevant theories: A review

Rang

Liu

et al. 2023

Phytotherapy Research

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Alzheimer's disease (AD) is one of the major neurological disorders causing death in the elderly worldwide. As a neurodegenerative disease that is difficult to prevent and cure, the pathogenesis of AD is complex and there is no effective cure. A variety of natural products derived from plants have been reported to have promising anti‐AD activities, including flavonoids, terpenes, phenolic acids and alkaloids, which can effectively relieve the symptoms of AD in a variety of ways. This paper mainly reviews the pharmacological activity and mechanisms of natural products against AD. Although the clinical efficacy of these plants still needs to be determined by further high‐quality studies, it may also provide a basis for future researchers to study anti‐AD in depth.

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“…Acetylcholinesterase (AChE) is a molecule that has important functions in AD. AchE promotes brain dysfunction by degrading acetylcholine (Sivaraman et al, 2022). Inhibition of AchE expression or activity is a potential strategy for the treatment of AD.…”

Section: Pharmacological Effects Of Sinomenine In Alzheimer's Diseasementioning

confidence: 99%

Potential therapeutic effects and pharmacological evidence of sinomenine in central nervous system disorders

Hong

et al. 2022

Front. Pharmacol.

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Sinomenine is a natural compound extracted from the medicinal plant Sinomenium acutum. Its supplementation has been shown to present benefits in a variety of animal models of central nervous system (CNS) disorders, such as cerebral ischemia, intracerebral hemorrhage, traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, depression, multiple sclerosis, morphine tolerance, and glioma. Therefore, sinomenine is now considered a potential agent for the prevention and/or treatment of CNS disorders. Mechanistic studies have shown that inhibition of oxidative stress, microglia-or astrocyte-mediated neuroinflammation, and neuronal apoptosis are common mechanisms for the neuroprotective effects of sinomenine. Other mechanisms, including activation of nuclear factor E2-related factor 2 (Nrf2), induction of autophagy in response to inhibition of protein kinase B (Akt)-mammalian target of rapamycin (mTOR), and activation of cyclic adenosine monophosphate-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), may also mediate the anti-glioma and neuroprotective effects of sinomenine. Sinomenine treatment has also been shown to enhance dopamine receptor D2 (DRD2)mediated nuclear translocation of αB-crystallin (CRYAB) in astrocytes, thereby suppressing neuroinflammation via inhibition of Signal Transducer and Activator of Transcription 3 (STAT3). In addition, sinomenine supplementation can suppress N-methyl-D-aspartate (NMDA) receptormediated Ca 2+ influx and induce γ-aminobutyric acid type A (GABA A ) receptor-mediated Cl − influx, each of which contributes to the improvement of morphine dependence and sleep disturbance. In this review, we outline the pharmacological effects and possible mechanisms of sinomenine in CNS disorders to advance the development of sinomenine as a new drug for the treatment of CNS disorders.

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Acetylcholinesterase Enzyme Inhibitor Molecules with Therapeutic Potential for Alzheimer's Disease

Cited by 7 publications

References 69 publications

Pharmacological rescue of motor circuit dysfunction in aDrosophilamodel of paroxysmal dyskinesia

Pharmacological rescue of motor circuit dysfunction in aDrosophilamodel of paroxysmal dyskinesia

Update on new trends and progress of natural active ingredients in the intervention of Alzheimer's disease, based on understanding of traditional Chinese and Western relevant theories: A review

Potential therapeutic effects and pharmacological evidence of sinomenine in central nervous system disorders

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