Xanomeline Protects Cortical Cells From Oxygen-Glucose Deprivation via Inhibiting Oxidative Stress and Apoptosis

Xin, Rujuan; Chen, Zhongjian; Fu, Jin; Shen, Fu‐Ming; Huang, Fang

doi:10.3389/fphys.2020.00656

Cited by 10 publications

(10 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These results support previous findings reporting the ability of Oxo treatment to significantly decrease ROS levels in the rat hippocampus (Frinchi et al 2019), and are corroborated by the observation that scopolamine (a mAchRs antagonist) treatment or M 1 receptor deficiency produces an increase in oxidative stress (Balaban et al 2017;Wong-Guerra et al 2017;Laspas et al 2019). On the contrary Xanomeline, a mAchR agonist, effective in attenuating behavioral disturbances in AD patients, protects cortical cells from oxygen-glucose deprivation via inhibiting oxidative stress and apoptosis (Xin et al 2020).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective and Antioxidant Role of Oxotremorine-M, a Non-selective Muscarinic Acetylcholine Receptors Agonist, in a Cellular Model of Alzheimer Disease

et al. 2022

View full text Add to dashboard Cite

Alzheimer disease (AD) is a multifactorial and age-dependent neurodegenerative disorder, whose pathogenesis, classically associated with the formation of senile plaques and neurofibrillary tangles, is also dependent on oxidative stress and neuroinflammation chronicization. Currently, the standard symptomatic therapy, based on acetylcholinesterase inhibitors, showed a limited therapeutic potential, whereas disease-modifying treatment strategies are still under extensive research. Previous studies have demonstrated that Oxotremorine-M (Oxo), a non-selective muscarinic acetylcholine receptors agonist, exerts neurotrophic functions in primary neurons, and modulates oxidative stress and neuroinflammation phenomena in rat brain. In the light of these findings, in this study, we aimed to investigate the neuroprotective effects of Oxo treatment in an in vitro model of AD, represented by differentiated SH-SY5Y neuroblastoma cells exposed to Aβ1-42 peptide. The results demonstrated that Oxo treatment enhances cell survival, increases neurite length, and counteracts DNA fragmentation induced by Aβ1-42 peptide. The same treatment was also able to block oxidative stress and mitochondria morphological/functional impairment associated with Aβ1-42 cell exposure. Overall, these results suggest that Oxo, by modulating cholinergic neurotransmission, survival, oxidative stress response, and mitochondria functionality, may represent a novel multi-target drug able to achieve a therapeutic synergy in AD. Graphical Abstract Illustration of the main pathological hallmarks and mechanisms underlying AD pathogenesis, including neurodegeneration and oxidative stress, efficiently counteracted by treatment with Oxo, which may represent a promising therapeutic molecule. Created with BioRender.com under academic license.

show abstract

Section: Discussionmentioning

confidence: 99%

Neuroprotective and Antioxidant Role of Oxotremorine-M, a Non-selective Muscarinic Acetylcholine Receptors Agonist, in a Cellular Model of Alzheimer Disease

et al. 2022

View full text Add to dashboard Cite

show abstract

“…In 2020, Maspero et al reported THA hybrids 712 – 717 with xanomeline, a selective muscarinic acetylcholine receptor agonist and M1/M4 preferring muscarinic acetylcholine receptor activator [ 106 , 193 ]. Hybrids 712 – 717 were able to inhibit AChE; eight methylene units were optimal for the highest AChE inhibition.…”

Section: Tacrine Hybrids With Modulators Of Cholinergic/serotonergic ...mentioning

confidence: 99%

Tacrine-Based Hybrids: Past, Present, and Future

Bubley

Erofeev

Gorelkin

et al. 2023

IJMS

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a neurodegenerative disorder which is characterized by β-amyloid (Aβ) aggregation, τ-hyperphosphorylation, and loss of cholinergic neurons. The other important hallmarks of AD are oxidative stress, metal dyshomeostasis, inflammation, and cell cycle dysregulation. Multiple therapeutic targets may be proposed for the development of anti-AD drugs, and the “one drug–multiple targets” strategy is of current interest. Tacrine (THA) was the first clinically approved cholinesterase (ChE) inhibitor, which was withdrawn due to high hepatotoxicity. However, its high potency in ChE inhibition, low molecular weight, and simple structure make THA a promising scaffold for developing multi-target agents. In this review, we summarized THA-based hybrids published from 2006 to 2022, thus providing an overview of strategies that have been used in drug design and approaches that have resulted in significant cognitive improvements and reduced hepatotoxicity.

show abstract

“…Compounds providing protection against apoptosis and motor neurone degeneration: sphingosine-1-phosphate [24], metformin [31], thymoquinone [44], citicoline [45], nitrovinyl benzoic acid (4-[(1E)-2-nitrovinyl] benzoic acid) [46], ambroxol [47], isofagomine [47], fingolimod [47], fasudil [48], Y-27632 [48], acerogenin [49]. Xanomeline [16], telmisartan [37], orientin [50], geniposide [51], licochalcone A [52], taraxasterol [53], acetylcarnitine [54], atorvastatin [55], riluzole [56] and sulforaphane [57] protect neurons against oxygen-glucose deprivation/reperfusion. 3-nitrotyrosine is an oxidative-stress marker [58].…”

Section: Compound Structuresmentioning

confidence: 99%

“…Neurons operate optimally within narrow glucose, oxygen and redox equilibrium parameters, and in cell culture several compounds protect against oxygen-glucose deprivation/reperfusion. The muscarinic agonist xanomeline, for example, protects rat cortical neurons by inhibiting reactive oxygen species (ROS) production and apoptosis; the mechanism is unknown [16].…”

Section: Introductionmentioning

confidence: 99%

Relative Molecular Similarity in Compound Structures Modulating Neurodegenerative Apoptosis

Williams¹

2023

JBM

View full text Add to dashboard Cite

Neurodegeneration is attributable to metabolic disturbances in the various cell types responsible for this condition, in respect of glucose utilisation and dysfunctional mitochondrial oxidative mechanisms. The properties of neurotoxins and antagonists that limit their action are well documented in disease models, whereas effective therapy is very limited. Cell apoptosis, a general marker of neurodegeneration, is also of therapeutic interest in the treatment of cancer. cGMP nucleotide influences apoptosis and has a role in maintaining equilibrium within cell redox parameters. The chemical structure of cGMP provides a comparative template for demonstrating relative molecular similarity within the structures of natural and synthetic compounds influencing tumour cell apoptosis. The present study uses computational software to investigate molecular similarity within the structures of cGMP and compounds that modulate cell apoptosis in experimental models of diabetic peripheral neuropathy (DPN), Parkinson's and multiple sclerosis. Differential molecular similarity demonstrated in neurotoxin and antagonist structures implicate metabolite impairment of cGMP signaling function as a common mechanism in the initial phases of these neurodegenerative conditions.

show abstract

Xanomeline Protects Cortical Cells From Oxygen-Glucose Deprivation via Inhibiting Oxidative Stress and Apoptosis

Cited by 10 publications

References 66 publications

Neuroprotective and Antioxidant Role of Oxotremorine-M, a Non-selective Muscarinic Acetylcholine Receptors Agonist, in a Cellular Model of Alzheimer Disease

Neuroprotective and Antioxidant Role of Oxotremorine-M, a Non-selective Muscarinic Acetylcholine Receptors Agonist, in a Cellular Model of Alzheimer Disease

Tacrine-Based Hybrids: Past, Present, and Future

Relative Molecular Similarity in Compound Structures Modulating Neurodegenerative Apoptosis

Contact Info

Product

Resources

About