Pharmacological properties of TV3326, a cholinesterase and brain selective monoamine oxidase inhibitor for the treatment of dementia co-morbid with depression

Weinstock, Marta; Youdim, Mbh

doi:10.1201/b14441-36

Cited by 2 publications

(5 citation statements)

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“…Such M1 muscarinic agonists appear to be disease-modifying agents in AD [ 51 ] while cholinergic modulation of APP via the M1 muscarinic receptor has offered a potential therapeutic route to activate alpha-secretase and thus reduce amyloid and increase the secretion of neuroprotective APP(s) [ 52 , 53 , 54 , 55 , 56 ]. Certainly, AF102B is an FDA approved drug currently used for the treatment of Sjogren’s syndrome (an autoimmune disease associated with difficulty breathing, dry mouth, and coughing) [ 57 ]. AF102B was shown to generate enhanced neuroprotective APP, likely resulting from alpha-secretase activation of the non-amyloidogenic and neuroprotective pathway of APP expression [ 51 , 58 ].…”

Section: App 5’utr Activators Shield Neurons From Acute Pb/mn Disrmentioning

confidence: 99%

“…AF102B was shown to generate enhanced neuroprotective APP, likely resulting from alpha-secretase activation of the non-amyloidogenic and neuroprotective pathway of APP expression [ 51 , 58 ]. We reported that this M1 muscarinic agonist confers neuroprotection while inducing APP translation as well as activating alpha-secretase to generate increased secretion of APP(s) from neural cell lines [ 57 ].…”

Section: App 5’utr Activators Shield Neurons From Acute Pb/mn Disrmentioning

confidence: 99%

“…In Figure 2 , we experimentally employed a transfection-based assay to confirm that AF102B indeed increases APP 5’UTR directed expression of a luciferase reporter gene ( Figure 2 ) [ 57 ]. SH-SY5Y cells were transfected with a PSV2(APP 5’UTR)–luciferase construct in which the 5’UTR of APP drives luciferase expression.…”

Section: App 5’utr Activators Shield Neurons From Acute Pb/mn Disrmentioning

confidence: 99%

“…For the purpose of a positive experimental comparison, the anti-cholinesterase phenserine acted as an APP 5’UTR inhibitor in Figure 2 [ 20 ]. The data in Figure 1 and Figure 2 shows that AF102B exemplifies a small molecule that activates the APP 5’untranslated region [ 57 ] while promoting neuroprotective alpha-secretase expression. This exemplifies a class of drug that activates APP 5’UTR to translate higher levels of APP as a neuroprotectant, a property that may explain its pro-cognitive functions while also generating anti amyloid efficacy via alpha-secretase [ 53 , 54 , 55 ].…”

Section: App 5’utr Activators Shield Neurons From Acute Pb/mn Disrmentioning

confidence: 99%

“… The effect of AF102B and phenserine to modulate amyloid precursor protein (APP) conferred expression via the 5’untranslated region (5’UTR) of the APP transcript. Adapted from Rogers et al (2005) [ 57 ]. ( Panel A ) Phylogenetically conserved sequences (underlined; [ 11 ]) encoding the 5’UTR APP mRNAs aligned with the CAGUGC H-ferritin IRE sequence that binds to IRP1/IRP2 [ 59 , 60 ].…”

Section: Figurementioning

confidence: 99%

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Targeting the Iron-Response Elements of the mRNAs for the Alzheimer’s Amyloid Precursor Protein and Ferritin to Treat Acute Lead and Manganese Neurotoxicity

Rogers

Xia

Wong

et al. 2019

IJMS

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The therapeutic value of inhibiting translation of the amyloid precursor protein (APP) offers the possibility to reduce neurotoxic amyloid formation, particularly in cases of familial Alzheimer’s disease (AD) caused by APP gene duplications (Dup–APP) and in aging Down syndrome individuals. APP mRNA translation inhibitors such as the anticholinesterase phenserine, and high throughput screened molecules, selectively inhibited the uniquely folded iron-response element (IRE) sequences in the 5’untranslated region (5’UTR) of APP mRNA and this class of drug continues to be tested in a clinical trial as an anti-amyloid treatment for AD. By contrast, in younger age groups, APP expression is not associated with amyloidosis, instead it acts solely as a neuroprotectant while facilitating cellular ferroportin-dependent iron efflux. We have reported that the environmental metallotoxins Lead (Pb) and manganese (Mn) cause neuronal death by interfering with IRE dependent translation of APP and ferritin. The loss of these iron homeostatic neuroprotectants thereby caused an embargo of iron (Fe) export from neurons as associated with excess unstored intracellular iron and the formation of toxic reactive oxidative species (ROS). We propose that APP 5’UTR directed translation activators can be employed therapeutically to protect neurons exposed to high acute Pb and/or Mn exposure. Certainly, high potency APP translation activators, exemplified by the Food and Drug Administration (FDA) pre-approved M1 muscarinic agonist AF102B and high throughput-screened APP 5’UTR translation activators, are available for drug development to treat acute toxicity caused by Pb/Mn exposure to neurons. We conclude that APP translation activators can be predicted to prevent acute metal toxicity to neurons by a mechanism related to the 5’UTR specific yohimbine which binds and targets the canonical IRE RNA stem loop as an H-ferritin translation activator.

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Section: App 5’utr Activators Shield Neurons From Acute Pb/mn Disrmentioning

confidence: 99%

Section: App 5’utr Activators Shield Neurons From Acute Pb/mn Disrmentioning

confidence: 99%

Section: App 5’utr Activators Shield Neurons From Acute Pb/mn Disrmentioning

confidence: 99%

Section: App 5’utr Activators Shield Neurons From Acute Pb/mn Disrmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

See 3 more Smart Citations

Targeting the Iron-Response Elements of the mRNAs for the Alzheimer’s Amyloid Precursor Protein and Ferritin to Treat Acute Lead and Manganese Neurotoxicity

Rogers

Xia

Wong

et al. 2019

IJMS

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Iron-responsive-like elements and neurodegenerative ferroptosis

Rogers

Cahill

2020

Learn. Mem.

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A set of common-acting iron-responsive 5′untranslated region (5′UTR) motifs can fold into RNA stem loops that appear significant to the biology of cognitive declines of Parkinson's disease dementia (PDD), Lewy body dementia (LDD), and Alzheimer's disease (AD). Neurodegenerative diseases exhibit perturbations of iron homeostasis in defined brain subregions over characteristic time intervals of progression. While misfolding of Aβ from the amyloid-precursor-protein (APP), alpha-synuclein, prion protein (PrP) each cause neuropathic protein inclusions in the brain subregions, iron-responsive-like element (IRE-like) RNA stem–loops reside in their transcripts. APP and αsyn have a role in iron transport while gene duplications elevate the expression of their products to cause rare familial cases of AD and PDD. Of note, IRE-like sequences are responsive to excesses of brain iron in a potential feedback loop to accelerate neuronal ferroptosis and cognitive declines as well as amyloidosis. This pathogenic feedback is consistent with the translational control of the iron storage protein ferritin. We discuss how the IRE-like RNA motifs in the 5′UTRs of APP, alpha-synuclein and PrP mRNAs represent uniquely folded drug targets for therapies to prevent perturbed iron homeostasis that accelerates AD, PD, PD dementia (PDD) and Lewy body dementia, thus preventing cognitive deficits. Inhibition of alpha-synuclein translation is an option to block manganese toxicity associated with early childhood cognitive problems and manganism while Pb toxicity is epigenetically associated with attention deficit and later-stage AD. Pathologies of heavy metal toxicity centered on an embargo of iron export may be treated with activators of APP and ferritin and inhibitors of alpha-synuclein translation.

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Pharmacological properties of TV3326, a cholinesterase and brain selective monoamine oxidase inhibitor for the treatment of dementia co-morbid with depression

Cited by 2 publications

References 1 publication

Targeting the Iron-Response Elements of the mRNAs for the Alzheimer’s Amyloid Precursor Protein and Ferritin to Treat Acute Lead and Manganese Neurotoxicity

Targeting the Iron-Response Elements of the mRNAs for the Alzheimer’s Amyloid Precursor Protein and Ferritin to Treat Acute Lead and Manganese Neurotoxicity

Iron-responsive-like elements and neurodegenerative ferroptosis

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