Synthesis of the Alzheimer Drug Posiphen into its Primary Metabolic Products (+)-N1-norPosiphen, (+)-N8-norPosiphen and (+)-N1, N8-bisnorPosiphen, their Inhibition of Amyloid Precursor Protein, &amp;#945; -Synuclein Synthesis, Interleukin-1&amp;#946; Release, and Cholinergic Action.

Yu, Qian; Reale, Marcella; Kamal, Mohammad Amjad; Holloway, Harold W.; Luo, Weiming; Sambamurti, Kumar; Ray, Balmiki; Lahiri, Debomoy K.; Rogers, Jack T.; Greig, Nigel H.

doi:10.2174/1871523011312020003

Cited by 24 publications

(18 citation statements)

References 57 publications

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“…The significant movement improvement (Table 2) achieved by pretreatment with (-)-phenserine or posiphen suggests that protection from soman toxicity stems from more than AChE shielding alone, particularly since posiphen lacks anticholinesterase action, albeit specific metabolites possess some [70]. In both humans and rats, posiphen remains the primary drug species as assessed by both its maximal concentration in plasma and brain, and time-dependent area under the plasma concentration curve [28].…”

Section: Discussionmentioning

confidence: 99%

(-)-Phenserine Attenuates Soman-Induced Neuropathology

Pan

Chen

et al. 2014

PLoS ONE

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Organophosphorus (OP) nerve agents are deadly chemical weapons that pose an alarming threat to military and civilian populations. The irreversible inhibition of the critical cholinergic degradative enzyme acetylcholinesterase (AChE) by OP nerve agents leads to cholinergic crisis. Resulting excessive synaptic acetylcholine levels leads to status epilepticus that, in turn, results in brain damage. Current countermeasures are only modestly effective in protecting against OP-induced brain damage, supporting interest for evaluation of new ones. (-)-Phenserine is a reversible AChE inhibitor possessing neuroprotective and amyloid precursor protein lowering actions that reached Phase III clinical trials for Alzheimer's Disease where it exhibited a wide safety margin. This compound preferentially enters the CNS and has potential to impede soman binding to the active site of AChE to, thereby, serve in a protective capacity. Herein, we demonstrate that (-)-phenserine protects neurons against soman-induced neuronal cell death in rats when administered either as a pretreatment or post-treatment paradigm, improves motoric movement in soman-exposed animals and reduces mortality when given as a pretreatment. Gene expression analysis, undertaken to elucidate mechanism, showed that (-)-phenserine pretreatment increased select neuroprotective genes and reversed a Homer1expression elevation induced by soman exposure. These studies suggest that (-)-phenserine warrants further evaluation as an OP nerve agent protective strategy.

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Section: Discussionmentioning

confidence: 99%

(-)-Phenserine Attenuates Soman-Induced Neuropathology

Pan

Chen

et al. 2014

PLoS ONE

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“…These metabolites have, likewise, been shown to reduce the levels of APP and α‐synuclein in primary neuron cultures. However, whereas Posiphen and N 8 ‐norPosiphen have no AChEI, N 1 ‐norPosiphen and N 1 , N 8 ‐bisnorPosiphen possess some AChEI activity and may be the metabolites that determine its maximum tolerated dose [14,27].…”

Section: Introductionmentioning

confidence: 99%

Translational inhibition of APP by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse

Teich

Sharma

Barnwell

et al. 2018

A&D Transl Res & Clin Interv

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IntroductionTranslational inhibition of amyloid precursor protein (APP) by Posiphen has been shown to reduce APP and its fragments in cell culture, animal models, and mildly cognitively impaired patients, making it a promising drug candidate for the treatment of Alzheimer's disease.MethodsWe used a mouse model of Alzheimer's disease (APP/presenilin-1) to examine Posiphen's efficacy, pharmacodynamics, and pharmacokinetics.ResultsPosiphen treatment normalized impairments in spatial working memory, contextual fear learning, and synaptic function in APP/presenilin-1 mice, without affecting their visual acuity, motor skills, or motivation and without affecting wild-type mice. Posiphen had a prolonged effect in reducing APP and all related peptides for at least 9 hours after the last dose. Its concentration was higher in the brain than in plasma, and the most abundant metabolite was N8-norPosiphen.DiscussionThis is the first study demonstrating the therapeutic efficacy of inhibiting the translation of APP and its fragments in an Alzheimer's disease model.

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“…However, iron can reverse the translation inhibition of α-Syn by IRPs and therefore facilitate α-Syn expression and aggregation [49]. The translation of α-Syn mRNA can be inhibited by new IRE chemical inhibitors [73, 74]. These findings suggest a pathological relevance of iron and the IRP-IRE signaling pathway in the α-Syn-dependent toxicity of DA neurons in PD.…”

Section: Main Textmentioning

confidence: 99%

Iron regulatory protein (IRP)-iron responsive element (IRE) signaling pathway in human neurodegenerative diseases

Zhou

Tan

2017

Mol Neurodegeneration

150

122

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The homeostasis of iron is vital to human health, and iron dyshomeostasis can lead to various disorders. Iron homeostasis is maintained by iron regulatory proteins (IRP1 and IRP2) and the iron-responsive element (IRE) signaling pathway. IRPs can bind to RNA stem-loops containing an IRE in the untranslated region (UTR) to manipulate translation of target mRNA. However, iron can bind to IRPs, leading to the dissociation of IRPs from the IRE and altered translation of target transcripts. Recently an IRE is found in the 5′-UTR of amyloid precursor protein (APP) and α-synuclein (α-Syn) transcripts. The levels of α-Syn, APP and amyloid β-peptide (Aβ) as well as protein aggregation can be down-regulated by IRPs but are up-regulated in the presence of iron accumulation. Therefore, inhibition of the IRE-modulated expression of APP and α-Syn or chelation of iron in patient’s brains has therapeutic significance to human neurodegenerative diseases. Currently, new pre-drug IRE inhibitors with therapeutic effects have been identified and are at different stages of clinical trials for human neurodegenerative diseases. Although some promising drug candidates of chemical IRE inhibitors and iron-chelating agents have been identified and are being validated in clinical trials for neurodegenerative diseases, future studies are expected to further establish the clinical efficacy and safety of IRE inhibitors and iron-chelating agents in patients with neurodegenerative diseases.

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Synthesis of the Alzheimer Drug Posiphen into its Primary Metabolic Products (+)-N1-norPosiphen, (+)-N8-norPosiphen and (+)-N1, N8-bisnorPosiphen, their Inhibition of Amyloid Precursor Protein, α -Synuclein Synthesis, Interleukin-1β Release, and Cholinergic Action.

Cited by 24 publications

References 57 publications

(-)-Phenserine Attenuates Soman-Induced Neuropathology

(-)-Phenserine Attenuates Soman-Induced Neuropathology

Translational inhibition of APP by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse

Iron regulatory protein (IRP)-iron responsive element (IRE) signaling pathway in human neurodegenerative diseases

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