The Experimental Alzheimer's Disease Drug Posiphen [(+)-Phenserine] Lowers Amyloid-β Peptide Levels in Cell Culture and Mice

@article{Lahiri2007TheEA,
  title={The Experimental Alzheimer's Disease Drug Posiphen [(+)-Phenserine] Lowers Amyloid-$\beta$ Peptide Levels in Cell Culture and Mice},
  author={Debomoy K. Lahiri and Demao Chen and Bryan Maloney and Harold W. Holloway and Qian-sheng Yu and Tadanobu Utsuki and Tony Giordano and K. Sambamurti and Nigel H. Greig},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2007},
  volume={320},
  pages={386 - 396}
}
  • D. LahiriDemao Chen N. Greig
  • Published 1 January 2007
  • Biology, Chemistry
  • Journal of Pharmacology and Experimental Therapeutics
Major characteristics of Alzheimer's disease (AD) are synaptic loss, cholinergic dysfunction, and abnormal protein depositions in the brain. The amyloid β-peptide (Aβ), a proteolytic fragment of amyloid β precursor protein (APP), aggregates to form neuritic plaques and has a causative role in AD. A present focus of AD research is to develop safe Aβ-lowering drugs. A selective acetylcholinesterase inhibitor, phenserine, in current human trials lowers both APP and Aβ. Phenserine is dose-limited… 
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125 Citations
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125 Citations

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This paper outlines and evaluates the current landscape of preclinical and clinical studies focusing on modulating Aβ pathophysiology and suggests the most promising approach seems to be the prevention of early Aβ oligomerization.

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General features of AD are discussed and several small molecules across different experimental AD drug classes that have been studied for their effects in the context of the molecular targets and responses associated with the AD progression are discussed.

In Silico and Ex Vivo Analyses of the Inhibitory Action of the Alzheimer Drug Posiphen and Primary Metabolites with Human Acetyl- and Butyrylcholinesterase Enzymes

Current Posiphen clinical trials in AD and related disorders should additionally evaluate AChE inhibition; particularly if Posipen should be combined with a known anticholinesterase, since this drug class is clinically approved and the standard of care for AD subjects, and excessive ACh E inhibition may impact drug tolerability.

Memantine lowers amyloid‐β peptide levels in neuronal cultures and in APP/PS1 transgenic mice

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Rivastigmine Lowers Aβ and Increases sAPPα Levels, Which Parallel Elevated Synaptic Markers and Metabolic Activity in Degenerating Primary Rat Neurons

Rivastigmine treatment enhances neuronal sAPP and shifts APP processing toward the α-secretase pathway in degenerating neuronal cultures, which mirrors the trend of synaptic proteins, and metabolic activity.

The "aged garlic extract:" (AGE) and one of its active ingredients S-allyl-L-cysteine (SAC) as potential preventive and therapeutic agents for Alzheimer's disease (AD).

Based on the reported positive preliminary results reviewed herein, further research is required to develop the full potential of AGE and/or SAC into an effective preventative strategy for AD.
...

References

SHOWING 1-10 OF 51 REFERENCES

Identification of Novel Small Molecule Inhibitors of Amyloid Precursor Protein Synthesis as a Route to Lower Alzheimer's Disease Amyloid-β Peptide

144 analogs of phenserine were screened to identify additional small molecules that inhibit APP protein synthesis, and thereby Aβ production, without possessing potent acetylcholinesterase (AChE) inhibitory activity.

Advances in the cellular and molecular biology of the beta-amyloid protein in Alzheimer’s disease

Advances in understanding of APP processing, trafficking, and turnover will pave the way for better drug discovery for the eventual treatment of AD.

The secretion of amyloid β-peptides is inhibited in the tacrine-treated human neuroblastoma cells

Pharmacological modulation of Alzheimer's beta-amyloid precursor protein levels in the CSF of rats with forebrain cholinergic system lesions.

Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss

This article verifies the predicted accumulation of soluble oligomers in AD frontal cortex and confirms the prediction that soluble oligomeric Aβ ligands are intrinsic to AD pathology, and validate their use in new approaches to therapeutic AD drugs and vaccines.

A partial failure of membrane protein turnover may cause Alzheimer's disease: a new hypothesis.

This theory would predict that focussing on specific reagents such as gamma-secretase inhibitors that hamper metabolism of APP, may initially show some beneficial effects on cognitive performance by elimination of acutely toxic ADDLs, but over the longer term may exacerbate the disease process by reducing membrane protein turnover.

Differential effects of two hexahydropyrroloindole carbamate-based anticholinesterase drugs on the amyloid beta protein pathway involved in alzheimer disease

Interestingly, these drugs share the same chemical backbone, inhibit acetylcholinesterase with similar potency, but differentially affect APP processing, indicating that the mechanisms underpinning the cholinergic and the amyloid-lowering properties for this class of drugs are independent of each other.

A critical analysis of new molecular targets and strategies for drug developments in Alzheimer's disease.

Recent trends in AD research are critically examined from molecular, genetic to clinical areas to lead to a deeper understanding of the pathobiochemical processes that occur in the AD brain in order to effectively diagnose and prevent their occurrence.

An overview of phenserine tartrate, a novel acetylcholinesterase inhibitor for the treatment of Alzheimer's disease.

Clinical studies reveal that (-)-phenserine had a favorable safety and pharmacological profile, produced significant improvements in cognitive function and was well tolerated in patients with AD treated for 12 weeks, and randomized, double-blind, placebo-controlled Phase III studies assessing the efficacy, safety/tolerability and potential disease-modifying effects of (-)- Phenserine in Patients with AD are currently ongoing.

Phenserine regulates translation of β-amyloid precursor protein mRNA by a putative interleukin-1 responsive element, a target for drug development

  • K. ShawT. Utsuki N. Greig
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2001
It is suggested that phenserine reduces Aβ levels by regulating βAPP translation via the recently described iron regulatory element in the 5′-untranslated region of βAPP mRNA, which has been shown previously to be up-regulated in the presence of interleukin-1.
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