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The anticholinesterase phenserine and its enantiomer posiphen as 5'untranslated-region-directed translation blockers of the Parkinson's alpha synuclein expression.

Mikkilineni S, Cantuti-Castelvetri I, Cahill CM, Balliedier A, Greig NH, Rogers JT - Parkinsons Dis (2012)

Bottom Line: Cholinesterase inhibitors can clinically slow cognitive decline in the later stages of PD etiology similar to their widespread use in Alzheimer's disease (AD).Pertinent to this, we identified that the well-tolerated anticholinesterase, phenserine, blocked neural SNCA mRNA translation and tested for targeting via its 5'untranslated region (5'UTR) in a manner similar to its action to limit the expression of the AD-specific amyloid precursor protein (APP).Posiphen, its better-tolerated (+) enantiomer (devoid of anticholinesterase action), repressed neural α-synuclein translation.

View Article: PubMed Central - PubMed

Affiliation: Neurochemistry Laboratory, Massachusetts General Hospital (East), CNY2, 149, 13th Street, Charlestown, MA 02129, USA.

ABSTRACT
There is compelling support for limiting expression of alpha-synuclein (α-syn) in the brains of Parkinson's disease (PD) patients. An increase of SNCA gene copy number can genetically cause familial PD where increased dose of this pathogenic protein correlates with severity of symptoms (triplication of the SNCA gene causes dementia in PD patients). Gene promoter polymorphisms were shown to increase α-synuclein expression as a risk for PD. Cholinesterase inhibitors can clinically slow cognitive decline in the later stages of PD etiology similar to their widespread use in Alzheimer's disease (AD). Pertinent to this, we identified that the well-tolerated anticholinesterase, phenserine, blocked neural SNCA mRNA translation and tested for targeting via its 5'untranslated region (5'UTR) in a manner similar to its action to limit the expression of the AD-specific amyloid precursor protein (APP). Posiphen, its better-tolerated (+) enantiomer (devoid of anticholinesterase action), repressed neural α-synuclein translation. Primary metabolic analogs of posiphen were, likewise, characterized using primary fetal neurons grown ex vivo from the brains of Parkinson's transgenic mice expressing the human SNCA gene.

No MeSH data available.


Related in: MedlinePlus

Metabolic analogs of posiphen and their respective anticholinesterase activities [60]. Posiphen is devoid of anticholinesterase activity. However, its phase 1 metabolites, N8 demethylated, N1 demethylated, and di-demethylated N1, N8-bisnorposiphen showed ex vivo AChE and BChE inhibitory activity of clinical relevance [61, 62]. The compound N8-bisnorposiphen demonstrated no AChE activity. This activity has proven to be dose limiting in human safety studies.
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fig5: Metabolic analogs of posiphen and their respective anticholinesterase activities [60]. Posiphen is devoid of anticholinesterase activity. However, its phase 1 metabolites, N8 demethylated, N1 demethylated, and di-demethylated N1, N8-bisnorposiphen showed ex vivo AChE and BChE inhibitory activity of clinical relevance [61, 62]. The compound N8-bisnorposiphen demonstrated no AChE activity. This activity has proven to be dose limiting in human safety studies.

Mentions: Following oral administration of posiphen to rodents, dogs, and human, the compound is subjected to metabolic processes and generates the same metabolic profile across these species. Specifically, via a phase 1 metabolism, posiphen undergoes N-demethylation in both the N1 and N8 positions to generate the respective primary metabolites, N1-norposiphen and N8-norposiphen (Figure 5). Each then undergoes further N-demethylation to generate the common metabolite, N1, N8-bisnorposiphen. Unlike phenserine, posiphen is devoid of cholinesterase inhibitory activity and, therefore, can be advantageously administered at higher clinical doses (in the order of 5, to 8-fold greater).


The anticholinesterase phenserine and its enantiomer posiphen as 5'untranslated-region-directed translation blockers of the Parkinson's alpha synuclein expression.

Mikkilineni S, Cantuti-Castelvetri I, Cahill CM, Balliedier A, Greig NH, Rogers JT - Parkinsons Dis (2012)

Metabolic analogs of posiphen and their respective anticholinesterase activities [60]. Posiphen is devoid of anticholinesterase activity. However, its phase 1 metabolites, N8 demethylated, N1 demethylated, and di-demethylated N1, N8-bisnorposiphen showed ex vivo AChE and BChE inhibitory activity of clinical relevance [61, 62]. The compound N8-bisnorposiphen demonstrated no AChE activity. This activity has proven to be dose limiting in human safety studies.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368596&req=5

fig5: Metabolic analogs of posiphen and their respective anticholinesterase activities [60]. Posiphen is devoid of anticholinesterase activity. However, its phase 1 metabolites, N8 demethylated, N1 demethylated, and di-demethylated N1, N8-bisnorposiphen showed ex vivo AChE and BChE inhibitory activity of clinical relevance [61, 62]. The compound N8-bisnorposiphen demonstrated no AChE activity. This activity has proven to be dose limiting in human safety studies.
Mentions: Following oral administration of posiphen to rodents, dogs, and human, the compound is subjected to metabolic processes and generates the same metabolic profile across these species. Specifically, via a phase 1 metabolism, posiphen undergoes N-demethylation in both the N1 and N8 positions to generate the respective primary metabolites, N1-norposiphen and N8-norposiphen (Figure 5). Each then undergoes further N-demethylation to generate the common metabolite, N1, N8-bisnorposiphen. Unlike phenserine, posiphen is devoid of cholinesterase inhibitory activity and, therefore, can be advantageously administered at higher clinical doses (in the order of 5, to 8-fold greater).

Bottom Line: Cholinesterase inhibitors can clinically slow cognitive decline in the later stages of PD etiology similar to their widespread use in Alzheimer's disease (AD).Pertinent to this, we identified that the well-tolerated anticholinesterase, phenserine, blocked neural SNCA mRNA translation and tested for targeting via its 5'untranslated region (5'UTR) in a manner similar to its action to limit the expression of the AD-specific amyloid precursor protein (APP).Posiphen, its better-tolerated (+) enantiomer (devoid of anticholinesterase action), repressed neural α-synuclein translation.

View Article: PubMed Central - PubMed

Affiliation: Neurochemistry Laboratory, Massachusetts General Hospital (East), CNY2, 149, 13th Street, Charlestown, MA 02129, USA.

ABSTRACT
There is compelling support for limiting expression of alpha-synuclein (α-syn) in the brains of Parkinson's disease (PD) patients. An increase of SNCA gene copy number can genetically cause familial PD where increased dose of this pathogenic protein correlates with severity of symptoms (triplication of the SNCA gene causes dementia in PD patients). Gene promoter polymorphisms were shown to increase α-synuclein expression as a risk for PD. Cholinesterase inhibitors can clinically slow cognitive decline in the later stages of PD etiology similar to their widespread use in Alzheimer's disease (AD). Pertinent to this, we identified that the well-tolerated anticholinesterase, phenserine, blocked neural SNCA mRNA translation and tested for targeting via its 5'untranslated region (5'UTR) in a manner similar to its action to limit the expression of the AD-specific amyloid precursor protein (APP). Posiphen, its better-tolerated (+) enantiomer (devoid of anticholinesterase action), repressed neural α-synuclein translation. Primary metabolic analogs of posiphen were, likewise, characterized using primary fetal neurons grown ex vivo from the brains of Parkinson's transgenic mice expressing the human SNCA gene.

No MeSH data available.


Related in: MedlinePlus