| ironjustice@aol.com 2006-08-01, 9:25 pm |
| <<snip>>
removal of amyloid-=DF and antioxidative treatment
<<snip>>
Neurobiology of Aging
Volume 27, Issue 9 , September 2006, Pages 1181-1192
doi:10.1016/j.neurobiolaging.2005.07.006
Copyright =A9 2005 Elsevier Inc. All rights reserved.
Amyloid-=DF impairs development of neuronal progenitor cells by
oxidative mechanisms
B=2E Mazur-Koleckaa, , , A. Golabeka, K. Nowickia, M. Floryb and J.
Frackowiaka
aDepartment of Developmental Neurobiology, New York State Institute for
Basic Research in Developmental Disabilities, Staten Island, NY 10314,
USA
bResearch Design and Analysis Service, New York State Institute for
Basic Research in Developmental Disabilities, Staten Island, NY 10314,
USA
Received 31 March 2005; revised 23 June 2005; accepted 10 July 2005.
Available online 18 August 2005.
Abstract
Neuronal progenitor cells (NPCs) are being considered for treatment of
neurodegenerative diseases associated with =DF-amyloidosis: Alzheimer's
disease (AD) and Down syndrome (DS). However, the neurotoxic properties
of amyloid-=DF peptide (A=DF) may impair survival and differentiation of
transplanted NPCs. Hence, we studied the influence of A=DF on
development of human NPCs - proliferation, migration, formation of
colonies of neurons, formation processes - in culture.
Pre-fibrillized human A=DF1-40 blocked development of neuronal
colonies. NPC development was impaired in the presence of soluble
A=DF1-40 (1.75-7 =B5M), and NPC differentiation into large and small
neurons was altered, as demonstrated by morphometry. Antioxidant
vitamin E partially abolished these effects, but not the reduced
formation of neuronal processes. NPCs cultured with 7 =B5M A=DF1-40
accumulated A=DF monomers and oligomers and contained higher levels of
protein carbonyls and lipid peroxidation products HNE and MDA. We
suggest that A=DF1-40 impairs development of NPCs by oxidative damage.
Hence, a prerequisite of successful neuroreplacement therapy using NPCs
in AD and DS/AD may be removal of amyloid-=DF and antioxidative
treatment.
Keywords: Amyloid-=DF; Cell culture; Neuronal progenitor cells;
Neuroreplacement therapy; Oxidative stress
Corresponding author. Tel.: +1 718 494 5115; fax: +1 718 494 4856.
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They say .. the amyloid plaque MUST be removed .. ?
Use an iron .. chelator .. ?
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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 8, 2006; DOI: 10.1124/jpet.106.103184
Received for publication February 22, 2006.
Revised May 31, 2006.
Accepted for publication June 7, 2006.
A novel phospholipid derivative of indomethacin, DP-155, shows superior
safety and similar efficacy in reducing brain amyloid in an
Alzheimer's disease model
Eran Dvir 1*, Jonathan E. Friedman 1, Joo-Yong Lee 2, Jae-Young Koh 2,
Firas Younis 1, Shaul Raz 1, Israel Shapiro 1, Amnon Hoffman 3, Arik
Dahan 3, Gilad Rosenberg 1, Itzchak Angel 1, Alex Kozak 1, Revital
Duvdevani 1
1 D-Pharm Ltd. 2 university of Ulsan 3 The Hebrew university of
Jerusalem
* Address correspondence to: E-mail: edvir@dpharm.com
Abstract
Indomethacin has been suggested for the treatment of Alzheimer's
disease (AD), but its use is limited by gastrointestinal and renal
toxicity. To overcome this limitation, D-Pharm developed DP-155, a
lecithin derivative of indomethacin. Safety was tested by daily oral
administration of DP-155 or indomethacin to rats in a dose range of
0=2E007-0.28 mmol/kg. The prevalence of gastrointestinal ulceration was
significantly lower (10- fold) for DP-155 than for indomethacin and the
ulcerations were delayed. Signs of renal toxicity, namely reduced urine
output and increased urine N-acetyl glycosaminidase to creatinine
ratio, were 5-fold lower for DP-155. Indomethacin, but not an equimolar
dose of DP-155, reduced urine bicyclo-PGE2. An equimolar oral dose of
DP-155 or indomethacin, administered every 4h for 3 days, was equally
efficacious in reducing the levels of A42 in the brains of Tg2576 mice.
Indomethacin was the principal metabolite of DP-155 in the serum. After
DP-155 oral administration, indomethacin's half-life in the serum and
the brain was 22h and 93h, respectively, compared to 10h and 24h
following indomethacin oral administration. The brain to serum ratio
was 3.5 times higher for DP-155 than indomethacin. This finding
explains the efficacy of DP-155, in reducing A42 brain levels, despite
the low systemic blood concentrations of indomethacin derived from
DP-155. In conclusion, compared to indomethacin, DP-155 has
significantly lower toxicity in the gut and kidney whilst maintaining
similar efficacy to indomethacin in lowering A42 in the brains of
Tg2576 mice. This superior safety profile highlights DP- 155's
potential as an improved indomethacin-based therapy for AD.
Key words: Alzheimer's disease, Amyloid beta, gastrointestinal safety,
indomethacin, nephrotoxicity, phospholipid
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Metab Brain Dis 2003 Mar;18(1):1-9
Indomethacin reduces lipid peroxidation in rat brain homogenate by
binding Fe2+.
Anoopkumar-Dukie S, Lack B, McPhail K, Nyokong T, Lambat Z, Maharaj D,
Daya S
Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa.
[Medline record in process]
One of the hallmarks of Alzheimer's disease (AD) is the progressive
degeneration of cholinergic neurons in the cerebral cortex and
hippocampus. It is generally accepted that this neuronal degeneration
is due to free-radical-induced damage. These free radicals attack
vital structural components of the neurons. This implies that agents
that reduce free radical generation could potentially delay the
progression of AD. Free radical generation in the brain is assisted by
the presence of iron, required by the Fenton reaction. Thus, agents
that reduce iron availability for this reaction could potentially
reduce free radical formation. Since non steroidal anti-inflammatory
drugs (NSAIDS) have been shown to reduce the severity of AD, we
investigated the possible mechanism by which indomethacin could afford
neuroprotection. Our results show that indomethacin (1 mM) is able to
reduce the iron-induced rise in lipid peroxidation in rat brain
homogenates. In addition, our NMR data indicate that indomethacin
binds the Fe(2+)/Fe(3+) ion. This was confirmed by a study using
UV/Vis spectrophotometry. The results imply that indomethacin provides
a neuroprotective effect by binding to iron and thus making it
unavailable for free radical production.
PMID: 12603077, UI: 22490682
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