I
Med Hypotheses. 2005;64(4):736-41. Related Articles, Links
Pharmacological manipulation of ataxia-telangiectasia kinase activity
as a treatment for Parkinson's disease.
Edwin Shackelford R, Manuszak RP, Heard SC, Link CJ, **** S.
Department of Pathology, Lousiana State University at Shreveport, 1501
Kings Hwy, P.O. Box 33932, Shreveport, LA 711030-3932, USA.
Parkinson's disease (PD) is a major cause of morbidity and mortality
among older individuals. Although the causes of Parkinson's disease are
multifactorial, considerable evidence indicates that elevated labile
iron in the substantia nigra pars compacta plays an important role in
producing oxyradicals which subsequently damage nigro-striatal neurons.
Based on this several researchers have suggested that blood-brain
barrier crossing iron chelators might have clinical efficacy in
treating PD. Work demonstrating that iron chelators protect
nigro-striatal neurons in the
N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and
6-hydroxydopamine-induced rodent PD models supports this hypothesis.
Recently, we found that the ATM gene product (mutated in
ataxia-telangiectasia, A-T), is required for cell survival and genomic
stability maintenance following exposure to low labile iron
concentrations. Iron chelators (desferal, quercetin, and apoferritin)
also increase A-T cell genomic stability and viability, and activate
ATM-dependent cellular events in normal cells. Additionally
Atm-deficient mice exhibit a selective loss of dopaminergic
nigro-striatal neurons. Based on this, we propose that iron chelators
protect the substantia nigra pars compacta not only by chelating labile
iron and reducing oxyradical formation, but also by inducing ATM
activity, leading to increased oxidative stress resistance and DNA
repair. Support for this hypothesis comes from the recent observation
that the iron chelating flavonoid quercetin both directly activates ATM
and protects neuronal cells from the toxic effects of the
N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Therefore since; (1) ATM
is required for iron toxicity resistance, (2) iron chelators such as
quercetin, desferal, and apoferritin induce ATM activity and/or
ATM-dependent events, and (3), Atm-deficient mice preferentially lose
dopaminergic nigro-striatal neurons, we propose that ATM activity has
an important function in PD. Furthermore, pharmacological manipulation
of ATM activity via iron chelation might have clinical efficacy in PD
treatment.
PMID: 15694690 [PubMed - in process]
--------------------------------------------------------------------------------
Who loves ya.
Tom
http://herbivore.7h.com
Pharmacological manipulation of ataxia-telangiectasia kinase activity
as a treatment for Parkinson's disease.
Edwin Shackelford R, Manuszak RP, Heard SC, Link CJ, **** S.
Department of Pathology, Lousiana State University at Shreveport, 1501
Kings Hwy, P.O. Box 33932, Shreveport, LA 711030-3932, USA.
Parkinson's disease (PD) is a major cause of morbidity and mortality
among older individuals. Although the causes of Parkinson's disease are
multifactorial, considerable evidence indicates that elevated labile
iron in the substantia nigra pars compacta plays an important role in
producing oxyradicals which subsequently damage nigro-striatal neurons.
Based on this several researchers have suggested that blood-brain
barrier crossing iron chelators might have clinical efficacy in
treating PD. Work demonstrating that iron chelators protect
nigro-striatal neurons in the
N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and
6-hydroxydopamine-induced rodent PD models supports this hypothesis.
Recently, we found that the ATM gene product (mutated in
ataxia-telangiectasia, A-T), is required for cell survival and genomic
stability maintenance following exposure to low labile iron
concentrations. Iron chelators (desferal, quercetin, and apoferritin)
also increase A-T cell genomic stability and viability, and activate
ATM-dependent cellular events in normal cells. Additionally
Atm-deficient mice exhibit a selective loss of dopaminergic
nigro-striatal neurons. Based on this, we propose that iron chelators
protect the substantia nigra pars compacta not only by chelating labile
iron and reducing oxyradical formation, but also by inducing ATM
activity, leading to increased oxidative stress resistance and DNA
repair. Support for this hypothesis comes from the recent observation
that the iron chelating flavonoid quercetin both directly activates ATM
and protects neuronal cells from the toxic effects of the
N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Therefore since; (1) ATM
is required for iron toxicity resistance, (2) iron chelators such as
quercetin, desferal, and apoferritin induce ATM activity and/or
ATM-dependent events, and (3), Atm-deficient mice preferentially lose
dopaminergic nigro-striatal neurons, we propose that ATM activity has
an important function in PD. Furthermore, pharmacological manipulation
of ATM activity via iron chelation might have clinical efficacy in PD
treatment.
PMID: 15694690 [PubMed - in process]
--------------------------------------------------------------------------------
Who loves ya.
Tom
http://herbivore.7h.com