TY - JOUR
T1 - In vivo induction of heat shock proteins in the substantia nigra following L-DOPA administration is associated with increased activity of mitochondrial complex I and nitrosative stress in rats
T2 - Regulation by glutathione redox state
AU - Calabrese, Vittorio
AU - Mancuso, Cesare
AU - Ravagna, Agrippino
AU - Perluigi, Marzia
AU - Cini, Chiara
AU - Marco, Carlo De
AU - Allan Butterfield, D.
AU - Stella, Anna Maria Giuffrida
PY - 2007/5
Y1 - 2007/5
N2 - Increasing evidence suggests a critical role for oxidative and nitrosative stress in the pathogenesis of most important neurodegenerative disorders. Parkinson's disease (PD) is a neurodegenerative disease characterized by a severe depletion in number of dopaminergic cells of the substantia nigra (SN). Administration of L-DOPA (LD) is the more effective treatment for patients with PD. However, the vast majority of patients suffer LD-related complications, which represent the major problem in the clinical management of PD. In the present study, LD administration to rats resulted in a significant dose-dependent increase in Hsp70 synthesis which was specific for the SN. The amount of 70 kDa protein increased after 6 h treatment reaching the maximal induction after 24-48 h. Induction of Hsp70 in the SN was associated with a significant increase in constitutive Hsc70 and mitochondrial Hsp60 stress proteins, and with increased expression of mitochondrial complex I whereas no significant changes were found in the activity of complex IV. In the same experimental conditions, a significant decrease in reduced glutathione was observed, which was associated with an increased content of oxidized glutathione content as well as nitric oxide (NO) synthase activity, NO metabolites and nitrotyrosine immunoreactivity. Interestingly, Hsp70 induction, iNOS up-regulation and nitrotyrosine formation have been confirmed also in SN and striatum of rats treated with LD and carbidopa, this latter being an inhibitor of the peripheral DOPA decarboxylase. Our data are in favor of the importance of the heat shock signal pathway as a basic mechanism of defense against neurotoxicity elicited by free radical oxygen and nitrogen species produced in aging and neurodegenerative disorders.
AB - Increasing evidence suggests a critical role for oxidative and nitrosative stress in the pathogenesis of most important neurodegenerative disorders. Parkinson's disease (PD) is a neurodegenerative disease characterized by a severe depletion in number of dopaminergic cells of the substantia nigra (SN). Administration of L-DOPA (LD) is the more effective treatment for patients with PD. However, the vast majority of patients suffer LD-related complications, which represent the major problem in the clinical management of PD. In the present study, LD administration to rats resulted in a significant dose-dependent increase in Hsp70 synthesis which was specific for the SN. The amount of 70 kDa protein increased after 6 h treatment reaching the maximal induction after 24-48 h. Induction of Hsp70 in the SN was associated with a significant increase in constitutive Hsc70 and mitochondrial Hsp60 stress proteins, and with increased expression of mitochondrial complex I whereas no significant changes were found in the activity of complex IV. In the same experimental conditions, a significant decrease in reduced glutathione was observed, which was associated with an increased content of oxidized glutathione content as well as nitric oxide (NO) synthase activity, NO metabolites and nitrotyrosine immunoreactivity. Interestingly, Hsp70 induction, iNOS up-regulation and nitrotyrosine formation have been confirmed also in SN and striatum of rats treated with LD and carbidopa, this latter being an inhibitor of the peripheral DOPA decarboxylase. Our data are in favor of the importance of the heat shock signal pathway as a basic mechanism of defense against neurotoxicity elicited by free radical oxygen and nitrogen species produced in aging and neurodegenerative disorders.
KW - Glutathione
KW - Heat shock protein
KW - Levodopa
KW - Mitochondria
KW - Nitrosative stress
KW - Substantia nigra
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U2 - 10.1111/j.1471-4159.2006.04367.x
DO - 10.1111/j.1471-4159.2006.04367.x
M3 - Article
C2 - 17241115
AN - SCOPUS:34247326430
SN - 0022-3042
VL - 101
SP - 709
EP - 717
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 3
ER -