Different susceptibility to the Parkinson's toxin MPTP in mice lacking the redox master regulator Nrf2 or its target gene heme oxygenase-1.
BACKGROUND
The transcription factor Nrf2 (NF-E2-related factor 2) and its target gene products, including heme oxygenase-1 (HO-1), elicit an antioxidant response that may have therapeutic value for Parkinson's disease (PD). However, HO-1 protein levels are increased in dopaminergic neurons of Parkinson's disease (PD) patients, suggesting its participation in free-iron deposition, oxidative stress and neurotoxicity. Before targeting Nrf2 for PD therapy it is imperative to determine if HO-1 is neurotoxic or neuroprotective in the basal ganglia.


METHODS
We addressed this question by comparing neuronal damage and gliosis in Nrf2- or HO-1-knockout mice submitted to intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for five consecutive days. Nrf2-knockout mice showed exacerbated gliosis and dopaminergic nigrostriatal degeneration, as determined by immunohistochemical staining of tyrosine hydroxylase in striatum (STR) and substantia nigra (SN) and by HPLC determination of striatal dopamine and 3,4- dihydroxyphenylacetic acid (DOPAC). On the other hand, the severity of gliosis and dopaminergic degeneration in HO-1-null mice was neither increased nor reduced. Regarding free-iron deposition, both Nrf2- and HO-1-deficient mice exhibited similar number of deposits as determined by Perl's staining, therefore indicating that these proteins do not contribute significantly to iron accumulation or clearance in MPTP-induced Parkinsonism.


CONCLUSIONS
These results suggest that HO-1 does not protect or enhance the sensitivity to neuronal death in Parkinson's disease and that pharmacological or genetic intervention on Nrf2 may provide a neuroprotective benefit as add on therapy with current symptomatic protocols.
Innamorato
Nadia G
NG
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Spain.
Jazwa
Agnieszka
A
Rojo
Ana I
AI
García
Concepción
C
Fernández-Ruiz
Javier
J
Grochot-Przeczek
Anna
A
Stachurska
Anna
A
Jozkowicz
Alicja
A
Dulak
Jozef
J
Cuadrado
Antonio
A
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005911:Gliosis / Q000139:chemically induced / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D007501:Iron / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction
D051267:NF-E2-Related Factor 2; D009498:Neurotoxins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D007501:Iron; D051547:Heme Oxygenase-1; D004298:Dopamine