Different Susceptibility to the Parkinson's Toxin MPTP in Mice Lacking the Redox Master Regulator Nrf2 or Its Target Gene Heme Oxygenase-1

Abstract

BackgroundThe 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.MethodologyWe 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.ConclusionsThese 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.

Pharmacological Targeting of the Transcription Factor Nrf2 at the Basal Ganglia Provides Disease Modifying Therapy for Experimental Parkinsonism

“…HPLCs were performed as previously described (9). For HPLC determination of SFN, STR and VMB were dissected and rapidly frozen at -80°C.…”

Role of the Transcription Factor Nrf2 in Parkinson’s Disease: New Insights

“…Furthermore, DJ-1 induces thioredoxin 1 expression through NRF2 pathway [85] and that DJ-1 stabilizes NRF2 by preventing association with KEAP1, and NRF2's subsequent ubiquitination and degradation [86]. DJ-1/-mice did not exhibit widespread neuronal loss in a PD disease model [87,88], but these neurons were more susceptible to death after toxic insults [87], indicating a similar behaviour between DJ-1/-and Nrf2/-mice [89] that could be explained due to the loss of antioxidant gene transcription.…”

Therapeutic Potential of the Activators of the Nuclear Factor Erythroid 2-Related Factor 2–Antioxidant Response Element Pathway in Brain Disorders

“…It was reported that Nrf2 −/− mice showed more severe neuronal loss than HO-1 −/− mice in response to MPTP. 24) This is believed to be because Nrf2 upregulates HO-1 expression as well as other phase II enzymes that may detoxify MPTP or 1-methyl-4-phenylpyridinium + . The second mechanism is the antiinflammatory effect of Nrf2.…”