Journal Article

Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: Critical role for the astrocyte

Chen, Pei-Chun, Kan, Yuet Wai, Pani, Amar K, Vargas, Marcelo R, Johnson, Delinda A, Smeyne, Richard J, Johnson, Jeffrey A

2009

Overview

Oxidative stress has been implicated in the etiology of Parkinson's disease (PD) and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of PD. It is known that under conditions of oxidative stress, the transcription factor NF-E2-related factor (Nrf2) binds to antioxidant response element (ARE) to induce antioxidant and phase II detoxification enzymes. To investigate the role of Nrf2 in the process of MPTP-induced toxicity, mice expressing the human placental alkaline phosphatase (hPAP) gene driven by a promoter containing a core ARE sequence (ARE-hPAP) were used. ARE-hPAP mice were injected (30 mg/kg) once per day for 5 days and killed 7 days after the last MPTP injection. In response to this design, ARE-dependent gene expression was decreased in striatum whereas it was increased in substantia nigra. The same MPTP protocol was applied in Nrf2⁺/⁺ and Nrf2⁻/⁻ mice; Nrf2 deficiency increases MPTP sensitivity. Furthermore, we evaluated the potential for astrocytic Nrf2 overexpression to protect from MPTP toxicity. Transgenic mice with Nrf2 under control of the astrocyte-specific promoter for the glial fribillary acidic protein (GFAP-Nrf2) on both a Nrf2⁺/⁺ and Nrf2⁻/⁻ background were administered MPTP. In the latter case, only the astrocytes expressed Nrf2. Independent of background, MPTP-mediated toxicity was abolished in GFAP-Nrf2 mice. These striking results indicate that Nrf2 expression restricted to astrocytes is sufficient to protect against MPTP and astrocytic modulation of the Nrf2-ARE pathway is a promising target for therapeutics aimed at reducing or preventing neuronal death in PD.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - pharmacology / alkaline phosphatase / Alkaline Phosphatase - genetics / Animal models / Animals / Antioxidants / Astrocytes / Astrocytes - pathology / Base Sequence / Binding sites / Biological Sciences / cell death / Corpus Striatum - drug effects / Corpus Striatum - pathology / Detoxification / Disease Models, Animal / DNA Primers / Dosage / Enzymes / etiology / Gene expression / Genes / Glial Fibrillary Acidic Protein - genetics / humans / Immunohistochemistry / metabolic detoxification / Mice / Mice, Transgenic / MPTP Poisoning - pathology / MPTP Poisoning - physiopathology / neurons / neuroprotective effect / Neurotoxicity / NF-E2-Related Factor 2 - genetics / NF-E2-Related Factor 2 - physiology / Oxidative stress / Parkinson disease / Parkinson Disease - pathology / Parkinson Disease - physiopathology / Parkinson's disease / Proteins / Response elements / Rodents / Special relativity / Substantia Nigra - drug effects / Substantia Nigra - pathology / therapeutics / Toxicity / transcription factors / transgenic animals / Vehicles