Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism
| Autor: | Ana I. Rojo, Antonio Cuadrado, Marlen Hesse, Agnieszka Jazwa, Nadia G. Innamorato, Javier Fernández-Ruiz |
|---|---|
| Přispěvatelé: | UAM. Departamento de Bioquímica |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Symptoms of Parkinson’s disease
Physiology Dopamine Dopamine Agents Clinical Biochemistry Pharmacology medicine.disease_cause Biochemistry Antioxidants Basal Ganglia Factor Nrf2 Mice chemistry.chemical_compound Neuroinflammation Isothiocyanates NAD(P)H Dehydrogenase (Quinone) General Environmental Science Mice Knockout Parkinsonism MPTP Dopaminergic Neuroprotective Agents 1-Methyl-4-phenyl-1 2 3 6-tetrahydropyridine Sulfoxides Disease Progression medicine.drug medicine.medical_specialty NF-E2-Related Factor 2 Medicina Neurotoxins Biology Neuroprotection Parkinsonian Disorders Downregulation and upregulation Internal medicine medicine Animals Anticarcinogenic Agents Molecular Biology Cell Biology medicine.disease Endocrinology chemistry Oxidative stress Astrocytes Therapies General Earth and Planetary Sciences Sulforaphane Heme Oxygenase-1 Thiocyanates Pathway |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Biblos-e Archivo. Repositorio Institucional de la UAM |
| DOI: | 10.1089/ars.2010.3731 |
| Popis: | Current therapies for motor symptoms of Parkinson's disease (PD) are based on dopamine replacement. However, the disease progression remains unaffected, because of continuous dopaminergic neuron loss. Since oxidative stress is actively involved in neuronal death in PD, pharmacological targeting of the antioxidant machinery may have therapeutic value. Here, we analyzed the relevance of the antioxidant phase II response mediated by the transcription factor NF-E2-related factor 2 (Nrf2) on brain protection against the parkinsonian toxin methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Intraperitoneal administration of the potent Nrf2 activator sulforaphane (SFN) increased Nrf2 protein levels in the basal ganglia and led to upregulation of phase II antioxidant enzymes heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase (NQO1). In wild-type mice, but not in Nrf2-knockout mice, SFN protected against MPTP-induced death of nigral dopaminergic neurons. The neuroprotective effects were accompanied by a decrease in astrogliosis, microgliosis, and release of pro-inflammatory cytokines. These results provide strong pharmacokinetic and biochemical evidence for activation of Nrf2 and phase II genes in the brain and also offer a neuroprotective strategy that may have clinical relevance for PD therapy. This work was supported by a Target Validation Grant of the Michael J. Fox Foundation for Parkinson’s Research and grant SAF2010-17822 from the Spanish Ministery of Science and Innovation. N.G.I. is recipient of a fellowship FPU from Universidad Autónoma of Madrid. |
| Databáze: | OpenAIRE |
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