title: Minocycline protects, rescues and prevents knockdown transgenic parkin Drosophila against paraquat/iron toxicity: Implications for autosomic recessive juvenile parkinsonism.
abstract: Autosomal recessive Juvenile Parkinsonism (AR-JP) is a chronic, progressive neurodegenerative disorder caused by mutation in the PARKIN gene, and invariably associated with dopaminergic (DAergic) neuronal loss and brain iron accumulation. Since current medical therapy is symptomatic and lacks significant disease-modifying effects, other treatment approaches are urgently needed it. In the present work, we investigate the role of minocycline (MC) in paraquat (PQ)/iron-induced neurotoxicity in the Drosophila TH>parkin-RNAi/+ (w[*]; UAS-parkin-RNAi; TH-GAL4) fly and have shown the following: (i) MC increased life span and restored the locomotor activity of knockdown (KD) transgenic parkin flies in comparison with the control (vehicle) group; (ii) MC at low (0.1 and 0.3mM) and middle (0.5mM) concentrations protected, rescued and prevented KD parkin Drosophila against PQ toxicity. However, MC at high (1mM) concentration aggravated the toxic effect of PQ; (iii) MC protected and rescued DAergic neurons against the PQ toxic effect according to tyrosine hydroxylase (TH)>green-fluorescent protein (GFP) reporter protein microscopy and anti-TH Western blotting analysis; (iv) MC protected DAergic neurons against PQ/iron toxicity; (v) MC significantly abridged lipid peroxidation (LPO) in the protection, rescue and prevention treatment in TH>parkin-RNAi/+ flies against PQ or iron alone or combined (PQ/iron)-induced neuronal oxidative stress (OS). Our results suggest that MC exerts neuroprotection against PQ/iron-induced OS in DAergic neurons most probably by the scavenging activity of reactive oxygen species (ROS), and by chelating iron. Therefore, MC might be a potential therapeutic drug to delay, revert, or prevent AR-JP.
authors.affiliation: Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, University of Antioquia (UdeA), Calle 70 No. 52-21, and Calle 62 # 52-59, Building 1, Room 412, SIU, Medellin, Colombia.
authors.forename: Hector Flavio
authors.initials: HF
authors.lastname: Ortega-Arellano
authors.affiliation: Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, University of Antioquia (UdeA), Calle 70 No. 52-21, and Calle 62 # 52-59, Building 1, Room 412, SIU, Medellin, Colombia. Electronic address: marlene.jimenez@udea.edu.co.
authors.forename: Marlene
authors.initials: M
authors.lastname: Jimenez-Del-Rio
authors.affiliation: Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, University of Antioquia (UdeA), Calle 70 No. 52-21, and Calle 62 # 52-59, Building 1, Room 412, SIU, Medellin, Colombia. Electronic address: calberto.velez@udea.edu.co.
authors.forename: Carlos
authors.initials: C
authors.lastname: Velez-Pardo
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster; D005260:Female; D055785:Gene Knockdown Techniques; D007501:Iron / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008911:Minocycline / Q000008:administration & dosage*; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000187:drug effects; D010269:Paraquat / Q000633:toxicity*; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism*; D016019:Survival Analysis; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D018696:Neuroprotective Agents; D007501:Iron; D044767:Ubiquitin-Protein Ligases; C487430:park protein, Drosophila; D008911:Minocycline; D010269:Paraquat
keywords: Iron; Lipid peroxidation; Minocyclin; Oxidative stress; Paraquat; Parkin; Parkinson’s disease