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Aging and disease    2018, Vol. 9 Issue (4) : 716-728     DOI: 10.14336/AD.2017.1018
Review Article |
Superoxide Radical Dismutation as New Therapeutic Strategy in Parkinson’s Disease
De Lazzari Federica1, Bubacco Luigi1, Whitworth Alexander J2, Bisaglia Marco1,*
1Molecular Physiology and Biophysics Unit, Department of Biology, University of Padova, 35131 Padova, Italy.
2Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XY, UK.
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Abstract  

Aging is the biggest risk factor for developing many neurodegenerative disorders, including idiopathic Parkinson’s disease (PD). PD is still an incurable disorder and the available medications are mainly directed to the treatment of symptoms in order to improve the quality of life. Oxidative injury has been identified as one of the principal factors involved in the progression of PD and several indications are now reported in the literature highlighting the prominent role of the superoxide radical in inducing neuronal toxicity. It follows that superoxide anions represent potential cellular targets for new drugs offering a novel therapeutic approach to cope with the progression of the disease. In this review we first present a comprehensive overview of the most common cellular reactive oxygen and nitrogen species, describing their cellular sources, their potential physiological roles in cell signalling pathways and the mechanisms through which they could contribute to the oxidative damage. We then analyse the potential therapeutic use of SOD-mimetic molecules, which can selectively remove superoxide radicals in a catalytic way, focusing on the classes of molecules that have therapeutically exploitable properties.

Keywords antioxidants      oxidative damage      Parkinson’s disease      SOD-mimetics      superoxide dismutases     
Corresponding Authors: Bisaglia Marco   
About author:

These authors equally contributed to this work.

Issue Date: 01 August 2018
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De Lazzari Federica
Bubacco Luigi
Whitworth Alexander J
Bisaglia Marco
Cite this article:   
De Lazzari Federica,Bubacco Luigi,Whitworth Alexander J, et al. Superoxide Radical Dismutation as New Therapeutic Strategy in Parkinson’s Disease[J]. Aging and disease, 2018, 9(4): 716-728.
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http://www.aginganddisease.org/EN/10.14336/AD.2017.1018     OR     http://www.aginganddisease.org/EN/Y2018/V9/I4/716
Figure 1.  Oxidative injury and PD

Mitochondrial dysfunction, dopamine metabolism and neuroinflammation co-participate in promoting oxidative damage in dopaminergic neurons. Complexes I and III of the mitochondrial electron transport chain are the main sources of O2•- inside cells. The PD-related toxins MPTP and rotenone are complex I inhibitors. Chronic activation of microglia represents a further mechanism of O2•- and NO radical’s generation through the action of NADPH-oxidase (NOX) and inducible nitric oxide synthase (iNOS), respectively. In activated microglia, myeloperoxidase (MPO) is responsible for the formation of HClO. The PD-associated proteins α-Synuclein and LRRK2 contribute to microglia activation. Specific to dopaminergic neurons, the cytosolic oxidation of dopamine to dopamine-quinones leads to the production of the O2•-. Cytosolic O2•- is transformed by the action of superoxide dismutase 1 (SOD1) in H2O2, which can produce the highly toxic radical HO through the Fenton reaction. Otherwise, O2•-can react with NO to form the very reactive molecule ONOO-. (FMN: flavin mononucleotide; IMS: intermembrane space; nNOS: neuronal nitric oxide synthase; VDAC: voltage-dependent anion channels).

ROS/RNS speciesPhysiological functionsReference
O2•-Inflammasome activation and cytokines release[65, 66]
H2O2Modification of protein activity. Modulation of signalling pathways (NF-kB) and gene expression (Nrf2)[64, 67]
NOVasodilatation, platelet aggregation, neuronal firing, synaptic plasticity, and neurotransmitter release[68, 69]
Table 1  Physiological functions ascribed to ROS and RNS.
Figure 2.  SOD-mimetic compounds

(A) MnTDE-2-ImP5+, a Mn-porphyrin and (B) M40403, a Mn(II)-cyclic polyamine are among the most interesting SOD-mimetic molecules from a therapeutic standpoint.

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