The Cyclic Nitroxide TEMPOL Ameliorates Oxidative Stress but Not Inflammation in a Cell Model of Parkinson's Disease.

Alexander Leathem,Joanne M Dennis,Martin Simone,Paul K Witting

doi:10.3390/antiox11020257

Alexander Leathem, Joanne M Dennis + Show 2 more

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https://doi.org/10.3390/antiox11020257

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Journal: Antioxidants	Publication Date: Jan 28, 2022
Citations: 5	License type: CC BY 4.0

Affiliation: University of Sydney, Griffith University

Abstract

The cyclic nitroxide TEMPOL exerts anti-oxidative and anti-inflammatory effects, and thus may provide therapeutic benefit in Parkinson’s disease (PD), in which mitochondrial dysfunction, oxidative damage and inflammation have been implicated as pathophysiological mechanisms underlying the selective loss of dopaminergic neurons. Markers of oxidative stress and inflammation were investigated in a cell model of differentiated human neuroblastoma (SH-SY5Y) cells treated with the neurotoxin, 6-hydroxydopamine (6-OHDA). Treatment with TEMPOL ameliorated 6-OHDA-mediated cytotoxicity and attenuated biomarkers of oxidative stress including: mitochondrial superoxide anion free radical production, lipid peroxidation, induction of heme oxygenase 1 (HO-1) protein expression and NFκB activation. Treatment with TEMPOL abated decreased gene expression of DRD2S and DRD2L induced by 6-OHDA indicating that TEMPOL may prevent mitochondrial dysfunction and activation of pathways that result in receptor desensitization. 6-OHDA insult decreased gene expression of the antioxidant, SOD-1, and this diminution was also mitigated by TEMPOL. Activation of NFκB increased pro-inflammatory IFNy and decreased IL-6, however, TEMPOL had no effect on these inflammation mediators. Overall, this data suggests that cyclic nitroxides may preserve dopaminergic neuronal cell viability by attenuating oxidative stress and mitochondrial dysfunction, but are unable to affect inflammatory mediators that propagate cellular damage and neurodegeneration in PD.

Highlights

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that arises due to a complex interplay of age, genetic and environmental risk factors
Differentiation with retinoic acid (RA) and TPA resulted in a mature neuronal phenotype
The(Figure development ofdevelopment axonal growthofand synaptic connections aptic connections mimics the of dopaminergic neurons in vivo

Summary

Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that arises due to a complex interplay of age, genetic and environmental risk factors. Pathological features of PD include selective loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of α-synuclein-containing Lewy bodies [1], which contribute to reduced dopamine modulation of basal ganglia functions [2] and manifest as characteristic motor symptoms of PD. The mechanism (s) of dopaminergic neuron loss and corresponding impaired motor function is unclear. While genetic risk polymorphisms are present in familial cases, PD remains a multi-factorial and largely idiopathic disease [4]. Oxidative stress is considered a convergent point for a raft of molecular events including mitochondrial dysfunction, inflammation, genetic mutations, and aberrant protein formation; all factors implicated in PD pathogenesis [4,5]. Oxidized biomolecules and decreased antioxidants, such as glutathione and superoxide dismutase (SOD), are evident in the substantia nigra

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