On the Role of DT-Diaphorase Inhibition in Aminochrome-Induced Neurotoxicity In Vivo
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Dopamine oxidation in the pathway leading to neuromelanin formation generates the ortho-quinone aminochrome, which is potentially neurotoxic but normally rapidly converted by DT-diaphorase to nontoxic leukoaminochrome. However, when administered exogenously into rat striatum, aminochrome is able to produce damage to dopaminergic neurons. Because of a recent report that substantia nigra pars compacta (SNpc) tyrosine hydroxylase (T-OH) levels were unaltered by aminochrome when there was cell shrinkage of dopaminergic neurons along with a reduction in striatal dopamine release, the following study was conducted to more accurately determine the role of DT-diaphorase in aminochrome neurotoxicity. In this study, a low dose of aminochrome (0.8 nmol) with or without the DT-diaphorase inhibitor dicoumarol (0.2 nmol) was injected into the left striatum of rats. Intrastriatal 6-hydroxydopamine (6-OHDA, 32 nmol) was used as a positive neurotoxin control in other rats. Two weeks later, there was significant loss in numbers of T-OH immunoreactive fibers in SNpc, also a loss in cell density in SNpc, and prominent apomorphine (0.5 mg/kg sc)-induced contralateral rotations in rats that had been treated with aminochrome, with aminochrome/dicoumarol, or with 6-OHDA. Findings demonstrate that neurotoxic aminochrome is able to exert neurotoxicity only when DT-diaphorase is suppressed—implying that DT-diaphorase is vital in normally suppressing toxicity of in vivo aminochrome, generated in the pathway towards neuromelanin formation.
KeywordsAminochrome DT-diaphorase Neurotoxicity Substantia nigra Dopamine Neurodegeneration Neuroprotection
The authors are thankful to Ali Jahanshahi (Postdoctoral Fellow at Maastricht University), João Oliveira (PhD student at Maastricht University) and Denise Hermes, and Hellen Steinbusch for all the technical support and guidance.
This work was supported by FONDECYT no. 1100165 (JSA), University of Chile ENL014/14 (JSA).
- Arriagada C, Paris I, Sanchez de las Matas MJ, Martinez-Alvarado P, Cardenas S, Castañeda P, Graumann R, Perez-Pastene C, Olea-Azar C, Couve E, Herrero MT, Caviedes P, Segura-Aguilar J (2004) On the neurotoxicity mechanism of leukoaminochrome o-semiquinone radical derived from dopamine oxidation: mitochondria damage, necrosis, and hydroxyl radical formation. Neurobiol Dis 16:468–477CrossRefPubMedGoogle Scholar
- Faunes M, Oñate-Ponce A, Fernández-Collemann S, Henny P (2015) Excitatory and inhibitory innervation of the mouse orofacial motor nuclei: a stereological study. J Comp Neuro l524:738–758Google Scholar
- Herrera A, Muñoz P, Paris I, Díaz-Veliz G, Mora S, Inzunza J, Hultenby K, Cardenas C, Jaña F, Raisman-Vozari R, Gysling K, Abarca J, Steinbusch HW, Segura-Aguilar J (2016) Aminochrome induces dopaminergic neuronal dysfunction: a new animal model for Parkinson's disease. Cell Mol Life Sci 73:3583–3597CrossRefPubMedGoogle Scholar
- Herrera A, Muñoz P, Steinbusch HW, Segura-Aguilar J. (2017) Are Dopamine Oxidation Metabolites Involved in the Loss of Dopaminergic Neurons in the Nigrostriatal System in Parkinson's Disease? ACS Chem Neurosci. 2017 Mar 3. doi: 10.1021/acschemneuro.7b00034
- Huenchuguala S, Muñoz P, Zavala P, Villa M, Cuevas C, Ahumada U, Graumann R, Nore BF, Couve E, Mannervik B, Paris I, Segura-Aguilar J (2014) Glutathione transferase mu 2 protects glioblastoma cells against aminochrome toxicity by preventing autophagy and lysosome dysfunction. Autophagy 10:618–630CrossRefPubMedPubMedCentralGoogle Scholar
- Muñoz P, Segura-Aguilar J (2016) Commentary: a humanized clinically calibrated quantitative systems pharmacology model for hypokinetic motor symptoms in Parkinson's disease. Front Pharmacol 27:179Google Scholar
- Muñoz P, Segura-Aguilar J. (2017) Why we cannot translate successful results to new therapies in Parkinson’s disease. Clin Pharmacol Transl Med. 1Google Scholar
- Muñoz P, Huenchuguala S, Paris I, Segura-Aguilar J (2012a) Dopamine oxidation and autophagy. Parkinsons Dis 920953Google Scholar
- Muñoz P, Paris I, Segura-Aguilar J (2016) Commentary: evaluation of models of Parkinson's disease. Front Neurosci 19:10–161Google Scholar
- Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates, 6th edn. Academic Press, San Diego, CAGoogle Scholar
- Segura-Aguilar J (2016d) New preclinical model are required to discover neuroprotective compound in Parkinson's disease. Pharmacol Res pii S1043-6618(16):31198–31197Google Scholar
- Segura-Aguilar J, Metodiewa D, Welch CJ. (1998) Metabolic activation of dopamine o-quinones to osemiquinones by NADPH cytochrome P450 reductase may play an important role in oxidative stress and apoptotic effects. Biochim Biophys Acta. 1381:1-6Google Scholar
- Segura-Aguilar J (2016c) New preclinical model are required to discover neuroprotective compound in Parkinson's disease. Pharmacol Res pii S1043-6618(16):31198–31197Google Scholar
- Zafar KS, Siegel D, Ross D (2006) A potential role for cyclized quinones derived from dopamine, DOPA, and 3,4-dihydroxyphenylacetic acid in proteasomal inhibition. MolPharmacol 70:1079–1086Google Scholar