Are Dopamine Oxidation Metabolites Involved in the Loss of

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Are Dopamine Oxidation Metabolites Involved in the Loss of Dopaminergic Neurons in the Nigrostriatal System in Parkinson’s Disease? Andrea Herrera,†,‡ Patricia Muñoz,† Harry W. M. Steinbusch,‡ and Juan Segura-Aguilar*,† †

Molecular & Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6211 LK Maastricht, The Netherlands

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‡

ABSTRACT: In 1967, L-dopa was introduced as part of the pharmacological therapy of Parkinson’s disease (PD) and, in spite of extensive research, no additional effective drugs have been discovered to treat PD. This brings forward the question: why have no new drugs been developed? We consider that one of the problems preventing the discovery of new drugs is that we still have no information on the pathophysiology of the neurodegeneration of the neuromelanin-containing nigrostriatal dopaminergic neurons. Currently, it is widely accepted that the degeneration of dopaminergic neurons, i.e., in the substantia nigra pars compacta, involves mitochondrial dysfunction, the formation of neurotoxic oligomers of alphasynuclein, the dysfunction of protein degradation systems, neuroinflammation, and oxidative and endoplasmic reticulum stress. However, the initial trigger of these mechanisms in the nigrostriatal system is still unknown. It has been reported that aminochrome induces the majority of these mechanisms involved in the neurodegeneration process. Aminochrome is formed within the cytoplasm of neuromelanin-containing dopaminergic neurons during the oxidation of dopamine to neuromelanin. The oxidation of dopamine to neuromelanin is a normal and harmless process, because healthy individuals have intact neuromelanin-containing dopaminergic neurons. Interestingly, aminochrome-induced neurotoxicity is prevented by two enzymes: DT-diaphorase and glutathione transferase M2-2, which explains why melanin-containing dopaminergic neurons are intact in healthy human brains. KEYWORDS: Neurodegeneration, astrocytes, alpha-synuclein, mitochondria dysfunction, autophagy dysfunction, proteasome dysfunction, neuroinflammation, endoplasmic reticulum stress line.6,7 This increase in acetylcholine also contributes to motor symptoms and, as a logical consequence, the pharmacotherapy of Parkinson’s disease is based on the use of both dopaminergic as well as anticholinergic compounds.2 It is amazing that, in spite of extensive research in this field and all of the new technology, there is no drug that halts the progression of the disease. The question is why? In our opinion, there are two reasons: (i) the absence of preclinical models that mimic the pathophysiology of the disease’s characteristics and (ii) the trigger for the loss of neuromelanin-containing dopaminergic neurons in Parkinson’s disease is still unknown. Over the past few decades, the most commonly used preclinical models have used exogenous neurotoxins, such as 6hydroxydopamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and rotenone.8 There is a long list of failed clinical studies based on successful preclinical studies, which have used these neurotoxins.9−11 A possible explanation for these failures is that the neurotoxins used do not naturally exist

1. PARKINSON’S DISEASE The discovery in 1957 that Parkinson’s disease (PD) is linked to a decrease in dopamine levels has been one of the most important milestones in the search for the causes and mechanisms of, and therapies for, this disease.1 This discovery has marked the development of research into PD over the last 60 years. In 1960, the first attempt was made to use L-dopa, and was followed in 1967 by spectacular results from using high concentrations of L-dopa. Until now, L-dopa has been the most important and effective drug in the treatment of PD.2 Unfortunately, L-dopa induced severe side effects in patients after 4−6 years of usage, such as dyskinesia, “on−off” fluctuations, and the wearing-off phenomenon.3,4 It is important to remark that it only took 10 years after the discovery that patients had low levels of dopamine to introduce L-dopa into the treatment of PD. The aim of this therapy was simply to increase and therefore reestablish dopamine levels, in particular in the basal ganglia and more specifically in the dorsal part of the caudate putamen complex.5 Low levels of dopamine induce an imbalance between neurotransmitters in the basal ganglia, resulting in increased glutamate, GABA, and acetylcho© 2017 American Chemical Society

Received: January 23, 2017 Accepted: February 24, 2017 Published: February 24, 2017 702

DOI: 10.1021/acschemneuro.7b00034 ACS Chem. Neurosci. 2017, 8, 702−711

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Figure 1. Dopamine synthesis and reuptake and storage in monoaminergic vesicles. Dopamine synthesis is performed in two stages: first, the amino acid tyrosine is converted to L-dopa using tyrosine hydroxylase, and second L-dopa is converted to dopamine using L-amino acid decarboxylase. Interestingly, the synthesis of dopamine occurs in the cytosol, but dopamine is immediately transported to the monoaminergic vesicles by VMAT-2, preventing the existence of free dopamine in the cytosol. Tyrosine hydroxylase and L-amino acid decarboxylase are associated with VMAT-2, forming a kind of complex. Dopamine is completely stable inside the monoaminergic vesicles due to its relatively low pH, preventing dopamine oxidation because dopamine uptake is coupled with a vacuolar H+-ATPase that pumps protons into the vesicles. The reuptake of dopamine into the cytosol of the dopaminergic neuron after neurotransmission is mediated by dopamine transporter. Dopamine in the cytosol has two possible fates: VMAT-2 uptake in the monoaminergic vesicles or monoamine oxidase-mediated degradation to 3,4-dihydroxyphenylacetaldehyde, hydrogen peroxide, and ammonia, which is converted to 3,4-dihydroxyphenylacetic acid by aldehyde dehydrogenase.

community continues to use exogenous neurotoxins as preclinical models for Parkinson’s disease, such as 6hydroxydopamine, MPTP, and rotenone,18−24 since there is no clear alternative. These preclinical models could be useful tools to study neurodegenerative mechanisms; however, they possess no translational value for testing new drugs or therapies related to Parkinson’s disease.9−11 An example of this is the observation of GDNF-induced tissue regeneration in animals

in the human brain and therefore cannot completely replicate the characteristics of the disease.12−16 Each of these preclinical models induces the rapid and extensive loss of nigrostriatal dopaminergic neurons. For example, MPTP induces severe parkinsonism after only 3 days in drug addicts who used synthetic drugs contaminated with this compound.17 This contrasts with the neurodegeneration of neuromelanincontaining dopaminergic neurons in PD, which takes years before typical motor symptoms appear. However, the scientific 703


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homovanillic acid by catechol ortho-methyltransferase (COMT).2 This enzyme catalyzes the methylation of DA to 3-methoxytyramine, which is further converted to 3-methoxy-4hydroxyphenylacetaldehyde by MAO-B. Finally, aldehyde dehydrogenase catalyzes the formation of homovanillic acid from 3-methoxy-4-hydroxyphenylacetaldehyde. Free dopamine in the cytosol of dopaminergic neurons can sequentially oxidize to o-quinones, where they finally polymerize, generating neuromelanin.61,2

treated with 6-hydroxydopamine or MPTP, which afterward had no translational value to clinical studies.25,26 Regarding the second point, the discovery of proteins associated with familial PD has made an enormous input in the field in terms of understanding the role of these proteins in the neurodegenerative processes of PD. These proteins include alpha-synuclein, parkin, glucocerebrosidase-1, ATPase 13A2, leucine-rich repeat kinase 2 (LRRK2), PTEN-induced putative kinase 1 (PINK1), and Park-7 (DJ-1).27−32 However, none of these mutations can explain what happens in the sporadic form of the disease, i.e., in the majority of disease sufferers, since, for example, alpha-synuclein mutations induce the formation of neurotoxic oligomers but in the sporadic form of the disease the patient does not have this mutation. Thus, the question is what induces these neurotoxic oligomers? The iron-induced Fenton reaction has been proposed to play a role in the loss of dopaminergic neurons in PD,33−35 and reactive oxygen species increase alpha-synuclein aggregation during the oxidation of ferrous to ferric iron.36 Having said that, the identity of the compound that triggers the loss of neuromelanin-containing dopaminergic neurons in the substantia nigra pars compacta remains unknown. However, there is a general agreement that mitochondrial dysfunction, alpha-synuclein aggregation to neurotoxic oligomers, the dysfunction of protein degradation in both the lysosomal and proteasomal systems, endoplasmic reticulum stress, neuroinflammation, and oxidative stress are all involved in these degenerative processes, resulting in the loss of neuromelanin-containing dopaminergic neurons.32−59

3. DOPAMINE OXIDATION TO NEUROMELANIN The oxidation of dopamine into neuromelanin is a normal and nontoxic pathway, since healthy individuals keep their neuromelanin-containing dopaminergic neurons intact in the substantia nigra, which accumulate with age.61,64 The formation of neuromelanin requires the sequential dopamine oxidation to o-quinones, which finally polymerize to this pigment. Thus, the pathway is as follows: dopamine → dopamine o-quinone → aminochrome → 5,6-indolequinone → neuromelanin.2,65,66,61 3.1. Dopamine o-Quinone. Dopamine o-quinone is a stable compound at a pH of lower than 2.0.67 Therefore, under the cytosolic conditions, pH dopamine o-quinone cyclizes immediately at rate of 0.15 s−1 in two steps to aminochrome.68 Proteomic analysis of mitochondria exposed to 14C-dopamine o-quinone (14C-dopamine oxidized by tyrosinase in the presence of mitochondria) revealed that dopamine o-quinone forms adducts with Parkinson protein 7 (DJ-1), ubiquitin Cterminal hydrolase-L1 (UCHL-1), complex I, III and V, isocitrate dehydrogenase, actin gamma, superoxide dismutase2, mitochondrial voltage-dependent anion channel 1, ubiquitous mitochondrial creatine kinase, heat shock protein 60 and mortalin/GRP75/mtHSP70, and other proteins.69 When SHSY5Y cells were incubated with 14C-dopamine, the oxidation of dopamine to dopamine o-quinone was expected to occur in the cytosol of the SH-SY5Y cells under more physiological conditions without the enzyme tyrosinase. Interestingly, only UCH-L1, DJ-1, mortalin/GRP75/mtHSP70, and actin were detected in both mitochondria exposed to 14C-dopamine oquinone and SH-SY5Y cells exposed to 14C-dopamine. One possible explanation for these different results could be that, in the experiment on isolated mitochondria, dopamine o-quinone does not have the interference of cytosolic proteins to bind to proteins during its short life before undergoing cyclization to aminochrome. This contrasts with SH-SY5Y, where dopamine oxidizes to dopamine o-quinone in the presence of cytosolic proteins, which prevent the formation of adducts between dopamine o-quinone and proteins. Therefore, it seems to be plausible that, in SH-SY5Y cells, the 14C-dopamine adducts correspond to the 14C-aminochrome adducts, since this oquinone is more stable.69 Dopamine o-quinone has been reported to form adducts with parkin,70 human dopamine transporter,71 mitochondrial glutathione peroxidase,47 and tyrosine hydroxylase.72 3.2. Aminochrome. Aminochrome is the most stable oquinone formed during the oxidation of dopamine; its conversion to 5,6-indolequinone was not detected in vitro until 40 min later.61,65 Aminochrome is able to form an adduct with proteins and can also be one-electron reduced to the radical leukoaminochrome o-semiquinone.73 Aminochrome has been reported to induce (i) mitochondrial dysfunction;74−78 (ii) the formation of neurotoxic oligomers of alpha-synuclein;79 (iii) oxidative stress; 73 (iv) autophagy and lysosomal dysfunction;80,81 (v) proteasomal dysfunction;82 (vi) endoplas-

2. DOPAMINE METABOLISM The neurotransmitter dopamine is sequentially synthesized in the cytosol of dopaminergic neurons by two enzymes. The amino acid tyrosine is first converted to L-dopa by the enzyme tyrosine hydroxylase. L-Dopa is subsequently decarboxylated to dopamine by the enzyme aromatic L-amino acid decarboxylase.2 It has been reported that tyrosine hydroxylase and aromatic Lamino acid decarboxylase form a kind of complex with vesicular monoamine transporter-2 (VMAT-2), which is localized in the membrane of monoaminergic vesicles.60 This complex is very important in preventing the existence of free dopamine in the cytosol and its oxidation to o-quinones. VMAT-2 in the monoaminergic vesicles is coupled to an ATPase, which pumps proton into the vesicle, decreasing its pH (Figure 1). Dopamine inside monoaminergic vesicles is completely stable and accumulates to be available for neurotransmission, since dopamine is unable to oxidize to o-quinones and to polymerize to neuromelanin at this pH.61 Dopamine, released into the synaptic cleft from dopaminergic axon terminals, binds to dopamine receptors localized in postsynaptic dendrites/neurons. At a later stage, free dopamine is removed from the synaptic cleft by dopamine transporter expressed on the dopaminergic nerve endings. Interestingly, surrounding astrocytes also have the capacity to take up dopamine in order to remove dopamine from the synaptic cleft, since they express dopamine transporter as well as other transporters.62,63 The degradation of dopamine is catalyzed by MAO-B and catechol ortho-methyltransferase, in conjunction with aldehyde dehydrogenase, to the final product of homovanillic acid. MAO-B catalyzes the oxidative deamination of dopamine to hydrogen peroxide, ammonia, and 3,4dihydroxyphenylacetaldehyde, which is converted to 3,4dihydroxyphenylacetic acid by aldehyde dehydrogenase (Figure 1). 3,4-Dihydroxyphenylacetic acid is finally converted to 704


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Figure 2. Aminochrome metabolism: neurotoxic and neuroprotective reactions. Dopamine oxidizes to dopamine o-quinone, which immediately cyclizes to aminochrome (reactions 1 and 2).47,51,52,54 Aminochrome participates in both neurotoxic and neuroprotective reactions. Neurotoxic reactions include: aminochrome forms adducts with alpha-synuclein, generating neurotoxic oligomers (reaction 3);64 aminochrome forms adducts with mitochondrial complex I and impairs the mitochondrial membrane potential, generating mitochondrial dysfunction (reaction 4);58−63 aminochrome induces oxidative stress during its one-electron reduction to leukoaminochrome radical, which is very reactive with oxygen (reaction 5);58,109 aminochrome induces autophagy dysfunction by preventing the formation of microtubules required for the fusion between autophagosomes and lysosomes, thus inducing lysosomal dysfunction (reaction 6);65,66 aminochrome induces proteasomal dysfunction (reaction 7);67 aminochrome induces endoplasmic reticulum stress (reaction 8).68 These neurotoxic reactions induce a chronic neurotoxicity in the dopaminergic neurons. Neuroprotective reactions include: DT-diaphorase prevents the neurotoxic reaction of aminochrome by two-electron reducing it to leukoaminochrome (reaction 9).62,58−60,75 GSTM2 catalyzes the GSH conjugation of both dopamine o-quinone (reaction 10)100 and aminochrome (reaction 11)76,77 in the astrocytes and in the dopaminergic neurons. Dopamine released from the dopaminergic neurons under neurotransmission is taken up into the astrocytes, where dopamine can oxidize to dopamine o-quinone, which subsequently cyclizes to aminochrome. GSTM2 catalyzes the GSH conjugation of both dopamine o-quinone (reaction 10)100 and aminochrome (reaction 11).76,77 Aminochrome increases the constitutive expression of GSTM2 (reaction 12),104 which is secreted to the extracellular medium where dopaminergic neurons internalize GSTM2,104−107 protecting the dopaminergic neurons by catalyzing the GSH conjugation of both dopamine o-quinone (reaction 10)100 and aminochrome (reaction 11)76,77 inside of the dopaminergic neurons. The neuromelanin picture was obtained by using transmission electron microscopy in RCSN-3 cells treated with 100 μM dopamine and 25 μM reserpine to inhibit VMAT-2.

mic reticulum stress;83 (vii) disruption of the cytoskeleton by inducing the aggregation of both actin and tubulin;84 (viii) inhibition of the formation of microtubules;85 and (ix) apoptotic cell death74,75 (Figure 2). 3.3. 5,6-Indolequinone. This is formed after aminochrome is rearranged to form 5,6-indolequinone (at a constant rate of 0.06 min−1), which is the direct precursor of neuromelanin.61,86−88 The 5,6-indolequinone polymerizes to neuromelanin, where 5,6-indolequenone is the basic unit from which this pigmented polymer is formed.89 It has been reported that 5,6-indolequinone forms adducts with alpha-synuclein in vitro, preventing the formation of neuromelanin, but it is unknown whether these oligomers are neurotoxic.65

3.4. Dopaminochrome. In the literature, we found reports of dopaminochrome,90−92 but its structure is not clear. Some reports claim to have used dopaminochrome, but they used the structure of aminochrome to describe dopaminochrome, or the absorption maximum corresponds to aminochrome.93−95 Dopaminochrome and aminochrome are two different compounds. Dopaminochrome purified with HPLC has an absorption maximum of 303 and 479 nm,96 but the structure was not confirmed by NMR, while aminochrome has an absorption maximum of 280 and 475 nm and its structure was confirmed by NMR.84 Dopaminochrome has been reported to form adducts with alpha-synuclein in vitro,90 and the unilateral injection of dopaminochrome induced a slow and progressive degeneration of the dopaminergic neurons within the 705


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ACS Chemical Neuroscience substantia nigra.97 On the other hand, aminochrome induces contralateral rotation without the loss of dopaminergic neurons, as detected by the presence of tyrosine hydroxylase and neuronal dysfunction.78 Therefore, it seems to be plausible that dopaminochrome corresponds to 5,6-indolequinone or an unidentified o-quinone.

aminochrome can be too high, thus surpassing the protective capacity of DT-diaphorase and GSTM2. 4.1. DT-Diaphorase. DT-Diaphorase is the unique flavoenzyme that catalyzes the two-electron reduction of quinones to hydroquinones. It is constitutively expressed in dopaminergic neurons and astrocytes.122 DT-diaphorase uses both NADH and NADPH as electron donators. DTDiaphorase catalyzes the two-electron reduction of aminochrome to leukoaminochrome,67 preventing (i) aminochromeinduced cell death;98 (ii) mitochondrial dysfunction;73−78 (iii) oxidative stress;73 (iv) both the formation of alpha-synuclein oligomers and their neurotoxicity;79 (v) autophagy dysfunction;80 (vi) proteasomal dysfunction;82 and (vii) the disruption of the cytoskeleton architecture and the aggregation of actin and α- and β-tubulin.84 4.2. Glutathione Transferase M2-2. GSTM2 is constitutively expressed in astrocytes and catalyzes the GSH conjugation of aminochrome to 4-S-glutathionyl-5,6-dihydroxyindoline, which is resistant to biological oxidants such as oxygen, superoxide, and hydrogen peroxide.99 GSTM2 was found to be the most active of all the forms of human glutathione transferase.99,100 GSTM2 also catalyzes the GSH conjugation of the aminochrome precursor dopamine-oquinone to 5-glutathionyldopamine.123 Interestingly, 5-cysteinyldopamine, the product of the degradation of 5-gluthationyldopamine, has been detected in human cerebrospinal fluid and neuromelanin,124−126 suggesting that 5-cysteinyldopamine is a final product. GSTM2 prevents (i) aminochrome-induced cell death in astrocytes;81 (ii) aminochrome-induced autophagy dysfunction causing astrocyte death;81 (iii) aminochromeinduced lysosomal dysfunction causing astrocyte death;81 and (iv) aminochrome-induced cell death in the dopaminergic neurons. This arises from the observation that astrocytes secrete GSTM2 into the medium where dopaminergic neurons internalize GSTM2 into the cytosol, preventing aminochromeinduced cell death in the dopaminergic neuron.12,127−129 Interestingly, astrocytes are also protected from aminochrome-induced neurotoxicity by DT-diaphorase.130 4.3. Aminochrome as a Preclinical Model for PD. The neurotoxic action of exogenous neurotoxins is relatively similar to aminochrome and differs in similar ways, by inducing mitochondrial dysfunction, endoplasmic reticulum and oxidative stress, the aggregation of alpha-synuclein, and the dysfunction of protein degradation.131−150 However, the effect of aminochrome on animals is completely different from that of exogenous neurotoxins, since exogenous neurotoxins induce a very rapid and extensive loss of dopaminergic neurons while aminochrome induces a slow and progressive loss of functions. The unilateral injection of aminochrome into the striatum induces contralateral behavior without any significant loss of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta. Aminochrome induces an imbalance between neurotransmitters in the basal ganglia, since dopamine is significantly reduced whereas GABA levels are significantly increased as a consequence of the lower release of dopamine. Aminochrome induces mitochondrial dysfunction, resulting in a significant decrease in ATP levels, which explains the significant decrease in the amount of synaptic vesicles at the synaptic cleft of animals treated with aminochrome. It also explains the decrease in dopamine release, since both the axonal transport of neurotransmitter vesicles to the terminals and dopamine release require ATP.78 By so doing, aminochrome induces a preclinical model of dopaminergic neuronal dysfunction, while exogenous

4. AMINOCHROME METABOLISM The production of neuromelanin requires the formation of aminochrome, which is neurotoxic under certain conditions, by inducing the dysfunction of mitochondrial and protein degradation, oxidative and endoplasmic reticulum stress, and the formation of neurotoxic alpha-synuclein oligomers.73−85 The question arises as to why healthy individuals have intact neuromelanin-containing dopaminergic neurons, when the formation of neuromelanin requires the formation of aminochrome. Aminochrome is neurotoxic when it forms adducts with proteins such as alpha-synuclein,79 actin,84 and tubulin,84 or when aminochrome is one-electron reduced by flavoenzymes, which transfer one electron from NADH or NADPH.73 However, aminochrome neurotoxic reactions can be prevented by two phase II enzymes: (i) DT-diaphorase (NAD(P)H:quinone oxidoreductase; NQO1), which catalyzes the twoelectron reduction of aminochrome67 and thus prevents aminochrome neurotoxicity98 and (ii) human glutathione transferase M2-2 (GSTM2), which catalyzes the glutathione conjugation of aminochrome.99,100 DT-diaphorase and GSTM2 prevent aminochrome-induced neurotoxicity, explaining why healthy seniors have intact neuromelanin-containing dopaminergic neurons in the substantia nigra, as noticed in obduction material produced by them. Interestingly, both DT-diaphorase and GSTM2 are Phase II enzymes and are regulated by nuclear factor-erythroid-2 (NrF2). NrF2 is a redox-transcription factor, which binds to the antioxidant responsive element (ARE) in the promoter region of antioxidant and detoxifying (Phase II) enzymes.101−103 Under basal conditions, NrF2 is negatively regulated by Kelch-like ECH-associated protein-1 (Keap1), which leads to NrF2 ubiquitination mediated by the ubiquitin ligase Cullin-3 and proteasomal degradation.104 Under conditions of oxidative stress, a cysteine residue of Keap-1 is oxidized, preventing NrF2 ubiquitination and proteasomal degradation. NrF2 accumulates in the nucleus and activates ARE-mediated gene expression, leading to an upregulation of both DT-diaphorase and GSTM2.105−118 The activation of NrF2 with either tert-butylhydroquinone or sulforaphane protects dopaminergic neurons against 6-hydroxydopamine neurotoxicity by increasing DT-diaphorase activity 17-fold.119 The question is why aminochrome is neurotoxic despite the protective action of both DT-diaphorase and GSTM2. It seems to be plausible that, under certain conditions, aminochrome levels are too high and thus surpass the enzymes’ capacity to prevent aminochrome neurotoxicity. The inhibition or downregulation of vesicular monoaminergic transporter-2 (VMAT2) will increase the level of cytosolic dopamine, promoting dopamine oxidation to aminochrome. The level of VMAT-2 expression is inversely correlated with the level of neuromelanin in dopaminergic neurons.120 Interestingly, monoaminergic vesicles isolated from PD patients revealed that both the uptake of dopamine and the binding of VMAT-2 inhibitor were significantly reduced by 87−90% and 71−80%, respectively, in comparison to control brains.121 These results support the idea that, under certain unknown conditions, the concentration of 706


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(4) Ko, J. H., Lerner, R. P., and Eidelberg, D. (2015) Effects of levodopa on regional cerebral metabolism and blood flow. Mov. Disord. 30, 54−63. (5) Schaeffer, E., Pilotto, A., and Berg, D. (2014) Pharmacological strategies for the management of levodopa-induced dyskinesia in patients with Parkinson’s disease. CNS Drugs 28, 1155−1184. (6) Aosaki, T., Miura, M., Suzuki, T., Nishimura, K., and Masuda, M. (2010) Acetylcholine-dopamine balance hypothesis in the striatum: an update. Geriatr. Gerontol. Int. 10, S148−S157. (7) Ismayilova, N., Verkhratsky, A., and Dascombe, M. J. (2006) Changes in mGlu5 receptor expression in the basal ganglia of reserpinised rats. Eur. J. Pharmacol. 545, 134−141. (8) Segura-Aguilar, J., and Kostrzewa, R. M. (2015) Neurotoxin mechanisms and processes relevant to Parkinson’s disease: an update. Neurotoxic. Res. 27, 328−354. (9) Lindholm, D., Mäkelä, J., Di Liberto, V., Mudò, G., Belluardo, N., Eriksson, O., and Saarma, M. (2016) Current disease modifying approaches to treat Parkinson’s disease. Cell. Mol. Life Sci. 73, 1365− 1379. (10) Park, A., and Stacy, M. (2015) Disease-Modifying Drugs in Parkinson’s disease. Drugs 75, 2065−2071. (11) Athauda, D., and Foltynie, T. (2015) The ongoing pursuit of neuroprotective therapies in Parkinson disease. Nat. Rev. Neurol. 11, 25−40. (12) Segura-Aguilar, J., Paris, I., and Muñoz, P. (2016) The need of a new and more physiological preclinical model for Parkinson’s disease. Cell. Mol. Life Sci. 73, 1381−2. (13) Segura-Aguilar, J. (2016) New preclinical model are required to discover neuroprotective compound in Parkinson’s disease. Pharmacol. Res., DOI: 10.1016/j.phrs.2016.11.034. (14) Segura-Aguilar, J. (2017) Why we cannot translate successful results to new therapies in Parkinsońs disease. Clin. Pharmacol. Transl. Med. 1, 6−14. (15) Muñoz, P., and Segura-Aguilar, J. (2016) Commentary: A Humanized Clinically Calibrated Quantitative Systems Pharmacology Model for Hypokinetic Motor Symptoms in Parkinson’s Disease. Front. Pharmacol. 7, 179. (16) Muñoz, P., Paris, I., and Segura-Aguilar, J. (2016) Commentary: Evaluation of Models of Parkinson’s Disease. Front. Neurosci. 10, 161. (17) Williams, A. (1986) MPTP toxicity: clinical features. J. Neural Transm. Suppl. 20, 5−9. (18) Tentillier, N., Etzerodt, A., Olesen, M. N., Rizalar, F. S., Jacobsen, J., Bender, D., Moestrup, S. K., and Romero-Ramos, M. (2016) Anti-Inflammatory Modulation of Microglia via CD163Targeted Glucocorticoids Protects Dopaminergic Neurons in the 6OHDA Parkinson’s Disease Model. J. Neurosci. 36, 9375−90. (19) Lee, J. A., Son, H. J., Kim, J. H., Park, K. D., Shin, N., Kim, H. R., Kim, E. M., Kim, D. J., and Hwang, O. (2016) A novel synthetic isothiocyanate ITC-57 displays antioxidant, anti-inflammatory, and neuroprotective properties in a mouse Parkinson’s disease model. Free Radical Res. 6, 1−12. (20) Yuan, J., Ren, J., Wang, Y., He, X., and Zhao, Y. (2016) Acteoside Binds to Caspase-3 and Exerts Neuroprotection in the Rotenone Rat Model of Parkinson’s Disease. PLoS One 11, e0162696. (21) Xiao-Feng, L., Wen-Ting, Z., Yuan-Yuan, X., Chong-Fa, L., Lu, Z., Jin-Jun, R., and Wen-Ya, W. (2016) Protective role of 6-Hydroxy-1H-indazole in an MPTP-induced mouse model of Parkinson’s disease. Eur. J. Pharmacol. 791, 348−354. (22) Yang, H. J., Gao, Y., Yun, J. Y., Kim, Y. E., Ehm, G., Lee, J. Y., Yoon, M. Y., Lee, Y. S., Kim, H. J., and Jeon, B. (2017) Acupuncture does not protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridineinduced damage of dopaminergic neurons in a preclinical mouse model of Parkinson’s disease. NeuroReport 28, 50−55. (23) Afshin-Majd, S., Bashiri, K., Kiasalari, Z., Baluchnejadmojarad, T., Sedaghat, R., and Roghani, M. (2017) Acetyl-l-carnitine protects dopaminergic nigrostriatal pathway in 6-hydroxydopamine-induced model of Parkinson’s disease in the rat. Biomed. Pharmacother. 89, 1−9. (24) Zhang, Z. N., Zhang, J. S., Xiang, J., Yu, Z. H., Zhang, W., Cai, M., Li, X. T., Wu, T., Li, W. W., and Cai, D. F. (2017) Subcutaneous

neurotoxins induce the massive loss of dopaminergic neurotoxins.

5. CONCLUSIONS It seems to be plausible that aminochrome plays an important role in the neurodegeneration of neuromelanin-containing dopaminergic neurons in the striatonigral system in Parkinson’s disease. This is induced because aminochrome is a neurotoxin generated within the cytosol of the apoptotic neurons, which are in the process of dying due to the disease. It induces mitochondrial dysfunction, the formation of neurotoxic oligomers of alpha-synuclein, the dysfunction of protein degradation systems, neuroinflammation, and oxidative and endoplasmic reticulum stress. In addition, DT-diaphorase and GSTM2 prevent the neurotoxicity of aminochrome in both the dopaminergic neurons and the astrocytes. Astrocytes seem to play an important role in protecting dopaminergic neurons by secreting GSTM2 to the extracellular medium, where dopaminergic neurons are able to internalize it and thus prevent aminochrome-induced neurotoxicity in these neurons. Thus, our new problem resembles the pathophysiological human conditions seen in PD patients far more. It could therefore be a more reliable model to study new treatment strategies in animal models for PD.

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AUTHOR INFORMATION

Corresponding Author

*Mailing address: Independencia 1027, Molecular & Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile. E-mail: [email protected]. Phone: 56 229786057. Fax: 227372783. ORCID

Juan Segura-Aguilar: 0000-0002-1018-673X Author Contributions

A.H.: References search and formatting, manuscript discussion, and text editing. P.M.: References search, manuscript discussion, and text editing. H.W.M.S.: Manuscript discussion and text editing. J.S.-A.: Writing of manuscript, manuscript discussion, and text editing. Funding

FONDECYT 1170033, Chile (J.S.-A.). Notes

The authors declare no competing financial interest.

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REFERENCES

(1) Carlsson, A., Lindqvist, M., and Magnusson, T. (1957) 3,4Dihydroxyphenylalanine and 5-Hydroxytryptophan as Reserpine Antagonists. Nature 180, 1200. (2) Segura-Aguilar, J., Muñoz, P., and Paris, I. (2016) Aminochrome as new preclinical model to find new pharmacological treatment that stop the development of Parkinsońs disease. Curr. Med. Chem. 23, 346−359. (3) Bastide, M. F., Meissner, W. G., Picconi, B., Fasano, S., Fernagut, P. O., Feyder, M., Francardo, V., Alcacer, C., Ding, Y., Brambilla, R., Fisone, G., Jon Stoessl, A., Bourdenx, M., Engeln, M., Navailles, S., De Deurwaerdère, P., Ko, W. K., Simola, N., Morelli, M., Groc, L., Rodriguez, M. C., Gurevich, E. V., Quik, M., Morari, M., Mellone, M., Gardoni, F., Tronci, E., Guehl, D., Tison, F., Crossman, A. R., Kang, U. J., Steece-Collier, K., Fox, S., Carta, M., Angela Cenci, M., and Bézard, E. (2015) Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson’s disease. Prog. Neurobiol. 132, 96−168. 707


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ACS Chemical Neuroscience rotenone rat model of Parkinson’s disease: Dose exploration study. Brain Res. 1655, 104−113. (25) Olanow, C. W., Bartus, R. T., Volpicelli-Daley, L. A., and Kordower, J. H. (2015) Trophic factors for Parkinson’s disease: To live or let die. Mov. Disord. 30, 1715−1724. (26) Olanow, C. W., Bartus, R. T., Baumann, T. L., Factor, S., Boulis, N., Stacy, M., Turner, D. A., Marks, W., Larson, P., Starr, P. A., Jankovic, J., Simpson, R., Watts, R., Guthrie, B., Poston, K., Henderson, J. M., Stern, M., Baltuch, G., Goetz, C. G., Herzog, C., Kordower, J. H., Alterman, R., Lozano, A. M., and Lang, A. E. (2015) Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: A double-blind, randomized, controlled trial. Ann. Neurol. 78, 248−257. (27) Hernandez, D. G., Reed, X., and Singleton, A. B. (2016) Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. J. Neurochem. 139, 59−74. (28) Kalinderi, K., Bostantjopoulou, S., and Fidani, L. (2016) The genetic background of Parkinson’s disease: current progress and future prospects. Acta Neurol. Scand. 134, 314−326. (29) Gan-Or, Z., Dion, P. A., and Rouleau, G. A. (2015) Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease. Autophagy 11, 1443−1457. (30) Verstraeten, A., Theuns, J., and Van Broeckhoven, C. (2015) Progress in unraveling the genetic etiology of Parkinson disease in a genomic era. Trends Genet. 31, 140−149. (31) Spatola, M., and Wider, C. (2014) Genetics of Parkinson’s disease: the yield. Parkinsonism Relat. Disord. 20, S35−S38. (32) Lin, M. K., and Farrer, M. J. (2014) Genetics and genomics of Parkinson’s disease. Genome Med. 6, 48. (33) Kienzl, E., Jellinger, K., Stachelberger, H., and Linert, W. (1999) Iron as catalyst for oxidative stress in the pathogenesis of Parkinson’s disease? Life Sci. 65, 1973−1976. (34) Linert, W., Herlinger, E., Jameson, R. F., Kienzl, l.E., Jellinger, K., and Youdim, M. B. (1996) Dopamine, 6-hydroxydopamine, iron, and dioxygen–their mutual interactions and possible implication in the development of Parkinson’s disease. Biochim. Biophys. Acta, Mol. Basis Dis. 1316, 160−168. (35) Kim, E. Y., Koh, J. Y., Kim, Y. H., Sohn, S., Joe, E., and Gwag, B. J. (1999) Zn2+ entry produces oxidative neuronal necrosis in cortical cell cultures. Eur. J. Neurosci. 11, 327−334. (36) Levin, J., Högen, T., Hillmer, A. S., Bader, B., Schmidt, F., Kamp, F., Kretzschmar, H. A., Bötzel, K., and Giese, A. (2011) Generation of ferric iron links oxidative stress to α-synuclein oligomer formation. J. Parkinson's Dis. 1, 205−216. (37) Mullin, S., and Schapira, A. (2013) α-Synuclein and Mitochondrial Dysfunction in Parkinson’s Disease. Mol. Neurobiol. 47, 587−597. (38) Yong-Kee, C. J., Sidorova, E., Hanif, A., Perera, G., and Nash, J. E. (2012) Mitochondrial dysfunction precedes other sub-cellular abnormalities in an in vitro model linked with cell death in Parkinson’s disease. Neurotoxic. Res. 21, 185−194. (39) Kalia, L. V., Kalia, S. K., McLean, P. J., Lozano, A. M., and Lang, A. E. (2013) α-Synuclein oligomers and clinical implications for Parkinson disease. Ann. Neurol. 73, 155−169. (40) Ebrahimi-Fakhari, D., Wahlster, L., and McLean, P. J. (2012) Protein degradation pathways in Parkinson’s disease: curse or blessing. Acta Neuropathol. 124, 153−172. (41) Franco-Iborra, S., Vila, M., and Perier, C. (2016) The Parkinson Disease Mitochondrial Hypothesis: Where Are We at? Neuroscientist 22, 266−277. (42) Zanellati, M. C., Monti, V., Barzaghi, C., Reale, C., Nardocci, N., Albanese, A., Valente, E. M., Ghezzi, D., and Garavaglia, B. (2015) Mitochondrial dysfunction in Parkinson disease: evidence in mutant PARK2 fibroblasts. Front. Genet. 6, 78. (43) Caito, S. W., and Aschner, M. (2015) Mitochondrial Redox Dysfunction and Environmental Exposures. Antioxid. Redox Signaling 23, 578−595.

(44) Morris, G., and Berk, M. (2015) The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders. BMC Med. 13, 68. (45) Zaltieri, M., Longhena, F., Pizzi, M., Missale, C., Spano, P., and Bellucci, A. (2015) Mitochondrial Dysfunction and α-Synuclein Synaptic Pathology in Parkinson’s Disease: Who’s on First? Parkinson's Dis. 2015, 108029. (46) Martinez-Vicente, M., and Vila, M. (2013) Alpha-synuclein and protein degradation pathways in Parkinson’s disease: A pathological feed-back loop. Exp. Neurol. 247, 308−313. (47) Hauser, D. N., and Hastings, T. G. (2013) Mitochondrial dysfunction and oxidative stress in Parkinson’s disease and monogenic parkinsonism. Neurobiol. Dis. 51, 35−42. (48) Mercado, G., Valdés, P., and Hetz, C. (2013) An ERcentric view of Parkinson’s disease. Trends Mol. Med. 19, 165−175. (49) Rohn, T. T. (2012) Targeting alpha-synuclein for the treatment of Parkinson’s disease. CNS Neurol. CNS Neurol. Disord.: Drug Targets 11, 174−179. (50) Taylor, J. M., Main, B. S., and Crack, P. J. (2013) Neuroinflammation and oxidative stress: Co-conspirators in the pathology of Parkinson’s disease. Neurochem. Int. 62, 803−819. (51) Exner, N., Lutz, A. K., Haass, C., and Winklhofer, K. F. (2012) Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J. 31, 3038−3062. (52) Hang, L., Thundyil, J., and Lim, K. L. (2015) Mitochondrial dysfunction and Parkinson disease: a Parkin-AMPK alliance in neuroprotection. Ann. N. Y. Acad. Sci. 1350, 37−47. (53) Moon, H. E., and Paek, S. H. (2015) Mitochondrial Dysfunction in Parkinson’s Disease. Exp. Neurobiol. 24, 103−16. (54) Moors, T., Paciotti, S., Chiasserini, D., Calabresi, P., Parnetti, L., Beccari, T., and van de Berg, W. D. (2016) Lysosomal Dysfunction and α-Synuclein Aggregation in Parkinson’s Disease. Mov. Disord. 31, 791−801. (55) Vos, M., Verstreken, P., and Klein, C. (2015) Stimulation of electron transport as potential novel therapy in Parkinson’s disease with mitochondrial dysfunction. Biochem. Soc. Trans. 43, 275−279. (56) Yamano, K., Matsuda, N., and Tanaka, K. (2016) The ubiquitin signal and autophagy: an orchestrated dance leading to mitochondrial degradation. EMBO Rep. 17, 300−316. (57) Xilouri, M., Brekk, O. R., and Stefanis, L. (2016) Autophagy and Alpha-Synuclein: Relevance to Parkinson’s Disease and Related Synucleopathies. Mov. Disord. 31, 178−192. (58) Joers, V., Tansey, M. G., Mulas, G., and Carta, A. R. (2016) Microglial phenotypes in Parkinson’s disease and animal models of the disease. Prog. Neurobiol., DOI: 10.1016/j.pneurobio.2016.04.006. (59) Mercado, G., Castillo, V., Soto, P., and Sidhu, A. (2016) ER stress and Parkinson disease: Pathological inputs that converge into the secretory pathway. Brain Res. 1648, 626−632. (60) Cartier, E. A., Parra, L. A., Baust, T. B., Quiroz, M., Salazar, G., Faundez, V., Egaña, L., and Torres, G. E. (2010) A biochemical and functional protein complex involving dopamine synthesis and transport into synaptic vesicles. J. Biol. Chem. 285, 1957−1966. (61) Segura-Aguilar, J., Paris, I., Muñoz, P., Ferrari, E., Zecca, L., and Zucca, F. A. (2014) Protective and toxic roles of dopamine in Parkinson’s disease. J. Neurochem. 129, 898−915. (62) Asanuma, M., Miyazaki, I., Murakami, S., Diaz-Corrales, F. J., and Ogawa, N. (2014) Striatal astrocytes act as a reservoir for LDOPA. PLoS One 9, e106362. (63) Inyushin, M. Y., Huertas, A., Kucheryavykh, Y. V., Kucheryavykh, L. Y., Tsydzik, V., Sanabria, P., Eaton, M. J., Skatchkov, S. N., Rojas, L. V., and Wessinger, W. D. (2012) LDOPA Uptake in Astrocytic Endfeet Enwrapping Blood Vessels in Rat Brain. Parkinson's Dis. 2012, 321406. (64) Zecca, L., Fariello, R., Riederer, P., Sulzer, D., Gatti, A., and Tampellini, D. (2002) The absolute concentration of nigral neuromelanin, assayed by a new sensitive method, increases throughout the life and is dramatically decreased in Parkinson’s disease. FEBS Lett. 510, 216−20. 708


Review

ACS Chemical Neuroscience (65) Bisaglia, M., Mammi, S., and Bubacco, L. (2007) Kinetic and structural analysis of the early oxidation products of dopamine: analysis of the interactions with alpha-synuclein. J. Biol. Chem. 282, 15597−15605. (66) Graham, D. G. (1984) Catecholamine toxicity: A proposal for the molecular pathogenesis of manganese neurotoxicity and Parkinsońs disease. NeuroToxicology 5, 83−96. (67) Segura-Aguilar, J., and Lind, C. (1989) On the mechanism of the Mn3(+)-induced neurotoxicity of dopamine:prevention of quinone-derived oxygen toxicity by DT diaphorase and superoxide dismutase. Chem.-Biol. Interact. 72, 309−324. (68) Tse, D. C. S., McCreery, R. L., and Adams, R. N. (1976) Potential oxidative pathways of brain catecholamines. J. Med. Chem. 19, 37−34. (69) Van Laar, V. S., Mishizen, A. J., Cascio, M., and Hastings, T. G. (2009) Proteomic identification of dopamine-conjugated proteins from isolated rat brain mitochondria and SH-SY5Y cells. Neurobiol. Dis. 34, 487−500. (70) LaVoie, M., Ostaszewski, B. L., Weihofen, A., Schlossmacher, M. G., and Selkoe, D. J. (2005) Dopamine covalently modifies and functionally inactivates parkin. Nat. Med. 11, 1214−1221. (71) Whitehead, R. E., Ferrer, J. V., Javitch, J. A., and Justice, J. B. (2001) Reaction of oxidized dopamine with endogenous cysteine residues in the human dopamine transporter. J. Neurochem. 76, 1242− 1251. (72) Xu, Y., Stokes, A. H., Roskoski, R., Jr., and Vrana, K. E. (1998) Dopamine, in the presence of tyrosinase, covalently modifies and inactivates tyrosine hydroxylase. J. Neurosci. Res. 54, 691−697. (73) Arriagada, C., Paris, I., Sanchez de las Matas, M. J., MartinezAlvarado, P., Cardenas, S., Castañeda, P., Graumann, R., PerezPastene, C., Olea-Azar, C., Couve, E., Herrero, M. T., Caviedes, P., and 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, 468−77. (74) Fuentes, P., Paris, I., Nassif, M., Caviedes, P., and SeguraAguilar, J. (2007) Inhibition of VMAT-2 and DT-diaphorase induce cell death in a substantia nigra-derived cell line an experimental cell model for dopamine toxicity studies. Chem. Res. Toxicol. 20, 776−783. (75) Paris, I., Muñoz, P., Huenchuguala, S., Couve, E., Sanders, L. H., Greenamyre, J. T., Caviedes, P., and Segura-Aguilar, J. (2011) Autophagy protects against aminochrome-induced cell death in substantia nigra-derived cell line. Toxicol. Sci. 121, 376−388. (76) Aguirre, P., Urrutia, P., Tapia, V., Villa, M., Paris, I., SeguraAguilar, J., and Nuñez, M. T. (2012) The dopamine metabolite aminochromeinhibits mitochondrial complex I and modifies the expression of iron transportersDMT1and FPN1. BioMetals 25, 795− 803. (77) Muñoz, P., Paris, I., Sanders, L. H., Greenamyre, J. T., and Segura-Aguilar, J. (2012) Overexpression of VMAT-2 and DTdiaphorase protects substantia nigra-derived cells against aminochrome neurotoxicity. Biochim. Biophys. Acta, Mol. Basis Dis. 1822, 1125−1136. (78) 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, H. W., and Segura-Aguilar, J. (2016) Aminochrome induces dopaminergic neuronal dysfunction: a new animal model for Parkinson’s disease. Cell. Mol. Life Sci. 73, 3583−3597. (79) Muñoz, P., Cardenas, S., Huenchuguala, S., Briceño, A., Couve, E., Paris, I., and Segura-Aguilar, J. (2015) DT Diaphorase prevents aminochrome-induced alpha-synuclein oligomer formation and neurotoxicity. Toxicol. Sci. 145, 37−47. (80) Muñoz, P., Huenchuguala, S., Paris, I., and Segura-Aguilar, J. (2012) Dopamine oxidation and autophagy. Parkinson's Dis. 2012, 920953. (81) Huenchuguala, S., Muñoz, P., Zavala, P., Villa, M., Cuevas, C., Ahumada, U., Graumann, R., Nore, B. F., Couve, E., Mannervik, B., Paris, I., and Segura-Aguilar, J. (2014) Glutathione transferase mu 2

protects glioblastoma cells against aminochrome toxicity by preventing autophagy and lysosome dysfunction. Autophagy 10, 618−630. (82) Zafar, K. S., Siegel, D., and Ross, D. (2006) A potential role for cyclized quinones derived from dopamine, DOPA, and 3,4dihydroxyphenylacetic acid in proteasomal inhibition. Mol. Pharmacol. 70, 1079−1086. (83) Xiong, R., Siegel, D., and Ross, D. (2014) Quinone-induced protein handling changes: implications for major protein handling systems in quinone-mediated toxicity. Toxicol. Appl. Pharmacol. 280, 285−295. (84) Paris, I., Perez-Pastene, C., Cardenas, S., Iturriaga-Vasquez, P., Muñoz, P., Couve, E., Caviedes, P., and Segura-Aguilar, J. (2010) Aminochrome induces disruption of actin, alpha- and beta-tubulin cytoskeleton networks in substantia-nigra-derived cell line. Neurotoxic. Res. 18, 82−92. (85) Briceño, A., Muñoz, P., Brito, P., Huenchuguala, S., SeguraAguilar, J., and Paris, I. B. (2016) Aminochrome toxicity is mediated by inhibition of microtubules polymerization through the formation of adducts with tubulin. Neurotoxic. Res. 29, 381−393. (86) Napolitano, A., Manini, P., and d’Ischia, M. (2011) Oxidation chemistry of catecholamines and neuronal degeneration: an update. Curr. Med. Chem. 18, 1832−45. (87) Bisaglia, M., Soriano, M. E., Arduini, I., Mammi, S., and Bubacco, L. (2010) Molecular characterization of dopamine-derived quinones reactivity toward NADH and glutathione: implications for mitochondrial dysfunction in Parkinson disease. Biochim. Biophys. Acta, Mol. Basis Dis. 1802, 699−706. (88) Pezzella, A., Crescenzi, O., Natangelo, A., Panzella, L., Napolitano, A., Navaratnam, S., Edge, R., Land, E. J., Barone, V., and d’Ischia, M. (2007) Chemical, pulse radiolysis and density functional studies of a new, labile 5,6-indolequinone and its semiquinone. J. Org. Chem. 72, 1595−603. (89) Zajac, G. W., Gallas, J. M., Cheng, J., Eisner, M., Moss, S. C., and Alvarado-Swaisgood, A. E. (1994) The fundamental unit of synthetic melanin: a verification by tunneling microscopy of X-ray scattering results. Biochim. Biophys. Acta, Gen. Subj. 1199, 271−278. (90) Norris, E. H., Giasson, B. I., Hodara, R., Xu, S., Trojanowski, J. Q., Ischiropoulos, H., and Lee, V. M. (2005) Reversible inhibition of alpha-synuclein fibrillization by dopaminochrome-mediated conformational alterations. J. Biol. Chem. 280, 21212−21219. (91) Linsenbardt, A. J., Breckenridge, J. M., Wilken, G. H., and Macarthur, H. (2012) Dopaminochrome induces caspase-independent apoptosis in the mesencephalic cell line, MN9D. J. Neurochem. 122 (1), 175−84. (92) Linsenbardt, A. J., Wilken, G. H., Westfall, T. C., and Macarthur, H. (2009) Cytotoxicity of dopaminochrome in the mesencephalic cell line, MN9D, is dependent upon oxidative stress. NeuroToxicology 30, 1030−1035. (93) Zoccarato, F., Toscano, P., and Alexandre, A. (2005) Dopaminederived dopaminochrome promotes H(2)O(2) release at mitochondrial complex I: stimulation by rotenone, control by Ca(2+), and relevance to Parkinson disease. J. Biol. Chem. 280, 15587−15594. (94) Galzigna, L., Schiappelli, M. P., Rigo, A., and Scarpa, M. (1999) A rat brain fraction and different purified peroxidases catalyzing the formation of dopaminochrome from dopamine. Biochim. Biophys. Acta, Gen. Subj. 1427, 329−336. (95) Galzigna, L., Zanatta, L., and Esposito, N. (1999) Toxicity of dopamine and dopaminochrome on cultured cells. Neurotoxic. Res. 1, 149−152. (96) Ochs, S. D., Westfall, T. C., and Macarthur, H. (2005) The separation and quantification of aminochromes using high-pressure liquid chromatography with electrochemical detection. J. Neurosci. Methods 142, 201−208. (97) Touchette, J. C., Breckenridge, J. M., Wilken, G. H., and Macarthur, H. (2016) Direct intranigral injection of dopaminochrome causes degeneration of dopamine neurons. Neurosci. Lett. 612, 178− 184. 709


Review


selective Anti-influenza A Virus Activity Involving Nrf2 Activation. J. Biol. Chem. 290, 28001−28017. (116) Li, H., He, H., Wang, Z., Cai, J., Sun, B., Wu, Q., Zhang, Y., Zhou, G., and Yang, L. (2016) Rice protein suppresses ROS generation and stimulates antioxidant gene expression via Nrf2 activation in adult rats. Gene 585, 256−64. (117) Zhang, Y., Duan, X., Li, J., Zhao, S., Li, W., Zhao, L., Li, W., Nie, H., Sun, G., and Li, B. (2016) Inorganic Arsenic Induces NRF2Regulated Antioxidant Defenses in Both Cerebral Cortex and Hippocampus in Vivo. Neurochem. Res. 41, 2119−28. (118) Williams, L. M., Lago, B. A., McArthur, A. G., Raphenya, A. R., Pray, N., Saleem, N., Salas, S., Paulson, K., Mangar, R. S., Liu, Y., Vo, A. H., and Shavit, J. A. (2016) The transcription factor, Nuclear factor, erythroid 2 (Nfe2), is a regulator of the oxidative stress response during Danio rerio development. Aquat. Toxicol. 180, 141−154. (119) Siebert, A., Desai, V., Chandrasekaran, K., Fiskum, G., and Jafri, M. S. (2009) Nrf2 activators provide neuroprotection against 6hydroxydopamine toxicity in rat organotypic nigrostriatal cocultures. J. Neurosci. Res. 87, 1659−1669. (120) Liang, C. L., Nelson, O., Yazdani, U., Pasbakhsh, P., and German, D. C. (2004) Inverse relationship between the contents of neuromelanin pigment and the vesicular monoamine transporter-2: human midbrain dopamine neurons. J. Comp. Neurol. 473, 97−106. (121) Pifl, C., Rajput, A., Reither, H., Blesa, J., Cavada, C., Obeso, J. A., Rajput, A. H., and Hornykiewicz, O. (2014) Is Parkinson’s disease a vesicular dopamine storage disorder? Evidence from a study in isolated synaptic vesicles of human and nonhuman primate striatum. J. Neurosci. 34, 8210−8218. (122) Schultzberg, M., Segura-Aguilar, J., and Lind, C. (1988) Distribution of DT diaphorase in the rat brain: biochemical and immunohistochemical studies. Neuroscience 27, 763−76. (123) Dagnino-Subiabre, A., Cassels, B. K., Baez, S., Johansson, A. S., Mannervik, B., and Segura-Aguilar, J. (2000) Glutathione transferase M2−2 catalyzes conjugation of dopamine and dopa o-quinones. Biochem. Biophys. Res. Commun. 274, 32−6. (124) Cheng, F. C., Kuo, J. S., Chia, L. G., and Dryhurst, G. (1996) Elevated 5-Scysteinyldopamine/homovanillic acid ratio and reduced homovanillic acid incerebrospinal fluid: possible markers for and potential insights into the pathoetiology of Parkinson’s disease. J. Neural. Transm. 103, 433−446. (125) Carstam, R., Brinck, C., Hindemith-Augustsson, A., Rorsman, H., and Rosengren, E. (1991) The neuromelanin of the human substantia nigra. Biochim. Biophys. Acta, Mol. Basis Dis. 1097, 152−160. (126) Rosengren, E., Linder-Eliasson, E., and Carlsson, A. (1985) Detection of 5-S-cysteinyldopamine in 559 human brain. J. Neural. Transm. 63, 247−253. (127) Cuevas, C., Huenchuguala, S., Muñoz, P., Villa, M., Paris, I., Mannervik, B., and Segura-Aguilar, J. (2015) Glutathione TransferaseM2−2 Secreted from Glioblastoma Cell Protects SH-SY5Y Cells from Aminochrome Neurotoxicity. Neurotoxic. Res. 27, 217−228. (128) Segura-Aguilar, J. (2015) A new mechanism for protection of dopaminergic neurons mediated by astrocytes. Neural Regener. Res. 10, 1225−1227. (129) Segura-Aguilar, J. Aminochrome as preclinical model for Parkinson’s disease. Oncotarget 2017, in press. (130) Huenchuguala, S., Muñoz, P., Graumann, R., Paris, I., and Segura-Aguilar, J. (2016) DT-diaphorase protects astrocytes from aminochrome-induced toxicity. NeuroToxicology 55, 10−12. (131) Prajapati, S. K., Garabadu, D., and Krishnamurthy, S. (2017) Coenzyme Q10 Prevents Mitochondrial Dysfunction and Facilitates Pharmacological Activity of Atorvastatin in 6-OHDA Induced Dopaminergic Toxicity in Rats. Neurotoxic. Res., DOI: 10.1007/ s12640-016-9693-6. (132) Elkon, H., Melamed, E., and Offen, D. (2004) Oxidative stress, induced by 6-hydroxydopamine, reduces proteasome activities in PC12 cells: implications for the pathogenesis of Parkinson’s disease. J. Mol. Neurosci. 24, 387−400. (133) Zhang, J., Cai, Q., Jiang, M., Liu, Y., Gu, H., Guo, J., Sun, H., Fang, J., and Jin, L. (2017) Mesencephalic astrocyte-derived

(98) Lozano, J., Muñoz, P., Nore, B. F., Ledoux, S., and SeguraAguilar, J. (2010) Stable expression of short interfering RNA for DTdiaphorase induces neurotoxicity. Chem. Res. Toxicol. 23, 1492−1496. (99) Segura-Aguilar, J., Baez, S., Widersten, M., Welch, C. J., and Mannervik, B. (1997) Human class Mu glutathione transferases, in particular isoenzyme M2−2, catalyze detoxication of the dopamine metabolite aminochrome. J. Biol. Chem. 272, 5727−5731. (100) Baez, S., Segura-Aguilar, J., Widersten, M., Johansson, A. S., and Mannervik, B. (1997) Glutathione transferases catalyse the detoxication of oxidized metabolites (o-quinones) of catecholamines and may serve as an antioxidant system preventing degenerative cellular processes. Biochem. J. 324, 25−28. (101) Ma, Q. (2013) Role of nrf2 in oxidative stress and toxicity. Annu. Rev. Pharmacol. Toxicol. 53, 401−26. (102) Kensler, T. W., Wakabayashi, N., and Biswal, S. (2007) Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu. Rev. Pharmacol. Toxicol. 47, 89−116. (103) Nguyen, T., Sherratt, P. J., and Pickett, C. B. (2003) Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu. Rev. Pharmacol. Toxicol. 43, 233− 260. (104) Zhang, Y., Hou, Y., Liu, C., Li, Y., Guo, W., Wu, J. L., Xu, D., You, X., Pan, Y., and Chen, Y. (2016) Identification of an adaptor protein that facilitates Nrf2-Keap1 complex formation and modulates antioxidant response. Free Radical Biol. Med. 97, 38−49. (105) Chen, S., Zhang, Z., Qing, T., Ren, Z., Yu, D., Couch, L., Ning, B., Mei, N., Shi, L., Tolleson, W. H., and Guo, L. (2017) Activation of the Nrf2 signaling pathway in usnic acid-induced toxicity in HepG2 cells. Arch. Toxicol. 91, 1293. (106) Esmaeili, M. A., and Alilou, M. (2014) Naringenin attenuates CCl4 -induced hepatic inflammation by the activation of an Nrf2mediated pathway in rats. Clin. Exp. Pharmacol. Physiol. 41, 416−422. (107) Gao, S., Duan, X., Wang, X., Dong, D., Liu, D., Li, X., Sun, G., and Li, B. (2013) Curcumin attenuates arsenic-induced hepatic injuries and oxidative stress in experimental mice through activation of Nrf2 pathway, promotion of arsenic methylation and urinary excretion. Food Chem. Toxicol. 59, 739−47. (108) Jin, W., Ming, X., Hou, X., Zhu, T., Yuan, B., Wang, J., Ni, H., Jiang, J., Wang, H., and Liang, W. (2014) Protective effects of erythropoietin in traumatic spinal cord injury by inducing the Nrf2 signaling pathway activation. J. Trauma Acute Care Surg. 76, 1228− 1234. (109) Wang, D., Wang, Y., Wan, X., Yang, C. S., and Zhang, J. (2015) Green tea polyphenol (−)-epigallocatechin-3-gallate triggered hepatotoxicity in mice: responses of major antioxidant enzymes and the Nrf2 rescue pathway. Toxicol. Appl. Pharmacol. 283, 65−74. (110) Lee, M. S., Lee, B., Park, K. E., Utsuki, T., Shin, T., Oh, C. W., and Kim, H. R. (2015) Dieckol enhances the expression of antioxidant and detoxifying enzymes by the activation of Nrf2-MAPK signalling pathway in HepG2 cells. Food Chem. 174, 538−546. (111) Deng, Y., Zhu, J., Mi, C., Xu, B., Jiao, C., Li, Y., Xu, D., Liu, W., and Xu, Z. (2015) Melatonin antagonizes Mn-induced oxidative injury through the activation of keap1-Nrf2-ARE signaling pathway in the striatum of mice. Neurotoxic. Res. 27, 156−71. (112) Byun, H. G., and Lee, J. K. (2015) Chlorella ethanol extract induced phase II enzyme through NFE2L2 (nuclear factor [erythroidderived] 2-like 2, NRF2) activation and protected ethanol-induced hepatoxicity. J. Med. Food 18, 182−189. (113) Das, L., and Vinayak, M. (2015) Long term effect of curcumin in restoration of tumour suppressor p53 and phase-II antioxidant enzymes via activation of Nrf2 signalling and modulation of inflammation in prevention of cancer. PLoS One 10, e0124000. (114) Duan, X., Li, J., Zhang, Y., Li, W., Zhao, L., Nie, H., Sun, G., and Li, B. (2015) Activation of NRF2 pathway in spleen, thymus as well as peripheral blood mononuclear cells by acute arsenic exposure in mice. Int. Immunopharmacol. 28, 1059−67. (115) Shoji, M., Arakaki, Y., Esumi, T., Kohnomi, S., Yamamoto, C., Suzuki, Y., Takahashi, E., Konishi, S., Kido, H., and Kuzuhara, T. (2015) Bakuchiol Is a Phenolic Isoprenoid with Novel Enantiomer710


Review

ACS Chemical Neuroscience neurotrophic factor alleviated 6-OHDA-induced cell damage via ROSAMPK/mTOR mediated autophagic inhibition. Exp. Gerontol. 89, 45− 56. (134) In, S., Hong, C. W., Choi, B., Jang, B. G., and Kim, M. J. (2016) Inhibition of Mitochondrial Clearance and Cu/Zn-SOD Activity Enhance 6-Hydroxydopamine-Induced Neuronal Apoptosis. Mol. Neurobiol. 53, 777−791. (135) Baluchnejadmojarad, T., Mansouri, M., Ghalami, J., Mokhtari, Z., and Roghani, M. (2017) Sesamin imparts neuroprotection against intrastriatal 6-hydroxydopamine toxicity by inhibition of astroglial activation, apoptosis, and oxidative stress. Biomed. Pharmacother. 88, 754−761. (136) Avagliano, C., Russo, R., De Caro, C., Cristiano, C., La Rana, G., Piegari, G., Paciello, O., Citraro, R., Russo, E., De Sarro, G., Meli, R., Mattace Raso, G., and Calignano, A. (2016) Palmitoylethanolamide protects mice against 6-OHDA-induced neurotoxicity and endoplasmic reticulum stress: In vivo and in vitro evidence. Pharmacol. Res. 113, 276−289. (137) Nataraj, J., Manivasagam, T., Thenmozhi, A. J., and Essa, M. M. (2016) Lutein protects dopaminergic neurons against MPTP-induced apoptotic death and motor dysfunction by ameliorating mitochondrial disruption and oxidative stress. Nutr. Neurosci. 19, 237−246. (138) Bové, J., Martínez-Vicente, M., Dehay, B., Perier, C., Recasens, A., Bombrun, A., Antonsson, B., and Vila, M. (2014) BAX channel activity mediates lysosomal disruption linked to Parkinson disease. Autophagy 10, 889−900. (139) Guo, H., Shi, F., Li, M., Liu, Q., Yu, B., and Hu, L. (2015) Neuroprotective effects of Eucommia ulmoides Oliv. and its bioactive constituent work via ameliorating the ubiquitin-proteasome system. BMC Complementary Altern. Med. 15, 151. (140) Cheng, Y. F., Zhu, G. Q., Wang, M., Cheng, H., Zhou, A., Wang, N., Fang, N., Wang, X. C., Xiao, X. Q., Chen, Z. W., and Li, Q. L. (2009) Involvement of ubiquitin proteasome system in protective mechanisms of Puerarin to MPP(+)-elicited apoptosis. Neurosci. Res. 63, 52−58. (141) Machado, V., Zöller, T., Attaai, A., and Spittau, B. (2016) Microglia-Mediated Neuroinflammation and Neurotrophic FactorInduced Protection in the MPTP Mouse Model of Parkinson’s Disease-Lessons from Transgenic Mice. Int. J. Mol. Sci. 17 (2), 151. (142) Tsujii, S., Ishisaka, M., Shimazawa, M., Hashizume, T., and Hara, H. (2015) Zonisamide suppresses endoplasmic reticulum stressinduced neuronal cell damage in vitro and in vivo. Eur. J. Pharmacol. 746, 301−307. (143) Yu, J., Xu, H., Shen, X., and Jiang, H. (2016) Ghrelin protects MES23.5 cells against rotenone via inhibiting mitochondrial dysfunction and apoptosis. Neuropeptides 56, 69−74. (144) Chou, A. P., Li, S., Fitzmaurice, A. G., and Bronstein, J. M. (2010) Mechanisms of rotenone-induced proteasome inhibition. NeuroToxicology 31, 367−372. (145) Wu, F., Xu, H. D., Guan, J. J., Hou, Y. S., Gu, J. H., Zhen, X. C., and Qin, Z. H. (2015) Rotenone impairs autophagic flux and lysosomal functions in Parkinson’s disease. Neuroscience 284, 900−911. (146) Dhanalakshmi, C., Janakiraman, U., Manivasagam, T., Justin Thenmozhi, A., Essa, M. M., Kalandar, A., Khan, M. A., and Guillemin, G. J. (2016) Vanillin Attenuated Behavioural Impairments, Neurochemical Deficts, Oxidative Stress and Apoptosis Against Rotenone Induced Rat Model of Parkinson’s Disease. Neurochem. Res. 41, 1899− 1910. (147) Ojha, S., Javed, H., Azimullah, S., Abul Khair, S. B., and Haque, M. E. (2016) Glycyrrhizic acid Attenuates Neuroinflammation and Oxidative Stress in Rotenone Model of Parkinson’s Disease. Neurotoxic. Res. 29, 275−287. (148) Su, L. Y., Li, H., Lv, L., Feng, Y. M., Li, G. D., Luo, R., Zhou, H. J., Lei, X. G., Ma, L., Li, J. L., Xu, L., Hu, X. T., and Yao, Y. G. (2015) Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/α-synuclein aggregation. Autophagy 11, 1745−1759. (149) Ren, R., Shi, C., Cao, J., Sun, Y., Zhao, X., Guo, Y., Wang, C., Lei, H., Jiang, H., Ablat, N., Xu, J., Li, W., Ma, Y., Qi, X., Ye, M., Pu, X.,

and Han, H. (2016) Neuroprotective Effects of A Standardized Flavonoid Extract of Safflower Against Neurotoxin-Induced Cellular and Animal Models of Parkinson’s Disease. Sci. Rep. 6, 22135. (150) Sharrad, D. F., Chen, B. N., Gai, W. P., Vaikath, N., El-Agnaf, O. M., and Brookes, S. J. (2016) Rotenone and elevated extracellular potassium concentration induce cell-specific fibrillation of α-synuclein in axons of cholinergic enteric neurons in the guinea-pig ileum. Neurogastroenterol. Motil., DOI: 10.1111/nmo.12985.

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