Approaches to Prevent Dopamine Quinone-Induced Neurotoxicity

Miyazaki, Ikuko; Asanuma, Masato

doi:10.1007/s11064-008-9843-1

Cited by 63 publications

(56 citation statements)

References 89 publications

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“…1, A and B), but it is plausible to suggest that increasing the ER exit of nAChRs could reorganize the COPII vesicle population and relieve ER stress caused by other environmental or genetic factors. Dopaminergic neurons contain potentially toxic metabolites of dopamine (Ahmadi et al, 2008;Miyazaki and Asanuma, 2009) and relatively high intracellular Ca 2ϩ levels (Surmeier et al, 2011). These factors probably lead to increased levels of ER stress under physiological conditions (Egawa et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Chaperoning of Nicotinic Acetylcholine Receptors Reduces the Endoplasmic Reticulum Stress Response

Srinivasan

Richards²,

Xia³

et al. 2012

Mol Pharmacol

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We report the first observation that endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) can decrease when a central nervous system drug acts as an intracellular pharmacological chaperone for its classic receptor. Transient expression of ␣4␤2 nicotinic receptors (nAChRs) in Neuro-2a cells induced the nuclear translocation of activating transcription factor 6 (ATF6), which is part of the UPR. Cells were exposed for 48 h to the full agonist nicotine, the partial agonist cytisine, or the competitive antagonist dihydro-␤-erythroidine; we also tested mutant nAChRs that readily exit the ER. Each of these four manipulations increased Sec24D-enhanced green fluorescent protein fluorescence of condensed ER exit sites and attenuated translocation of ATF6-enhanced green fluorescent protein to the nucleus. However, we found no correlation among the manipulations regarding other tested parameters [i.e., changes in nAChR stoichiometry (␣4 2 ␤2 3 versus ␣4 3 ␤2 2 ), changes in ER and trans-Golgi structures, or the degree of nAChR up-regulation at the plasma membrane]. The four manipulations activated 0 to 0.4% of nAChRs, which shows that activation of the nAChR channel did not underlie the reduced ER stress. Nicotine also attenuated endogenously expressed ATF6 translocation and phosphorylation of eukaryotic initiation factor 2␣ in mouse cortical neurons transfected with ␣4␤2 nAChRs. We conclude that, when nicotine accelerates ER export of ␣4␤2 nAChRs, this suppresses ER stress and the UPR. Suppression of a sustained UPR may explain the apparent neuroprotective effect that causes the inverse correlation between a person's history of tobacco use and susceptibility to developing Parkinson's disease. This suggests a novel mechanism for neuroprotection by nicotine.

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Section: Discussionmentioning

confidence: 99%

Pharmacological Chaperoning of Nicotinic Acetylcholine Receptors Reduces the Endoplasmic Reticulum Stress Response

Srinivasan

Richards²,

Xia³

et al. 2012

Mol Pharmacol

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“…Dopaminergic (DA) neurons are subjected to Ca ϩ2 influx and to potentially toxic byproducts of dopamine metabolism that can affect proteostasis (Ahmadi et al, 2008;Miyazaki and Asanuma, 2009;Surmeier et al, 2011). Under normal circumstances, intraorganelle sensors for unfolded or misfolded proteins activate unfolded protein responses (UPRs): homeostatic, adaptive, and compensatory pathways transiently reprogram gene activation, organelle physiology, and catabolic processes.…”

Section: Introductionmentioning

confidence: 99%

Smoking-Relevant Nicotine Concentration Attenuates the Unfolded Protein Response in Dopaminergic Neurons

et al. 2016

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Retrospective epidemiological studies show an inverse correlation between susceptibility to Parkinson's disease and a person's history of tobacco use. Animal model studies suggest nicotine as a neuroprotective agent and nicotinic acetylcholine (ACh) receptors (nAChRs) as targets for neuroprotection, but the underlying neuroprotective mechanism(s) are unknown. We cultured mouse ventral midbrain neurons for 3 weeks. Ten to 20% of neurons were dopaminergic (DA), revealed by tyrosine hydroxylase (TH) immunoreactivity. We evoked mild endoplasmic reticulum (ER) stress with tunicamycin (Tu), producing modest increases in the level of nuclear ATF6, phosphorylated eukaryotic initiation factor 2␣, nuclear XBP1, and the downstream proapoptotic effector nuclear C/EBP homologous protein.We incubated cultures for 2 weeks with 200 nM nicotine, the approximate steady-state concentration between cigarette smoking or vaping, or during nicotine patch use. Nicotine incubation suppressed Tu-induced ER stress and the unfolded protein response (UPR). Study of mice with fluorescent nAChR subunits showed that the cultured THϩ neurons displayed ␣4, ␣6, and ␤3 nAChR subunit expression and ACh-evoked currents. Gene expression profile in cultures from TH-eGFP mice showed that the THϩ neurons also express several other genes associated with DA release. Nicotine also upregulated ACh-induced currents in DA neurons by ϳ2.5-fold. Thus, nicotine, at a concentration too low to activate an appreciable fraction of plasma membrane nAChRs, induces two sequelae of pharmacological chaperoning in the ER: UPR suppression and nAChR upregulation. Therefore, one mechanism of neuroprotection by nicotine is pharmacological chaperoning, leading to UPR suppression. Measuring this pathway may help in assessing neuroprotection.

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“…For example, the cellular toxicity associated with chronic Amp (73) and chronic exposure to high levels of air pollutants has been attributed to oxidative stress (56). In the case of the amphetamines, the oxidative stress induced by DA quinone and its redox activity has been proposed to be the basis for cellular oxidation (54,55). Air pollutant effects are also attributed to the components of the particle phase, which we have shown are primarily prooxidant.…”

Section: Discussionmentioning

confidence: 73%

“…These PD/PK studies provided further support for the exchange diffusion model for neurotransmitter release by the amphetamines, instead of a depolarization and neuronal release process for the stimulation of the postsynaptic receptors. The resultant micromolar concentrations of catecholamines and 5-HT present in extracellular space and their ability to generate hydrogen peroxide provided a mechanism by which neuronal damage may occur during a protracted abuse period; its role in a model of DA neurotoxicity has been reviewed recently (54,55).…”

Section: Amphetamine and Methamphetaminementioning

confidence: 99%

A Chemical Perspective of Pharmacology and Toxicology

Cho

2018

Annu. Rev. Pharmacol. Toxicol.

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My chemical training provided a somewhat different perspective of biological problems, in the problem itself and approaches to its solution. I was fortunate to have in my laboratory postdocs and students who shared this perspective and used appropriate tools to address problems in amphetamine pharmacology and air pollution toxicology. These apparently disparate areas of research shared two chemical reactions: prooxidant-based generation of reactive oxygen and formation of covalent bonds between electrophiles and biological nucleophiles. This article is an attempt to summarize that research and to identify those individuals who made the contributions.

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Approaches to Prevent Dopamine Quinone-Induced Neurotoxicity

Cited by 63 publications

References 89 publications

Pharmacological Chaperoning of Nicotinic Acetylcholine Receptors Reduces the Endoplasmic Reticulum Stress Response

Pharmacological Chaperoning of Nicotinic Acetylcholine Receptors Reduces the Endoplasmic Reticulum Stress Response

Smoking-Relevant Nicotine Concentration Attenuates the Unfolded Protein Response in Dopaminergic Neurons

A Chemical Perspective of Pharmacology and Toxicology

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