Evidence for non‐oxidative dopamine cytotoxicity: potent activation of NF‐κ B and lack of protection by anti‐oxidants

Weingarten, Paul; Bermak, Jason C.; Zhou, Qun‐Yong

doi:10.1046/j.1471-4159.2001.00190.x

Cited by 26 publications

(22 citation statements)

References 53 publications

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“…In addition, apoptosis induced via a mitochondria-dependent cascade involving the activation of caspase-9 and the apoptosome complex is enhanced in cerebral cortex from VMAT2 deficient mice during early postnatal developmental (P1-P3) (Stankovski et al, 2007). Even though apoptotic mechanisms underlying dopamine dysregulation is not the focus of this paper, it has been shown by others that the stress-inducible transcription factor NF-kappa B can be activated by intracellular dopamine, a process resistant to antioxidant protection (Weingarten et al, 2001). In this way, a low expression of VMAT2 could trigger apoptotic cascades via the increase in cytosolic dopamine.…”

Section: Discussionmentioning

confidence: 94%

Vesicular monoamine transporter 2 regulates the sensitivity of rat dopaminergic neurons to disturbed cytosolic dopamine levels

Vergo¹,

Johansen²,

Leist³

et al. 2007

Brain Research

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A B S T R A C TAn abnormal accumulation of cytosolic dopamine resulting in reactive oxygen species and dopamine-quinone products may play an important role in the rather selective degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons in Parkinson's disease. The neuronal-specific vesicular monoamine transporter (VMAT2), responsible for uptake of dopamine into vesicles, has been shown to play a central role both in intracellular dopamine homeostasis and sequestration of dopaminergic neurotoxins. Direct or indirect enhancement of VMAT2 activity could therefore have neuroprotective effects by decreasing cytosolic dopamine levels. Here, we demonstrate that transfection of VMAT2 in the dopaminergic cell line, PC12, increases intracellular dopamine content, augments potassium-induced dopamine release and attenuates cell death induced by the cytosolic dopamine enhancer, methamphetamine, suggesting an enhancement in vesicular dopamine storage. In rat ventral mesencephalic cultures highly enriched for dopaminergic neurons, lentiviral delivery of recombinant VMAT2 using a neuronal-specific promoter also resulted in elevated intracellular dopamine content and neurotransmitter release after depolarization. The opposite was seen after downregulation of VMAT2 using virally delivered shRNAs. Furthermore, using this VMAT2 knockdown model, we are the first to report a direct link between enhanced cytoplasmic dopamine levels, measured following mild permeabilization of the plasma membrane using digitonin, and neurite degeneration in primary dopaminergic neurons. In conclusion, our data support the hypothesis that an increase in vesicular sequestration of dopamine by modulation of VMAT2 activity could restore neuronal function and enhance dopaminergic cell survival in conditions of dysregulated dopamine homeostasis such as Parkinson's disease.

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Section: Discussionmentioning

confidence: 94%

Vesicular monoamine transporter 2 regulates the sensitivity of rat dopaminergic neurons to disturbed cytosolic dopamine levels

Vergo¹,

Johansen²,

Leist³

et al. 2007

Brain Research

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“…Excess dopamine may also be a potent pro-oxidant or a neurotoxic agent via non-oxidative pathways (Luo et al 1999; Hattori et al 1998), and its enzymatic or non-enzymatic oxidation yields redox-active free radicals and the robust pro-oxidant dopamine-quinones and semiquinones which may generate tetra-hydroisoquinones that generate even more dopamine-induced oxidative stress (Vallone, Picetti, Borelli 2000). Finally, dopamine may be oxidized Weingarten, Bermak, Zhou 2001; Pedrosa and Soares-da-Silva 2002), boosting its neuronal killing potential, provoking univalent reduction of oxygen and consequent production of superoxide anion, hydrogen peroxide, and hydroxyl radical (Bindoli, Rigobello, Deeble 1992). Moreover, as the non-catalyzed, physiological oxidation of dopamine is slow, free-transition metal ions like iron and manganese may accelerate its oxidation via biochemical processing mentioned above (Lloyd 1995; Jimenez et al 1993), closing a cycle that we may label as an “oxi-dopamatergic cascade” (oxidation-glutamate-dopamine oxidative stress).…”

Section: Psychosocial Stress-anxiety-depression and Oxidative Stressmentioning

confidence: 99%

Parallels Between Major Depressive Disorder and Alzheimer’s Disease: Role of Oxidative Stress and Genetic Vulnerability

2014

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The thesis of this review is that oxidative stress is the central factor in major depressive disorder (MDD) and Alzheimer’s disease (AD). The major elements involved are inflammatory cytokines, the hypothalamic pituitary axis, the hypothalamic pituitary gonadal, and arginine vasopressin systems, which induce glucocorticoid and “oxidopamatergic” cascades when triggered by psychosocial stress, severe life threatening events, and mental-affective and somatic diseases. In individuals with a genomic vulnerability to depression these cascades may result in chronic depression-anxiety-stress spectra, resulting in MDD and other known depressive syndromes. In contrast, in subjects with genomic vulnerability to Alzheimer’s disease, oxidative stress-induced brain damage triggers specific antioxidant defenses, i.e. increased levels of amyloid-β (Aβ) and aggregation of hyper-phosphorylated tau, resulting in paired helical filaments and impaired functions related to the ApoEε4 isoform, leading to complex pathological cascades culminating in AD. Surprisingly, all the AD associated molecular pathways mentioned in this review have been shown to be similar or analogous to those found in depression, including structural damage, i.e. hippocampal and frontal cortex atrophy. Other interacting molecular signals, i.e. GSK-3β, convergent survival factors (brain-derived neurotrophic factor and heat shock proteins), and transition-redox metals are also mentioned to emphasize the vast array of intermediates that could interact via comparable mechanisms in both MDD and AD.

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“…Purified D2R couples to the heterotrimeric G proteins G i 1, G i 2, and G i 3, and preferably activates G i 2 (Senogles et al, 1990), whereas in the brain, D2R preferentially couples to G o (Jiang et al, 2001). Several investigators recently reported that dopamine could induce NF-B activation in PC12, Jurkat, and Chinese hamster ovary cells, and contributes to regulation of apoptosis (Luo et al, 1999;Lee et al, 2001;Panet et al, 2001;Weingarten et al, 2001) and expression of HIV-1 genes (Rohr et al, 1999). However, the specific receptors and the underlying signaling mechanisms for this activity have not been characterized.…”

mentioning

confidence: 99%

Requirement of Gβγ and c-Src in D2 Dopamine Receptor-Mediated Nuclear Factor-κB Activation

Yang¹,

Zhang²,

Voyno-Yasenetskaya³

et al. 2003

Molecular Pharmacology

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The D2 dopamine receptor (D2R) was examined for its ability to mediate nuclear factor-B (NF-B) activation through G proteins. Stimulation of D2R-transfected HeLa cells with its agonist quinpirole induced the expression of a NF-B luciferase reporter and formation of NF-B-DNA complex. This response was blocked by pertussis toxin, and by the G␤␥ scavengers transducin and ␤-adrenergic receptor kinase 1 carboxyl-terminal fragment. Unlike G i -coupled chemoattractant receptors, D2R activated NF-B without an increase in phospholipase C-␤ activity, and the response was only slightly affected by the phosphoinositide 3-kinase inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). In contrast, treatment with genistein and 4-amino-1-tert-butyl-3-(p-methylphenyl)pyrazolo [3,4-d] pyrimidine abolished the induced NF-B activation, suggesting involvement of protein tyrosine kinases. Activation of D2R led to phosphorylation of c-Src at Tyr-418, and expression of a kinase-deficient c-Src inhibited D2R-mediated NF-B activation. The D2R-mediated NF-B activation was not dependent on epidermal growth factor (EGF) receptor transactivation since 4-(3Ј-chloroanilino)-6,7-dimethoxyquinazoline (AG1478), an EGF receptor-selective tyrphostin used at 1 M, blocked EGF-induced NF-B activation but not the quinpirole-induced response. In addition, the D2R-mediated NF-B activation was enhanced by over-expression of ␤-arrestin 1. These results suggest that D2R-mediated NF-B activation requires G␤␥ and c-Src, and possibly involves ␤-arrestin 1.The transcription factor nuclear factor B (NF-B) regulates the expression of a large number of genes coding for cytokines, growth factors, inducible effector enzymes, and regulators of apoptosis (reviewed in Ghosh et al., 1998). Activation of NF-B can be induced by a variety of environmental factors such as UV, as well as by cytokines such as TNF␣ and interleukin-1␤. The prototypical NF-B activation pathway, as seen in cells stimulated with TNF␣, involves inducible phosphorylation of IB␣ at Ser-32 and Ser-36 and subsequent degradation of this and similar inhibitory proteins.

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Evidence for non‐oxidative dopamine cytotoxicity: potent activation of NF‐κ B and lack of protection by anti‐oxidants

Cited by 26 publications

References 53 publications

Vesicular monoamine transporter 2 regulates the sensitivity of rat dopaminergic neurons to disturbed cytosolic dopamine levels

Vesicular monoamine transporter 2 regulates the sensitivity of rat dopaminergic neurons to disturbed cytosolic dopamine levels

Parallels Between Major Depressive Disorder and Alzheimer’s Disease: Role of Oxidative Stress and Genetic Vulnerability

Requirement of Gβγ and c-Src in D2 Dopamine Receptor-Mediated Nuclear Factor-κB Activation

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