PKCδ inhibition enhances tyrosine hydroxylase phosphorylation in mice after methamphetamine treatment

Shin, Eun Joo; Duong, Chu Xuan; Nguyen, Xuan Khanh Thi; Bing, Guoying; Bach, Jae Hyung; Park, Dae-Hun; Nakayama, Keiichi I.; Ali, Syed F.; Kanthasamy, Anumantha G.; Cadet, Jean Lud; Nabeshima, Toshitaka; Kim, Hyoung Chun

doi:10.1016/j.neuint.2011.03.022

Cited by 36 publications

(38 citation statements)

References 74 publications

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“…Consistent with these studies, we demonstrated in an in vivo study that administering rottlerin, a PKC␦-specific inhibitor, protected against MPTP-induced loss of tyrosine hydroxylase-positive neurons in the nigrostriatum and the depletion of striatal dopamine and its metabolites, as well as MPTP-induced locomotor deficits (16). In a methamphetamine-intoxicated animal model, PKC␦ deficiency and rottlerin effectively attenuated methamphetamine-induced dopaminergic damage and behavioral deficits, further supporting that PKC␦ could represent a valid pharmacological target for the treatment of dopaminergic neuronal degeneration (17,18). Interestingly, we also showed that PKC␦ negatively modulates dopamine synthesis by inhibiting the rate-limiting enzyme, tyrosine hydroxylase (3).…”

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confidence: 64%

Histone Hyperacetylation Up-regulates Protein Kinase Cδ in Dopaminergic Neurons to Induce Cell Death

Jin

Harischandra

Kondru

et al. 2014

Journal of Biological Chemistry

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Background: Dysregulation of neuronal acetylation homeostasis promotes neurodegeneration. Results: Histone hyperacetylation up-regulates PKC␦ in dopaminergic neurons and augments susceptibility to oxidative damage. Conclusion: Epigenetic regulation of PKC␦ plays a proapoptotic role in neuronal cell death. Significance: The up-regulation of PKC␦ expression by hyperacetylation provides an epigenetic molecular basis of neurodegenerative disease.

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confidence: 64%

Histone Hyperacetylation Up-regulates Protein Kinase Cδ in Dopaminergic Neurons to Induce Cell Death

Jin

Harischandra

Kondru

et al. 2014

Journal of Biological Chemistry

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“…Likewise, protein kinase Cδ knock-out animals have reduced lipid peroxidation, protein oxidation, and behavioral deficits in response to methamphetamine. These studies were corroborated using pharmacological interventions, which also indicate increased tyrosine hydroxylase phosphorylation in response to methamphetamine (Shin et al, 2011, 2012). …”

Section: Partmentioning

confidence: 77%

Neuroimmune Basis of Methamphetamine Toxicity

Loftis

Janowsky

2014

International Review of Neurobiology

105

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Although it is not known which antigen-specific immune responses (or if antigen-specific immune responses) are relevant or required for methamphetamine's neurotoxic effects, it is apparent that methamphetamine exposure is associated with significant effects on adaptive and innate immunity. Alterations in lymphocyte activity and number, changes in cytokine signaling, impairments in phagocytic functions, and glial activation and gliosis have all been reported. These drug-induced changes in immune response, particularly within the CNS, are now thought to play a critical role in the addiction process for methamphetamine dependence as well as for other substance use disorders. In Section 2, methamphetamine's effects on glial cell (e.g., microglia and astrocytes) activity and inflammatory signaling cascades are summarized, including how alterations in immune cell function can induce the neurotoxic and addictive effects of methamphetamine. Section 2 also describes neurotransmitter involvement in the modulation of methamphetamine's inflammatory effects. Section 3 discusses the very recent use of pharmacological and genetic animal models which have helped elucidate the behavioral effects of methamphetamine's neurotoxic effects and the role of the immune system. Section 4 is focused on the effects of methamphetamine on blood–brain barrier integrity and associated immune consequences. Clinical considerations such as the combined effects of methamphetamine and HIV and/or HCV on brain structure and function are included in Section 4. Finally, in Section 5, immune-based treatment strategies are reviewed, with a focus on vaccine development, neuroimmune therapies, and other anti-inflammatory approaches.

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“…Similarly, our recent report showed that PKCδ activation may be, at least in part, a factor in MA-induced hyperthermia [9]. However, pretreatment with reserpine, a drug known to produce hypothermia, does not prevent MA-induced neurotoxicity [95, 96].…”

Section: Discussionmentioning

confidence: 93%

“…The 4 × 7–10 mg/kg paradigm of methamphetamine (MA) administration in naïve animals is currently the most frequently used model that mimics acute toxic dosing of MA [1, 7-9]. This paradigm provides excellent relevance to intravenous and smoked routes of MA exposure in humans.…”

Section: Introductionmentioning

confidence: 99%

Role of oxidative stress in methamphetamine-induced dopaminergic toxicity mediated by protein kinase Cδ

Shin

Duong

Nguyen

et al. 2012

Behavioural Brain Research

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This study examined the role of protein kinase C (PKC) isozymes in methamphetamine (MA)-induced dopaminergic toxicity. Multiple-dose administration of MA did not significantly alter PKCα, PKCβI, PKCβII, or PKCζ expression in the striatum, but did significantly increase PKCδ expression. Gö6976 (a co-inhibitor of PKCα and -β), hispidin (PKCβ inhibitor), and PKCζ pseudosubstrate inhibitor (PKCζ inhibitor) did not significantly alter MA-induced behavioral impairments. However, rottlerin (PKCδ inhibitor) significantly attenuated behavioral impairments in a dose-dependent manner. In addition, MA-induced behavioral impairments were not apparent in PKCδ knockout (–/–) mice. MA-induced oxidative stress (i.e., lipid peroxidation and protein oxidation) was significantly attenuated in rottlerin-treated mice and was not apparent in PKCδ (–/–) mice. Consistent with this, MA-induced apoptosis (i.e., terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptotic cells) was significantly attenuated in rottlerin-treated mice. Furthermore, MA-induced increases in the dopamine (DA) turnover rate and decreases in tyrosine hydroxylase (TH) activity and the expression of TH, dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) were not significantly observed in rottlerin-treated or PKCδ (–/–) mice. Our results suggest that PKCδ gene expression is a key mediator of oxidative stress and dopaminergic damage induced by MA. Thus, inhibition of PKCδ may be a useful target for protection against MA-induced neurotoxicity.

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PKCδ inhibition enhances tyrosine hydroxylase phosphorylation in mice after methamphetamine treatment

Cited by 36 publications

References 74 publications

Histone Hyperacetylation Up-regulates Protein Kinase Cδ in Dopaminergic Neurons to Induce Cell Death

Histone Hyperacetylation Up-regulates Protein Kinase Cδ in Dopaminergic Neurons to Induce Cell Death

Neuroimmune Basis of Methamphetamine Toxicity

Role of oxidative stress in methamphetamine-induced dopaminergic toxicity mediated by protein kinase Cδ

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