PKCδ-dependent p47phox activation mediates methamphetamine-induced dopaminergic neurotoxicity

Duy Khanh Dang, Eun Joo Shin, Dae Joong Kim, Hai Quyen Tran, Ji Hoon Jeong, Choon Gon Jang, Ole Petter Ottersen, Seung Yeol Nah, Jau Shyong Hong, Toshitaka Nabeshima, Hyoung Chun Kim

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Abstract

Protein kinase C (PKC) has been recognized to activate NADPH oxidase (PHOX). However, the interaction between PKC and PHOX in vivo remains elusive. Treatment with methamphetamine (MA) resulted in a selective increase in PKCδ expression out of PKC isoforms. PKCδ co-immunoprecipitated with p47phox, and facilitated phosphorylation and membrane translocation of p47phox. MA-induced increases in PHOX activity and reactive oxygen species were attenuated by knockout of p47phox or PKCδ. In addition, MA-induced impairments in the Nrf-2-related glutathione synthetic system were also mitigated by knockout of p47phox or PKCδ. Glutathione-immunoreactivity was co-localized in Iba-1-labeled microglial cells and in NeuN-labeled neurons, but not in GFAP-labeled astrocytes, reflecting the necessity for self-protection against oxidative stress by mainly microglia. Buthionine-sulfoximine, an inhibitor of glutathione biosynthesis, potentiated microglial activation and pro-apoptotic changes, leading to dopaminergic losses. These neurotoxic processes were attenuated by rottlerin, a pharmacological inhibitor of PKCδ, genetic inhibitions of PKCδ [i.e., PKCδ knockout mice (KO) and PKCδ antisense oligonucleotide (ASO)], or genetic inhibition of p47phox (i.e., p47phox KO or p47phox ASO). Rottlerin did not exhibit any additive effects against the protective activity offered by genetic inhibition of p47phox. Therefore, we suggest that PKCδ is a critical regulator for p47phox activation induced by MA, and that Nrf-2-dependent GSH induction via inhibition of PKCδ or p47phox, is important for dopaminergic protection against MA insult.

Original languageEnglish
Pages (from-to)318-337
Number of pages20
JournalFree Radical Biology and Medicine
Volume115
DOIs
Publication statusPublished - 01-02-2018

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Methamphetamine
Protein Kinase C
Chemical activation
Glutathione
Antisense Oligonucleotides
Knockout Mice
Buthionine Sulfoximine
Phosphorylation
Oxidative stress
NADPH Oxidase
Biosynthesis
Microglia
Astrocytes
Neurons
Reactive Oxygen Species
Protein Isoforms
Oxidative Stress

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

Cite this

Dang, D. K., Shin, E. J., Kim, D. J., Tran, H. Q., Jeong, J. H., Jang, C. G., ... Kim, H. C. (2018). PKCδ-dependent p47phox activation mediates methamphetamine-induced dopaminergic neurotoxicity. Free Radical Biology and Medicine, 115, 318-337. https://doi.org/10.1016/j.freeradbiomed.2017.12.018
Dang, Duy Khanh ; Shin, Eun Joo ; Kim, Dae Joong ; Tran, Hai Quyen ; Jeong, Ji Hoon ; Jang, Choon Gon ; Ottersen, Ole Petter ; Nah, Seung Yeol ; Hong, Jau Shyong ; Nabeshima, Toshitaka ; Kim, Hyoung Chun. / PKCδ-dependent p47phox activation mediates methamphetamine-induced dopaminergic neurotoxicity. In: Free Radical Biology and Medicine. 2018 ; Vol. 115. pp. 318-337.
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title = "PKCδ-dependent p47phox activation mediates methamphetamine-induced dopaminergic neurotoxicity",
abstract = "Protein kinase C (PKC) has been recognized to activate NADPH oxidase (PHOX). However, the interaction between PKC and PHOX in vivo remains elusive. Treatment with methamphetamine (MA) resulted in a selective increase in PKCδ expression out of PKC isoforms. PKCδ co-immunoprecipitated with p47phox, and facilitated phosphorylation and membrane translocation of p47phox. MA-induced increases in PHOX activity and reactive oxygen species were attenuated by knockout of p47phox or PKCδ. In addition, MA-induced impairments in the Nrf-2-related glutathione synthetic system were also mitigated by knockout of p47phox or PKCδ. Glutathione-immunoreactivity was co-localized in Iba-1-labeled microglial cells and in NeuN-labeled neurons, but not in GFAP-labeled astrocytes, reflecting the necessity for self-protection against oxidative stress by mainly microglia. Buthionine-sulfoximine, an inhibitor of glutathione biosynthesis, potentiated microglial activation and pro-apoptotic changes, leading to dopaminergic losses. These neurotoxic processes were attenuated by rottlerin, a pharmacological inhibitor of PKCδ, genetic inhibitions of PKCδ [i.e., PKCδ knockout mice (KO) and PKCδ antisense oligonucleotide (ASO)], or genetic inhibition of p47phox (i.e., p47phox KO or p47phox ASO). Rottlerin did not exhibit any additive effects against the protective activity offered by genetic inhibition of p47phox. Therefore, we suggest that PKCδ is a critical regulator for p47phox activation induced by MA, and that Nrf-2-dependent GSH induction via inhibition of PKCδ or p47phox, is important for dopaminergic protection against MA insult.",
author = "Dang, {Duy Khanh} and Shin, {Eun Joo} and Kim, {Dae Joong} and Tran, {Hai Quyen} and Jeong, {Ji Hoon} and Jang, {Choon Gon} and Ottersen, {Ole Petter} and Nah, {Seung Yeol} and Hong, {Jau Shyong} and Toshitaka Nabeshima and Kim, {Hyoung Chun}",
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Dang, DK, Shin, EJ, Kim, DJ, Tran, HQ, Jeong, JH, Jang, CG, Ottersen, OP, Nah, SY, Hong, JS, Nabeshima, T & Kim, HC 2018, 'PKCδ-dependent p47phox activation mediates methamphetamine-induced dopaminergic neurotoxicity', Free Radical Biology and Medicine, vol. 115, pp. 318-337. https://doi.org/10.1016/j.freeradbiomed.2017.12.018

PKCδ-dependent p47phox activation mediates methamphetamine-induced dopaminergic neurotoxicity. / Dang, Duy Khanh; Shin, Eun Joo; Kim, Dae Joong; Tran, Hai Quyen; Jeong, Ji Hoon; Jang, Choon Gon; Ottersen, Ole Petter; Nah, Seung Yeol; Hong, Jau Shyong; Nabeshima, Toshitaka; Kim, Hyoung Chun.

In: Free Radical Biology and Medicine, Vol. 115, 01.02.2018, p. 318-337.

Research output: Contribution to journalArticle

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T1 - PKCδ-dependent p47phox activation mediates methamphetamine-induced dopaminergic neurotoxicity

AU - Dang, Duy Khanh

AU - Shin, Eun Joo

AU - Kim, Dae Joong

AU - Tran, Hai Quyen

AU - Jeong, Ji Hoon

AU - Jang, Choon Gon

AU - Ottersen, Ole Petter

AU - Nah, Seung Yeol

AU - Hong, Jau Shyong

AU - Nabeshima, Toshitaka

AU - Kim, Hyoung Chun

PY - 2018/2/1

Y1 - 2018/2/1

N2 - Protein kinase C (PKC) has been recognized to activate NADPH oxidase (PHOX). However, the interaction between PKC and PHOX in vivo remains elusive. Treatment with methamphetamine (MA) resulted in a selective increase in PKCδ expression out of PKC isoforms. PKCδ co-immunoprecipitated with p47phox, and facilitated phosphorylation and membrane translocation of p47phox. MA-induced increases in PHOX activity and reactive oxygen species were attenuated by knockout of p47phox or PKCδ. In addition, MA-induced impairments in the Nrf-2-related glutathione synthetic system were also mitigated by knockout of p47phox or PKCδ. Glutathione-immunoreactivity was co-localized in Iba-1-labeled microglial cells and in NeuN-labeled neurons, but not in GFAP-labeled astrocytes, reflecting the necessity for self-protection against oxidative stress by mainly microglia. Buthionine-sulfoximine, an inhibitor of glutathione biosynthesis, potentiated microglial activation and pro-apoptotic changes, leading to dopaminergic losses. These neurotoxic processes were attenuated by rottlerin, a pharmacological inhibitor of PKCδ, genetic inhibitions of PKCδ [i.e., PKCδ knockout mice (KO) and PKCδ antisense oligonucleotide (ASO)], or genetic inhibition of p47phox (i.e., p47phox KO or p47phox ASO). Rottlerin did not exhibit any additive effects against the protective activity offered by genetic inhibition of p47phox. Therefore, we suggest that PKCδ is a critical regulator for p47phox activation induced by MA, and that Nrf-2-dependent GSH induction via inhibition of PKCδ or p47phox, is important for dopaminergic protection against MA insult.

AB - Protein kinase C (PKC) has been recognized to activate NADPH oxidase (PHOX). However, the interaction between PKC and PHOX in vivo remains elusive. Treatment with methamphetamine (MA) resulted in a selective increase in PKCδ expression out of PKC isoforms. PKCδ co-immunoprecipitated with p47phox, and facilitated phosphorylation and membrane translocation of p47phox. MA-induced increases in PHOX activity and reactive oxygen species were attenuated by knockout of p47phox or PKCδ. In addition, MA-induced impairments in the Nrf-2-related glutathione synthetic system were also mitigated by knockout of p47phox or PKCδ. Glutathione-immunoreactivity was co-localized in Iba-1-labeled microglial cells and in NeuN-labeled neurons, but not in GFAP-labeled astrocytes, reflecting the necessity for self-protection against oxidative stress by mainly microglia. Buthionine-sulfoximine, an inhibitor of glutathione biosynthesis, potentiated microglial activation and pro-apoptotic changes, leading to dopaminergic losses. These neurotoxic processes were attenuated by rottlerin, a pharmacological inhibitor of PKCδ, genetic inhibitions of PKCδ [i.e., PKCδ knockout mice (KO) and PKCδ antisense oligonucleotide (ASO)], or genetic inhibition of p47phox (i.e., p47phox KO or p47phox ASO). Rottlerin did not exhibit any additive effects against the protective activity offered by genetic inhibition of p47phox. Therefore, we suggest that PKCδ is a critical regulator for p47phox activation induced by MA, and that Nrf-2-dependent GSH induction via inhibition of PKCδ or p47phox, is important for dopaminergic protection against MA insult.

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