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

研究成果: Article

14 引用 (Scopus)

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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.

元の言語English
ページ(範囲)318-337
ページ数20
ジャーナルFree Radical Biology and Medicine
115
DOI
出版物ステータスPublished - 01-02-2018

    フィンガープリント

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

これを引用

Dang, D. K., Shin, E. J., Kim, D. J., Tran, H. Q., Jeong, J. H., Jang, C. G., Ottersen, O. P., Nah, S. Y., Hong, J. S., Nabeshima, T., & 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