Ginsenoside Re protects methamphetamine-induced dopaminergic neurotoxicity in mice via upregulation of dynorphin-mediated Κ-opioid receptor and downregulation of substance P-mediated neurokinin 1 receptor

Duy Khanh Dang, Eun Joo Shin, Dae Joong Kim, Hai Quyen Tran, Ji Hoon Jeong, Choon Gon Jang, Seung Yeol Nah, Jung Hwan Jeong, Jae Kyung Byun, Sung Kwon Ko, Guoying Bing, Jau Shyong Hong, Hyoung Chun Kim

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Background: We previously reported that ginsenoside Re (GRe) attenuated against methamphetamine (MA)-induced neurotoxicity via anti-inflammatory and antioxidant potentials. We also demonstrated that dynorphin possesses anti-inflammatory and antioxidant potentials against dopaminergic loss, and that balance between dynorphin and substance P is important for dopaminergic neuroprotection. Thus, we examined whether GRe positively affects interactive modulation between dynorphin and substance P against MA neurotoxicity in mice. Methods: We examined changes in dynorphin peptide level, prodynorphin mRNA, and substance P mRNA, substance P-immunoreactivity, homeostasis in enzymatic antioxidant system, oxidative parameter, microglial activation, and pro-apoptotic parameter after a neurotoxic dose of MA to clarify the effects of GRe, prodynorphin knockout, pharmacological inhibition of Κ-opioid receptor (i.e., nor-binaltorphimine), or neurokinin 1 (NK1) receptor (i.e., L-733,060) against MA insult in mice. Results: GRe attenuated MA-induced decreases in dynorphin level, prodynorphin mRNA expression in the striatum of wild-type (WT) mice. Prodynorphin knockout potentiated MA-induced dopaminergic toxicity in mice. The imbalance of enzymatic antioxidant system, oxidative burdens, microgliosis, and pro-apoptotic changes led to the dopaminergic neurotoxicity. Neuroprotective effects of GRe were more pronounced in prodynorphin knockout than in WT mice. Nor-binaltorphimine, a Κ-opioid receptor antagonist, counteracted against protective effects of GRe. In addition, we found that GRe significantly attenuated MA-induced increases in substance P-immunoreactivity and substance P mRNA expression in the substantia nigra. These increases were more evident in prodynorphin knockout than in WT mice. Although, we observed that substance P-immunoreactivity was co-localized in NeuN-immunreactive neurons, GFAP-immunoreactive astrocytes, and Iba-1-immunoreactive microglia. NK1 receptor antagonist L-733,060 or GRe selectively inhibited microgliosis induced by MA. Furthermore, L-733,060 did not show any additive effects against GRe-mediated protective activity (i.e., antioxidant, antimicroglial, and antiapoptotic effects), indicating that NK1 receptor is one of the molecular targets of GRe. Conclusions: Our results suggest that GRe protects MA-induced dopaminergic neurotoxicity via upregulatgion of dynorphin-mediated Κ-opioid receptor and downregulation of substance P-mediated NK1 R.

Original languageEnglish
Article number52
JournalJournal of Neuroinflammation
Volume15
Issue number1
DOIs
StatePublished - Feb 21 2018

Bibliographical note

Funding Information:
This study is supported by a grant (no. S111415L020100) from the Forestry Technology Projects (provided by the Korea Forest Service) and a grant (no. 14182MFDS979) from the Korea Food and Drug Administration, Republic of Korea. Duy-Khanh Dang and Hai-Quyen Tran were supported by the BK21 PLUS program.

Publisher Copyright:
© 2018 The Author(s).

Keywords

  • Dynorphin
  • Methamphetamine
  • Microglia
  • Neurokinin 1 receptor
  • Κ-opioid receptor

ASJC Scopus subject areas

  • Neuroscience (all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

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