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
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.
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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.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Dang, Duy-Khanh; Shin, Eun-Joo; Kim, Dae-Joong; Tran, Hai-Quyen; Jeong, Ji Hoon; Jang, Choon-Gon; Nah, Seung-Yeol; Jeong, Jung Hwan; Byun, Jae Kyung; Ko, Sung Kwon; Bing, Guoying; Hong, Jau-Shyong; and Kim, Hyoung-Chun, "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" (2018). Neuroscience Faculty Publications. 49.