Ouabain inhibitor rostafuroxin attenuates dextromethorphan-induced manic potential.

Abstract

Dextromethorphan (DM) abuse produces mania-like symptoms in humans. ERK/Akt signaling activation involved in manic potential can be attenuated by the inhibition of ouabain-like cardiac steroids. In this study, increased phosphorylations of ERK/Akt and hyperlocomotion induced by DM (30 mg/kg, i.p./day × 7) were significantly protected by the ouabain inhibitor rostafuroxin (ROSTA), suggesting that DM induces the manic potential. ROSTA significantly attenuated DM-induced protein kinase C δ (PKCδ) phosphorylation, GluN2B (i.e., MDA receptor subunit) expression, and phospho-PKCδ/GluN2B interaction. DM instantly upregulated the nuclear factor erythroid-2-related factor 2 (Nrf2)-dependent system. However, DM reduced Nrf2 nuclear translocation, Nrf2 DNA binding activity, γ-glutamylcysteine mRNA expression, and subsequent GSH/GSSG level and enhanced oxidative parameters following 1-h of administration. ROSTA, PKCδ inhibitor rottlerin, and GluN2B inhibitor traxoprodil significantly attenuated DM-induced alterations in Nrf2-related redox parameters and locomotor activity induced by DM in wild-type mice. Importantly, in PKCδ knockout mice, DM failed to alter the above parameters. Further, ROSTA and traxoprodil also failed to enhance PKCδ depletion effect, suggesting that PKCδ is a critical target for the anti-manic potential of ROSTA or GluN2B antagonism. Our results suggest that ROSTA inhibits DM-induced manic potential by attenuating ERK/Akt activation, GluN2B/PKCδ signalings, and Nrf2-dependent system.

• Authors: Eun-Joo Shin, Bao-Trong Nguyen, Ji Hoon Jeong, Bao-Chau Hoai Nguyen, Ngoc Kim Cuong Tran, Naveen Sharma, Dae-Joong Kim, Seung-Yeol Nah, David Lichtstein, Toshitaka Nabeshima, Hyoung-Chun Kim
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 158 Pg. 112657 (Dec 2021) ISSN: 1873-6351 [Electronic] England
• PMID: 34740715 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Androstanols
• Ouabain
• Dextromethorphan
• rostafuroxin

Topics

• Androstanols (pharmacology)
• Animals
• Bipolar Disorder (chemically induced, metabolism)
• Dextromethorphan (adverse effects)
• Disease Models, Animal
• Locomotion (drug effects)
• Male
• Mice
• Ouabain (antagonists & inhibitors)
• Signal Transduction (drug effects)