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3-Hydroxymorphinan protects against hypoxia-induced cell death in primary astrocyte by regulating Ca2+ influx and the glutamate homeostasis

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Abstract

Background

Hypoxia is a pathological phenomenon of the central nervous system that occurs during ischemia and stroke, leading to brain cell damage. Astrocytes play an important role in maintaining homeostasis in the brain microenvironment under normal as well as in pathological conditions. 3-hydroxymorphinan (3-HM) is an active metabolite of dextromethorphan (DM) that is widely used in anti-cough remedies and is more potent and safer than DM in the treatment of neurological disorders. However, previous research has not examined whether 3-HM has a protective effect in ischemic condition.

Objective

In this study, we aimed to confirm the effect of 3-HM on hypoxia-induced astrocyte death. We also investigated the protective mechanism of 3-HM and its potential applicability in ischemia brain injury.

Result

For the in vitro hypoxic conditions, CoCl2, a hypoxia-mimetic agent, was added to mouse primary astrocytes. 200 μM of CoCl2 showed cytotoxicity, whereas pre-incubation with 3-HM attenuated cell death by CoCl2. Moreover, pre-treatment with 3-HM dramatically reduced oxidative stress and mitochondrial damage by CoCl2. Further, 3-HM significantly reduced intracellular calcium influx induced by extracellular glutamate and finally modulated the glutamate released from the astrocytes.

Conclusion

Taken together, these results suggest that 3-HM has a potential to regulate glutamate release from the astrocytic cell death in hypoxic condition and could be used as a promising preventive or therapeutic agent for ischemic brain injury.

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Acknowledgements

Not applicable.

Funding

This research was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (Grant No. 2020R1A2C2011617) and by the Chung-Ang University Research Scholarship Grant in 2020.

Author information

Author notes

  1. Ok-Hyeon Kim, Gyeong Yun Lee, and Kyung Yong Kim have contributed equally to the work.

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, College of Medicine, Chung-Ang University, Seoul, 06974, South Korea

    Ok-Hyeon Kim, Gyeong Yun Lee, Kyung Yong Kim, Jong In Son, Yoon Hee Chung & Hyun Jung Lee

  2. Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, South Korea

    Ok-Hyeon Kim, Ji Hoon Jeong & Hyun Jung Lee

  3. Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, South Korea

    Tae Woo Jung & Ji Hoon Jeong

  4. College of Pharmacy, Sookmyung Women’s University, Seoul, South Korea

    Joon Seok Bang

  5. Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chuncheon, South Korea

    Hyoung-Chun Kim

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  1. Ok-Hyeon Kim
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Contributions

Ok-Hyeon Kim contributed to investigation, methodology, data curation, and writing—original draft. Gyeong Yun Lee contributed to methodology and writing—original draft. Kyung Yong Kim contributed to conceptualization, investigation and writing—original draft. Jong In Son contributed to investigation and methodology. Tae Woo Jung, Ji Hoon Jeong, Joon Seok Bang, and Hyoung-Chun Kim contributed to conceptualization and investigation. Yoon Hee Chung contributed to conceptualization and methodology. Hyun Jung Lee contributed to conceptualization, investigation, formal analysis, funding acquisition, writing—original draft, and writing—review and editing.

Corresponding author

Correspondence to Hyun Jung Lee.

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Conflict of interest

Ok-Hyeon Kim declares that she has no conflict of interest. Gyeong Yun Lee declares that he has no conflict of interest. Kyung Yong Kim declares that he has no conflict of interest. Jong In Son declares that he has no conflict of interest. Tae Woo Jung declares that he has no conflict of interest. Ji Hoon Jeong declares that he has no conflict of interest. Joon Seok Bang declares that he has no conflict of interest. Hyoung-Chun Kim declares that he has no conflict of interest. Yoon Hee Chung declares that she has no conflict of interest. Hyun Jung Lee declares that she has no conflict of interest.

Ethical approval

This research was approved by the Institutional Animal Care Use Committee (IACUC) of Chung-Ang University (Approval ID: 202100006).

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Kim, OH., Lee, G.Y., Kim, K.Y. et al. 3-Hydroxymorphinan protects against hypoxia-induced cell death in primary astrocyte by regulating Ca2+ influx and the glutamate homeostasis. Mol. Cell. Toxicol. 19, 145–153 (2023). https://doi.org/10.1007/s13273-022-00276-4

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