2. Academic Validation
  3. Discovery of the therapeutic potential of naltriben against glutamate-induced neurotoxicity

Discovery of the therapeutic potential of naltriben against glutamate-induced neurotoxicity

  • Neurochem Int. 2025 Feb:183:105928. doi: 10.1016/j.neuint.2025.105928.
Hyomin Ahn 1,  Hyomin Lee 2,  Wonseok Choi 3,  Hyebin Lee 4,  Kang-Gon Lee 5,  Inchan Youn 6,  Wooyoung Hur 7,  Sungmin Han 8,  Chiman Song 9
Affiliations

Affiliations

  • 1 Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Hwarangro 14 Gil, Seongbuk-gu, Seoul, 02792, Republic of Korea; Department of Life Sciences, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea.
  • 2 Medicinal Materials Research Center, Korea Institute of Science and Technology (KIST), Hwarangro 14 Gil, Seongbuk-gu, Seoul, 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Hwarangro 14 Gil, Seongbuk-gu, Seoul, 02792, Republic of Korea.
  • 3 Bionics Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Hwarangro 14 Gil, Seongbuk-gu, Seoul, 02792, Republic of Korea.
  • 4 Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Hwarangro 14 Gil, Seongbuk-gu, Seoul, 02792, Republic of Korea; Department of Pharmacology, Korea University College of Medicine, 73 Goryeodae-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea.
  • 5 Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Hwarangro 14 Gil, Seongbuk-gu, Seoul, 02792, Republic of Korea.
  • 6 Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Hwarangro 14 Gil, Seongbuk-gu, Seoul, 02792, Republic of Korea; Bionics Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Hwarangro 14 Gil, Seongbuk-gu, Seoul, 02792, Republic of Korea.
  • 7 Medicinal Materials Research Center, Korea Institute of Science and Technology (KIST), Hwarangro 14 Gil, Seongbuk-gu, Seoul, 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Hwarangro 14 Gil, Seongbuk-gu, Seoul, 02792, Republic of Korea; HY-KIST Bioconvergence, Hanyang University, 222 Wangsimniro, Seongdong-gu, Seoul, 04763, Republic of Korea.
  • 8 Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Hwarangro 14 Gil, Seongbuk-gu, Seoul, 02792, Republic of Korea; Bionics Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Hwarangro 14 Gil, Seongbuk-gu, Seoul, 02792, Republic of Korea; KHU-KIST, Department of Converging Science and Technology, Kyung Hee University, 26 Kyungheedaero, Dongdaemun-gu, Seoul, 02447, Republic of Korea.
  • 9 Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Hwarangro 14 Gil, Seongbuk-gu, Seoul, 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Hwarangro 14 Gil, Seongbuk-gu, Seoul, 02792, Republic of Korea. Electronic address: scman84@kist.re.kr.
PMID: 39756586 DOI: 10.1016/j.neuint.2025.105928
Abstract

Glutamate-induced neuronal death is associated with neurodegeneration including cerebral ischemia. Several μ-opioid receptor antagonists exhibit a neuroprotective activity and have been considered as a potential therapeutic option for neurodegenerative disorders. For the first time, our current study unveiled the neuroprotective activity of selective δ-opioid receptor antagonists. A potent, selective δ-opioid receptor antagonist naltriben, also known as a potent TRPM7 agonist, displayed the prominent protective effect against glutamate-induced toxicity through opioid receptor-independent, TRPM7-independent mechanisms in HT22 cells. Naltriben activated Nrf2 pathway, and alleviated glutamate-induced CA2+ influx, ROS production, and Apoptosis. Moreover, intraperitoneal administration of naltriben at 20 mg/kg greatly reduced the infarct volume in the subcortical photothrombotic ischemia mouse model in vivo. The neuroprotective activity of naltriben was enhanced by a longer pretreatment, indicating that like Nrf2 activators, naltriben also requires the cellular priming for its full protective effects. Together, these results suggested naltriben as a potential therapeutic agent in conditions related with glutamate-induced neurotoxicity.

Keywords

Cerebral ischemia; Delta-opioid receptor antagonist; Exitotoxicity; Glutamate; Naltriben; Neuroprotection.

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