Ahn, Hyomin Lee, Hyomin Choi, Wonseok Lee, Hyebin Lee, Kang-Gon Youn, In chan Hur, Woo young Han, Sungmin Song, Chiman 2025-01-10T07:00:19Z 2025-01-10T07:00:19Z 2025-01-05 2025-02 0197-0186 https://pubs.kist.re.kr/handle/201004/151522 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. English Elsevier BV Discovery of the therapeutic potential of naltriben against glutamate-induced neurotoxicity Article 10.1016/j.neuint.2025.105928 1 Neurochemistry International, v.183 Neurochemistry International 183 N scie scopus 001414607700001 Biochemistry & Molecular Biology Neurosciences Biochemistry & Molecular Biology Neurosciences & Neurology Article MOLECULAR-MECHANISMS OXIDATIVE STRESS OPIOID RECEPTOR CELL-DEATH BRAIN EXCITOTOXICITY ISCHEMIA RELEASE INJURY Delta-opioid receptor antagonist Naltriben Glutamate Exitotoxicity Neuroprotection Cerebral ischemia