Ahn Hyomin, Lee Hyomin, Choi Wonseok, Lee Hyebin, Lee Kang-Gon, Youn Inchan, Hur Wooyoung, Han Sungmin, Song Chiman
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.
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.
Neurochem Int. 2025 Feb;183:105928. doi: 10.1016/j.neuint.2025.105928. Epub 2025 Jan 3.
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 Ca 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.
谷氨酸诱导的神经元死亡与包括脑缺血在内的神经退行性变有关。几种μ-阿片受体拮抗剂具有神经保护活性，被认为是神经退行性疾病的一种潜在治疗选择。我们目前的研究首次揭示了选择性δ-阿片受体拮抗剂的神经保护活性。一种强效、选择性δ-阿片受体拮抗剂纳曲苄，也被称为一种强效的瞬时受体电位通道蛋白7（TRPM7）激动剂，通过在HT22细胞中不依赖阿片受体、不依赖TRPM7的机制，对谷氨酸诱导的毒性表现出显著的保护作用。纳曲苄激活了核因子E2相关因子2（Nrf2）通路，并减轻了谷氨酸诱导的钙内流、活性氧生成和细胞凋亡。此外，在体内皮下光血栓性缺血小鼠模型中，腹腔注射20mg/kg的纳曲苄可显著减少梗死体积。更长时间的预处理可增强纳曲苄的神经保护活性，这表明与Nrf2激活剂一样，纳曲苄也需要细胞预处理才能发挥其完全的保护作用。总之，这些结果表明纳曲苄是与谷氨酸诱导的神经毒性相关疾病的一种潜在治疗药物。
