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

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.