Neuroprotective Effects of AG490 in Neonatal Hypoxic-Ischemic Brain Injury

In infants and children, neonatal hypoxic-ischemic (HI) brain injury represents a major cause of chronic neurological morbidity. The transient receptor potential melastatin 2 (TRPM2), a non-selective cation channel that conducts calcium, can mediate neuronal death following HI brain injury. An important endogenous activator of TRPM2 is H₂O₂, which has previously been reported to be upregulated in the neonatal brain after hypoxic ischemic injury. Here, incorporating both in vitro (H₂O₂-induced neuronal cell death model) and in vivo (mouse HI brain injury model) approaches, we examined the effects of AG490, which can inhibit the H₂O₂-induced TRPM2 channel. We found that AG490 elicited neuroprotective effects. We confirmed that AG490 reduced H₂O₂-induced TRPM2 currents. Specifically, application of AG490 to neurons ameliorated H₂O₂-induced cell injury in vitro. In addition, AG490 administration reduced brain damage and improved neurobehavioral performance following HI brain injury in vivo. The neuroprotective benefits of AG490 suggest that pharmacological inhibition of H₂O₂-activated TRPM2 currents can be exploited as a potential therapeutic strategy to treat HI-induced neurological complications.