TRPM7 kinase inhibitor TG100-115 provides neuroprotection against neonatal hypoxic-ischemic brain injury.

Abstract

Hypoxic-ischemic brain injury (HIBI) is a major cause of perinatal brain damage, contributing to significant neonatal mortality and disability, yet its therapeutics remain limited. Transient receptor potential melastatin 7 (TRPM7), a channel-kinase with kinase activity involved in neuronal death and neuroinflammation, has been implicated in ischemic and hypoxic brain damage. Although the ion channel function of TRPM7 has been widely explored, the specific contribution of its kinase activity to HIBI pathophysiology remains poorly understood, mainly due to the lack of potent TRPM7 kinase inhibitors. TG100-115 (TG) is the first identified potent TRPM7 kinase inhibitor. Using a neonatal mouse model of HIBI, we examined the in vivo neuroprotective effects of TG across different treatment paradigms, including pre-treatment and post-treatment at various time points. TG significantly reduced infarct volume when administered before HIBI or up to 3 h post-HIBI, improved brain morphology, and enhanced both short- and long-term functional recovery. Mechanistically, TG treatment normalized TRPM7 protein levels, modulated caspase-3-associated apoptotic pathway, and preserved neuronal integrity. Additionally, TG attenuated the NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation, indicated by reduced expression of NLRP3 and its adaptor protein ASC, as well as IL-18 levels, suggesting a role in modulating neuroinflammation. These findings demonstrate that TG protects against HIBI by modulating TRPM7 expression and apoptotic signaling, and suppressing NLRP3 inflammasome-associated neuroinflammation. This study highlights the pharmacological inhibition of TRPM7 kinase as a promising therapeutic strategy for HIBI. TG100-115, a TRPM7 kinase inhibitor, provides neuroprotection and attenuates NLRP3 inflammasome-mediated neuroinflammation in a neonatal mouse model of hypoxic-ischemic brain injury.