TAT-EE3 is a neuroprotective peptide that dissociates the interaction between TRPM2 and NMDARs. It inhibits the TRPM2-induced enhancement of NMDAR surface expression and current amplitude. TAT-EE3 protects neurons from ischemic damage both in vitro and in vivo, and is utilized for research on ischemic stroke.

TAT-EE3 (10 μM, overnight) disrupts the interaction between TRPM2 and GluN2a/GluN2b in HEK293T cells and neurons, inhibiting TRPM2-induced enhancement of NMDA receptor surface expression and current amplitude. TAT-EE3 (10 μM, overnight) reduces OGD-induced intracellular Ca2+ overload, neuronal death, and mitochondrial depolarization in wild-type neurons, but has no effect on global TRPM2 knockout (gM2KO) neurons. TAT-EE3 (10 μM, 30-90 min) eliminates PMA-induced enhancement of NMDA receptor current in wild-type neurons without additional inhibitory effects on gM2KO neurons.

Fifteen minutes prior to middle cerebral artery occlusion (MCAO), or every 12 hours post-MCAO for 7 days, TAT-EE3 (0.33 mg/kg [100 nmol/kg], administered via intraperitoneal injection) reduced infarct volume and improved neurological deficit scores in wild-type mice. However, this compound did not exhibit enhanced protective effects in neuron-specific TRPM2 knockout (nM2KO) mice.