Ischemic stroke has many devastating effects within the brain. At the cellular level, excitotoxicity has been a popular pharmacological target for therapeutics. To date, many clinical trials have been performed with drugs that target excitatory neurotransmitter receptors, such as NMDA receptor agonists. The results, however, have been lackluster. Most efforts to understand the impacts of excitotoxicity on the brain have focused primarily on neurons, and to a lesser degree, on gliocytes as cellular targets. Recent evidence suggests that oligodendrocytes (OLGs), the myelin-forming cells in the central nervous system, are damaged by ischemia in a manner completely different from that in neurons. Whereas ischemia primarily damages neurons through overactivation of ionotropic glutamate receptors, the ischemia damage in OLGs occurs through overactivation of H+-gated transient receptor potential channels. Given the differential mechanisms of ischemic injury between neurons and OLGs, strategies to target non-glutamate receptors to prevent OLG damage/demyelination deserve greater attention in drug development. Such strategies, combined with neuroprotective measures, could provide an excellent therapeutic avenue for the treatment of ischemic stroke. (C) 2017 S. Karger AG, Basel