Therapeutic window for YC-1 following glutamate-induced neuronal damage and transient focal cerebral ischemia

3-(5 '-Hydroxymethyl-2 '-furyl)-1-benzylindazole (YC-1), has been demonstrated to inhibit platelet aggregation, vascular contraction and hypoxia-inducible factor 1 activity in vitro and in vivo. The present study investigated the neuroprotective efficacy of YC-1 in cultured neurons exposed to glutamate-induced excitotoxicity and in an animal model of stroke. In a cortical neuronal culture model, YC-1 demonstrated neurotoxicity at a concentration >100 mu M, and YC-1 (10-30 mu M) achieved potent cytoprotection against glutamate-induced neuronal damage. Additionally, YC-1 (30 mu M) effectively attenuated the increase in intracellular Ca2+ levels. Delayed treatment of YC-1 (30 mu M) also protected against glutamate-induced neuronal damage and cell swelling in cultured neurons, though only at 4 h post-treatment. In addition, immediate treatment of YC-1 (30 mu M) following the exposure of cortical neurons to glutamate (300 mu M) produced a marked reduction in intracellular pH. Delayed treatment of YC-1 (25 mg/kg) protected against ischemic brain damage in vivo, though only when administered at 3 h post-insult. Thus, YC-1 exhibited neuroprotection against glutamate-induced neuronal damage and in mice subjected to transient focal cerebral ischemia. This neuroprotection may be mediated via its ability to limit the glutamate-induced excitotoxicity. However, the neuroprotective therapeutic window of YC-1 is only at 3 h in vivo and 4 h in vitro, which may, at least in part, be attributed to its ability to reduce the intracellular pH in the early phase of ischemic stroke. Although YC-1 provided the potential for clinical therapy, the treatment time point must be carefully evaluated following ischemia.