1. 17‐β‐oestradiol (E2) plays a critical role in neuroprotection through both genomic and non‐genomic mechanisms. The aim of the present study was to investigate the role of G‐protein‐coupled receptor 30 (GPR30), a new kind of oestrogen receptor, in the neuroprotection against oxidative insult.

2. The neuroprotection evoked by GPR30 stimulation was examined in cultured cortical neurons. Hoechst 33258/propidium iodide double staining, flow cytometric analysis and western blotting were applied to assess neuronal apoptosis induced by H₂O₂.

3. We found that the GPR30 agonist, G1, and E2 attenuated apoptosis induced by H₂O₂ exposure. Furthermore, G1 (1 nmol/L) or E2 (1 nmol/L) significantly increased the levels of phosphorylated extracellular signal‐regulated kinase 1/2 (p‐ERK1/2), Bcl‐2 and pro‐caspase‐3. Pretreatment with ICI182780, a highly selective nuclear oestrogen receptor antagonist that is used to block the classical ERα and ERβ receptors, did not totally block the neuroprotective effects of E2 (1 nmol/L) and had no effect on the neuroprotective effects of G1 (1 nmol/L).

4. Our data suggest that GPR30 is involved in the neuroprotection against oxidative insult. The neuroprotection evoked by GPR30 stimulation was associated with the signalling through the ERK1/2 kinase pathway. In addition, the anti‐apoptotic activity of GPR30 was dependent on the expression of Bcl‐2 and pro‐caspase‐3. GPR30 might be a potential therapeutic target for neuroprotection and oxidative stress.