Ischemic stroke is one of the main causes of disability and death. However, recanalization of occluded cerebral arteries is effective only within a very narrow time window. Therefore, it is particularly important to find neuroprotective biological targets for cerebral artery recanalization. Here, gene expression profiles of datasets GSE160500 and GSE97537 were downloaded from the GEO database, which were related to ischemic stroke in rats. Olfactory receptor 78 (Olfr78) was screened, and which highly associated with Calcium signalling pathway and MAPK pathway. Interacting protein of Olfr78, Prkaca, was predicted by STRING, and their interaction was validated by Co‐IP analysis. Then, a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) and a neuronal cell model stimulated by oxygen–glucose deprivation/reoxygenation (OGD/R) were constructed, and the results showed that expression of Olfr78 and Prkaca was downregulated in MCAO rats and OGD/R‐stimulated neurons. Overexpression of Olfr78 or Prkaca inhibited the secretion of inflammatory factors, Ca2+ overload, and OGD/R‐induced neuronal apoptosis. Moreover, Overexpression of Prkaca increased protein levels of cAMP, PKA and phosphorylated p38 in OGD/R‐stimulated neurons, while SB203580, a p38 inhibitor, treatment inhibited activation of the cAMP/PKA‐MAPK pathway and counteracted the effect of Olfr78 overexpression on improvement of neuronal functions. Meanwhile, overexpression of Olfr78 or Prkaca markedly inhibited neuronal apoptosis and improved brain injury in MCAO/R rats. In conclusion, overexpression of Olfr78 inhibited Ca2+ overload and reduced neuronal apoptosis in MCAO/R rats by promoting Prkaca‐mediated activation of the cAMP/PKA‐MAPK pathway, thereby improving brain injury in cerebral ischaemia–reperfusion.
