In this work we showed that OEC‐CM exerts a concentration‐ and time‐dependent protective effect on SH‐SY5Y and SK‐N‐SH cells subjected to H/R injury. Our aim was to investigate the molecular mechanism underlying this effect. A number of evidence revealed that, in the CNS, intercellular communication among neurons and glial cells via GJs and/or HCs could be critical in the spread of protective and/or deleterious signals. Cxs are dynamically expressed during injury and stress conditions and, for each condition and context, up‐ or down‐regulation of such proteins likely influencing gate properties of GJs and free HCs, may influence cell survival or cell death 21, 43, 44, 45, 46. In particular, several independent studies have pointed out that onset and progression of homeostatic imbalances observed during neurodegeneration could be associated with an enhanced HC activity in the CNS 60, 61, 62, 63, 64, 65, 66. Here we demonstrated in vitro that SH‐SY5Y and SK‐N‐SH cells grown in normoxia displayed no or low expression of Cx47, Cx43, Cx40, Cx36, Cx32 and Cx30 with or without the addition of OEC‐CM. When cells are cultured under hypoxic conditions, the Cx43 exhibited an increased expression whereas, the addition of OEC‐CM to the growth medium, restored the basal expression observed in normoxia. These evidence suggest that, while Cx43 may be involved in hypoxic response, the protective effect of OEC‐CM may be exerted through the modulation of this specific Cxs.