Long non-coding RNA C2dat1 regulates CaMKIIδ expression to promote neuronal survival through the NF-κB signaling pathway following cerebral ischemia

Increasing evidence has demonstrated a significant role of long non-coding RNAs (lncRNAs) in diverse biological processes. However, their functions in cerebral ischemia remain largely unknown. Through an lncRNA array analysis in a rat model of focal cerebral ischemia/reperfusion (I/R), we have identified CAMK2D -associated transcript 1 ( C2dat1 ) as a novel I/R-induced lncRNA that regulated the expression of CaMKII δ in murine models of focal cerebral ischemia. C2dat1 mRNA was upregulated in a time-dependent manner in mouse cortical penumbra after focal ischemic brain injury, which was accompanied by increased expression of CaMKII δ at transcript and protein levels. The expression patterns of C2dat1 and CAMK2D were confirmed in mouse Neuro-2a cells in response to in vitro ischemia (oxygen-glucose deprivation/reoxygenation, OGD/R). Knockdown of C2dat1 resulted in a significant blockade of CaMKII δ expression, and potentiated OGD/R-induced cell death. Mechanistically, reduced CaMKII δ expression upon silencing C2dat1 inhibited OGD/R-induced activation of the NF- κ B signaling pathway. Further analysis showed that the downregulation of IKK α and IKK β expression and phosphorylation, and subsequent inhibition of I κ B α degradation accounted for the inhibition of the NF- κ B signaling activity caused by silencing C2dat1 . In summary, we discovered a novel I/R-induced lncRNA C2dat1 that modulates the expression of CaMKII δ to impact neuronal survival, and may be a potential target for therapeutic intervention of ischemic brain injury.