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 delta 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 delta 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 delta expression, and potentiated OGD/R-induced cell death. Mechanistically, reduced CaMKII delta expression upon silencing C2dat1 inhibited OGD/R-induced activation of the NF-kappa B signaling pathway. Further analysis showed that the downregulation of IKK alpha and IKK beta expression and phosphorylation, and subsequent inhibition of I kappa B alpha degradation accounted for the inhibition of the NF-kappa B signaling activity caused by silencing C2dat1. In summary, we discovered a novel I/R-induced lncRNA C2dat1 that modulates the expression of CaMKII delta to impact neuronal survival, and may be a potential target for therapeutic intervention of ischemic brain injury.