D-Ala2, D-Leu5] encephalin (DADLE) reversibly inhibits cellular transcription in neurons without causing cell injury

[d-Ala(2)-d-Leu(5)]-Enkephalin (DADLE) has shown promising results in protecting neurons from damages. However, the mechanism for this protection is still under investigation. The current study was carried out to test the hypothesis that DADLE may regulate cellular transcription in neurons. SH-SY5Y cells and primary cortical neurons were treated with various doses of DADLE for 24–72h. Results demonstrated that DADLE, at all doses and time points examined, significantly inhibited cellular transcription in both cells without causing cell injury. Following recovery for 72h without DADLE in primary neurons, the transcriptional activity fully resumed. Delta opioid receptor (DOR) is not involved in this process, as Naltrindole could not abolish DADLE׳s transcriptional inhibitory effects. Further studies in primary cortical neurons show that DADLE significantly inhibited phosphorylation of Ser2 and Ser5 of the C-terminal domain (CTD) of RNA polymerase II. These data indicate that DADLE is able to decrease cellular transcription through inhibiting phosphorylation of RNA polymerase II in neurons, which may provide mechanistic insight into its reported neuroprotective effects, and suggests that it warrants further exploration as a potential therapeutic strategy for neuroprotection.