Inhibition of PARP-1 participates in the mechanisms of propofol-induced amnesia in mice and human

Abstract

Poly(ADP-ribose) polymerase 1 (PARP-1) has emerged as an important regulator in learning and memory. Propofol leads to amnesia, however, the mechanism remains unclear. The present study was designed to examine whether and how PARP-1 plays a role in propofol-induced amnesia. Mice were injected intraperitoneally with propofol before acquisition training. Cognitive function was evaluated by object recognition test. PARP-1 and PAR expression was determined through Western blot. The protein and mRNA levels of Arc and c-Fos were detected by Western blot and real-time PCR. Thirty volunteers were assigned to three groups according to codon 762 variation of PARP-1 gene (rs1136410). They learned word lists awake and during propofol sedation. Their cognitive traits were evaluated through fMRI. Rodent data demonstrated that propofol inhibited acquisition-induced increase in PARP-1 and PAR, thereby suppressing Arc and c-Fos, which impaired object recognition 24h after learning. Consistent with this, carriers of a low-catalyzing function PARP-1 variant (Val762Ala) exhibited decreased retrieval-induced hippocampal reactivity 24h after learning under propofol-sedative condition. These findings suggested that inhibition of PARP-1 might participate in the mechanism of propofol-induced amnesia in mice and human. More generally, our approach illustrated a potential translational research bridging animal models and human studies.