Poly(ADP-ribose) Polymerase-1 Participates In The Mechanisms Of Propofol-induced Amnesia In Mice And Human

Backgrounds and aimPropofol is a widely used intravenous anesthetic in clinic.Despite being a well-established phenomenon,the molecular mechanism of propofol-induced amnesia remains poorly understood.Propofol inhibits expression of numerous proteins associated with memory,such as activity-regulated cytoskeletal protein?Arc?and c-fos.Poly?ADP-ribose?polymerase 1?PARP-1?has been reported recently to regulate learning-caused expression of Arc and c-fos in mice.In addition,there was evidence that PARP-1 gene variants associated with a cognitive phenotype in human.However,it is still unknown whether PARP-1 is involved in the mechanism of propofol-induced amnesia.We speculated that propofol might decrease PARP-1 activity during learning procedure,thereby inducing amnesia through abnormal down-regulation of Arc and c-fos in hippocampus.To test this hypothesis,we investigated mice and volunteers using bio-molecular measurements and imaging genetics respectively in the current study.Materials and methodsSixty eight-week-old male C57BL/6 mice were randomly assigned to 4 groups.Mice were injected intraperitoneally with normal saline,propofol or PARP-1inhibitor INO-1001 before acquisition training.30 minunts later,some mice were sacrificed.Left hippocampus was used to determine PARP-1,poly?ADP-ribose?polymer?PAR?,Arc and c-fos expression through Western blotting.Right hippocampus was used to extract RNA.The mRNA levels of Arc and c-fos were detected by real-time PCR.24 hours later,cognitive function was evaluated by object recognition test.Thirty healthy 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(1.5?g ml^-1,TCI).Their cognitive traits were evaluated through fMRI and process dissociation procedure.Results1)Rodent data demonstrated that propofol inhibited acquisition-induced increase in PARP-1 expression and activity?i.e.PAR expression?.In the behavior,propofol impaired object recognition 24 hours after learning.2)Propofol inhibits downstream products,Arc and c-Fos,pending on PARP-1 activation,at both protein and mRNA levels.3)Consistent with rodent's data,carriers of a low-catalyzing function PARP-1 variant?Val762Ala,CC genotype?exhibited decreased retrieval-induced hippocampal reactivity 24 hours after learning under propofol-sedative condition.ConclusionsThese 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.