title: Cellular NAD depletion and decline of SIRT1 activity play critical roles in PARP-1-mediated acute epileptic neuronal death in vitro.
abstract: Intense poly(ADP-ribose) polymerase-1 (PARP-1) activation was implicated as a major cause of caspase-independent cell death in the hippocampal neuronal culture (HNC) model of acute acquired epilepsy (AE). The molecular mechanisms are quite complicated. The linkage among neuronal death, cellular nicotinamide adenine dinucleotide (NAD) levels, apoptosis-inducing factor (AIF) translocation, SIRT1 expression and activity were investigated here. The results showed that PARP-1 over-activation caused by Mg²⁺-free stimuli led to cellular NAD depletion which could block AIF translocation from mitochondria to nucleus and attenuate neuronal death. Also, SIRT1 deacetylase activity was reduced by Mg²⁺-free treatment, accompanied by elevated ratio of neuronal death, which could be rescued by NAD repletion. These data demonstrated that cellular NAD depletion and decline of SIRT1 activity play critical roles in PARP-1-mediated epileptic neuronal death in the HNC model of acute AE.
authors.affiliation: Department of Neurology, Qilu Hospital, Shandong University, 107#, Wenhua Xi Road, Jinan, China.
authors.forename: Shengjun
authors.initials: S
authors.lastname: Wang
authors.forename: Xue
authors.initials: X
authors.lastname: Yang
authors.forename: Youting
authors.initials: Y
authors.lastname: Lin
authors.forename: Xiaoxue
authors.initials: X
authors.lastname: Qiu
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Xiuhe
authors.initials: X
authors.lastname: Zhao
authors.forename: Lili
authors.initials: L
authors.lastname: Cao
authors.forename: Xuewu
authors.initials: X
authors.lastname: Liu
authors.forename: Yuejiu
authors.initials: Y
authors.lastname: Pang
authors.forename: Xuping
authors.initials: X
authors.lastname: Wang
authors.forename: Zhaofu
authors.initials: Z
authors.lastname: Chi
mesh_terms: D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D016923:Cell Death; D004827:Epilepsy / Q000378:metabolism* / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D009243:NAD / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D051033:Apoptosis Inducing Factor; D009243:NAD; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D056564:Sirtuin 1
keywords: 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone; AE; AIF; Acquired epilepsy; Apoptosis-inducing factor; COXIV; Cytochrome oxidase subunit IV; DPQ; Epilepsy; HNC; Hippocampal neuronal culture; MPT; Mitochondrial permeability transition; NAD; Neuronal death; Nicotinamide adenine dinucleotide; PAR; PARP-1; Poly(ADP-ribose); Poly(ADP-ribose) polymerase-1; Poly(ADP-ribose)polymerase-1; SIRT1; SREDs; Spontaneous recurrent epileptiform discharges; TUNEL; Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; WCC; Whole-cell current-clamp