γ-secretase inhibitor DAPT prevents neuronal death and memory impairment in sepsis associated encephalopathy in septic rats

• Published in: Chinese medical journal 2014, Vol.127 (5), p.924-928
• Main Authors: Huang, Man, Liu, Chunhui, Hu, Yueyu, Wang, Pengfei, Ding, Meiping
• Format: Article
• Language: English
• Subjects: Amyloid Precursor Protein Secretases - antagonists & inhibitors; Animals; Apoptosis - drug effects; Dipeptides - therapeutic use; Hippocampus - drug effects; Hippocampus - metabolism; Male; Neurons - cytology; Neurons - drug effects; Neuroprotective Agents; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases - metabolism; Rats; Rats, Sprague-Dawley; Receptors, Notch - metabolism; SD大鼠; Sepsis - complications; Sepsis-Associated Encephalopathy - drug therapy; Sepsis-Associated Encephalopathy - enzymology; Signal Transduction - drug effects; 分泌; 神经元; 神经细胞死亡; 脑病; 脓毒症; 记忆障碍; 酶抑制剂
• ISSN: 0366-6999; 2542-5641
• DOI: 10.3760/cma.j.issn.0366-6999.20132366

Background Brain dysfunction is a frequent complication of sepsis,usually defined as sepsis-associated encephalopathy （SAE）.Although the Notch signaling pathway has been proven to be involved in both ischemia and neuronal proliferation,its role in SAE is still unknown.Here,the effect of the Notch signaling pathway involved γ-secretase inhibitor DAPT on SAE in septic rats was investigated in a cecal ligation and puncture （CLP） model.Methods Fifty-nine Sprague-Dawley rats were randomly divided into four groups,with the septic group receiving the CLP operation.Twenty-four hours after CLP or sham treatment,rats were sacrificed and their hippocampus was harvested for Western blot analysis.TNF-αexpression was determined using an enzyme-linked immunosorbent assay （ELISA） kit.Neuronal apoptosis was assessed by TUNEL staining,and neuronal cell death was detected by H＆E staining.Finally,a novel object recognition experiment was used to evaluate memory impairment.Results Our data showed that sepsis can increase the expression of hippocampal Notch receptor intracellular domain （NICD） and poly （adenosine diphosphate [ADP]-ribose） polymerase-1 （PARP-1）,as well as the inflammatory response,neuronal apoptosis,neuronal death,and memory dysfunction in rats.The γ-secretase inhibitor N-[N-（3,5-difluorophenacetyl）-1-alanyl]-S-phenylglycine t-butyl ester （DAPT） can significantly decrease the level of NICD and PARP-1,reduce hippocampal neuronal apoptosis and death,attenuate TNF-α release and rescue cognitive impairment caused by CLP.Conclusion The neuroprotective effect of DAPT on neuronal death and memory impairment in septic rats,which could be a new therapeutic approach for treating SAE in the future.