Injection of Anti-proBDNF Attenuates Hippocampal-Dependent Learning and Memory Dysfunction in Mice With Sepsis-Associated Encephalopathy

Yan-Hui Cui; Shi-Fen Zhou; Yu Liu; Shuang Wang; Fang Li; Ru-Ping Dai; Zhao-Lan Hu; Chang-Qi Li

doi:10.3389/fnins.2021.665757

Injection of Anti-proBDNF Attenuates Hippocampal-Dependent Learning and Memory Dysfunction in Mice With Sepsis-Associated Encephalopathy

Front Neurosci. 2021 Jul 20:15:665757. doi: 10.3389/fnins.2021.665757. eCollection 2021.

Authors

Yan-Hui Cui^{1

2}, Shi-Fen Zhou¹, Yu Liu^{1

3}, Shuang Wang⁴, Fang Li¹, Ru-Ping Dai³, Zhao-Lan Hu³, Chang-Qi Li¹

Affiliations

¹ Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, China.
² Department of Respiratory and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, China.
³ Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China.
⁴ Department of Medical Research Center and Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, China.

Abstract

Sepsis-associated encephalopathy (SAE) is a risk factor for cognitive and memory dysfunction; however, the mechanism remains unclear. Brain-derived neurotrophic factor (BDNF) was reported to have a positive effect on cognition and emotion regulation, but the study of its precursor, proBDNF, has been limited. This study aimed to elucidate the effects and associated mechanisms of hippocampal proBDNF in a lipopolysaccharide (LPS)-induced SAE mouse model. In this study, we found that the mice exhibited cognitive dysfunction on day 7 after LPS injection. The expression of proBDNF and its receptor, p75 ^NTR , was also increased in the hippocampus, while the levels of BDNF and its receptor, TrkB, were decreased. A co-localization study showed that proBDNF and p75 ^NTR were mainly co-localized with neurons. Furthermore, LPS treatment reduced the expression of NeuN, Nissl bodies, GluR4, NR1, NR2A, and NR2B in the hippocampus of SAE mice. Furthermore, an intrahippocampal or intraperitoneal injection of anti-proBDNF antibody was able to ameliorate LPS-induced cognitive dysfunction and restore the expression of NeuN, Nissl bodies, GluR4, NR1, NR2A, NR2B, and PSD95. These results indicated that treatment with brain delivery by an intrahippocampal and systemic injection of mAb-proBDNF may represent a potential therapeutic strategy for treating patients with SAE.

Keywords: cognition and memory dysfunction; hippocampus; p75NTR; proBDNF; sepsis associated encephalopathy.