Memantine Attenuates Cognitive and Emotional Dysfunction in Mice with Sepsis-Associated Encephalopathy

XiaoYu Zheng; WenYu Li; Qian Xiang; YanXue Wang; TingYu Qu; Wei Fang; HongNa Yang

doi:10.1021/acsomega.3c06250

Memantine Attenuates Cognitive and Emotional Dysfunction in Mice with Sepsis-Associated Encephalopathy

ACS Omega. 2023 Oct 16;8(43):40934-40943. doi: 10.1021/acsomega.3c06250. eCollection 2023 Oct 31.

Authors

XiaoYu Zheng¹, WenYu Li², Qian Xiang¹, YanXue Wang², TingYu Qu³, Wei Fang², HongNa Yang^{1

2}

Affiliations

¹ Department of Critical-Care Medicine, Shandong Provincial Hospital, Shandong University, Jinan 250021, China.
² Department of Critical-Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong First Medical University, Jinan 250021, China.
³ The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, 1601 West Taylor Street, Chicago, Illinois 60612, United States.

Abstract

Sepsis-associated encephalopathy (SAE) is the most common complication of sepsis, with increased morbidity and mortality. To date, there has still been no established pharmacological therapy. Memantine, as an NMDA (N-methyl-d-aspartate) receptor antagonist, exhibited neuroprotective effects against cognitive and emotional dysfunction in many disorders. We performed cecal ligation and puncture (CLP) inducing sepsis as the ideal animal model of SAE. CLP-induced septic mice were given a memantine treatment through intragastric administration. The novel object recognition test indicated that memantine significantly improved cognitive dysfunction in septic mice. The open field test revealed that the anxiety-like behaviors and locomotion ability of septic mice were relieved by memantine. The pole test further confirmed the protective effects of memantine against immobility. Memantine significantly inhibited the excessive glutamate production and improved impaired neurogenesis on first and seventh day after sepsis, accompanying with reducing proinflammatory cytokines production (tumor necrosis factor alpha (TNF-α), interleukin (IL)-1beta (IL-1β), and IL-10) and microglia activation in the brain of SAE. In addition, memantine treatment also reducing sepsis-induced brain blood barrier disruption via inhibiting the expression of metalloproteinase-9 (MMP-9). In conclusion, memantine exerted neuro-protective effects against cognitive and emotional defects, which might be considered as a promising therapy for SAE.