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Published on: July 17, 2017
Memantine, an NMDA receptor antagonist, protected the brain against the long-term consequences of sepsis in mice
Zahra Bardaghi1, Arezoo Rajabian2, Farimah Beheshti3
1Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
Aims:
Long-term neuroinflammation and brain dysfunction have frequently been reported in sepsis survivors. In this study, the protective effect of memantine (an NMDA receptor antagonist) on the long-term consequences of sepsis on the brain was investigated in mice.
Materials And Methods:
Eighty-five male C57 mice were included. Memantine was administrated through gavage at 5, 10, and 20 mg/kg three days before sepsis and continued for three days after sepsis induction. Sepsis was induced by intraperitoneal injection of 5 mg/kg LPS. A cohort of mice was sacrificed on the 4th day post sepsis to measure NF-κB, TNF-α, and IL-1β mRNA expression and oxidative stress markers in the brain. The second cohort was used for behavioral tests one month after sepsis induction and then sacrificed for oxidative stress markers and acetylcholinesterase (AChE) activity measurement.
Key Findings:
MDA levels and mRNA expression of NF-κB, TNF-α, and IL-1β ameliorated by memantine at the early days of sepsis induction, and total thiol content and SOD activity were increased. Post-septic mice showed significant disruption of recognition memory in novel object recognition (NOR) and depressive and anxiety-like behaviors in tail suspension test, elevated plus maze (EPM), and open field tests one month after sepsis. Memantine at 10 and 20 mg/kg dose-dependently ameliorated behavioral abnormalities, reduced AChE activity and MDA levels, and enhanced SOD activity and thiol content one month after sepsis.
Significance:
These findings suggest that early treatment of septic mice with memantine could ameliorate brain inflammation and oxidative damage and prevent long-term behavioral consequences of sepsis.
Insights
Early memantine treatment in sepsis survivors reduced brain inflammation and oxidative stress. This intervention also prevented long-term cognitive deficits and behavioral issues in mice, highlighting its neuroprotective potential.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Sepsis survivors often experience long-term neuroinflammation and cognitive dysfunction.
- Neuroinflammation and oxidative stress contribute to sepsis-induced brain injury.
Purpose of the Study:
- To investigate the neuroprotective effects of memantine, an NMDA receptor antagonist, against long-term sepsis-induced brain consequences.
- To evaluate memantine's impact on neuroinflammation, oxidative damage, and behavioral deficits in a mouse model of sepsis.
Main Methods:
- Mice received varying doses of memantine pre- and post-sepsis induction via LPS injection.
- Early and late-stage assessments included measuring inflammatory markers (NF-κB, TNF-α, IL-1β), oxidative stress markers (MDA, thiol, SOD), and acetylcholinesterase (AChE) activity.
- Behavioral tests (NOR, tail suspension, EPM, open field) were conducted one month post-sepsis.
Main Results:
- Memantine administration reduced early inflammatory and oxidative markers in the brain.
- Sepsis induced significant memory impairment, depression-like, and anxiety-like behaviors one month post-sepsis.
- Memantine treatment dose-dependently improved behavioral outcomes, reduced AChE activity, and mitigated oxidative stress.
Conclusions:
- Early memantine treatment offers neuroprotection by reducing brain inflammation and oxidative damage following sepsis.
- Memantine administration can prevent long-term behavioral and cognitive impairments in sepsis survivors.
