Amantadine attenuates sepsis-induced cognitive dysfunction possibly not through inhibiting toll-like receptor 2.

Abstract

Amantadine has been shown to reduce anesthesia and surgery-induced neuroinflammation and cognitive dysfunction. It is known that sepsis can impair brain function. We determined whether amantadine-attenuated sepsis-induced neuroinflammation and dysfunction of learning and memory and whether toll-like receptors (TLRs) play a role in the effects. Six- to eight-week-old mice were subjected to cecal ligation and puncture (CLP). Amantadine at 30 mg/kg/day was injected intraperitoneally for 3 days. CU-CPT22, a TLR1/TLR2 inhibitor, at 3 mg/kg/day was injected intraperitoneally for 2 days. Mice were subjected to Barnes maze and fear conditioning tests from 1 week after CLP. CLP induced neuroinflammation and cognitive dysfunction. CLP also increased the expression of toll-like receptor 2 (TLR2), TLR4, and TLR9, three major TLRs in the brain, in CD-1 male mice. Amantadine attenuated CLP-induced neuroinflammation and dysfunction of learning and memory but did not have significant effects on the expression of TLRs. CU-CPT22 also attenuated sepsis-induced neuroinflammation and cognitive dysfunction. Similarly, sepsis induced neuroinflammation and cognitive dysfunction in the C57BL/6J mice. Interestingly, sepsis also induced neuroinflammation and cognitive dysfunction in the TLR2 knockout mice. The effects of amantadine on the neuroinflammation and cognitive dysfunction were still apparent in these knockout mice. TLR2 contributes to sepsis-induced neuroinflammation and cognitive dysfunction. However, inhibiting TLR2 may not be a major mechanism for amantadine to inhibit sepsis-induced neuroinflammation and cognitive dysfunction.

KEY MESSAGES:

Sepsis induces neuroinflammation and cognitive impairment, which were attenuated by amantadine. Toll-like receptors 2 mediates these sepsis effects but may not be the major target for amantadine to reduce these effects.

• Authors: Wei Xing, Pinjie Huang, Yang Lu, Weian Zeng, Zhiyi Zuo
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 96 Issue 5 Pg. 391-402 (05 2018) ISSN: 1432-1440 [Electronic] Germany
• PMID: 29502203 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Neuroprotective Agents
• Toll-Like Receptors
• Amantadine

Topics

• Amantadine (pharmacology, therapeutic use)
• Animals
• Behavior, Animal (drug effects)
• Cognitive Dysfunction (drug therapy, etiology, metabolism)
• Hippocampus (drug effects, metabolism)
• Male
• Maze Learning (drug effects)
• Mice, Inbred C57BL
• Mice, Knockout
• Neuroprotective Agents (pharmacology, therapeutic use)
• Sepsis (complications, drug therapy, metabolism)
• Toll-Like Receptors (genetics, metabolism)