Long-term efavirenz exposure induced neuroinflammation and cognitive deficits in C57BL/6 mice

Biochem Biophys Res Commun. 2021 Dec 20:584:46-52. doi: 10.1016/j.bbrc.2021.11.015. Epub 2021 Nov 6.

Abstract

Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor (NNRTI), which is widely used for anti-HIV-1. Evidences revealed that several central nervous system side effects could be observed in mice and patients with administration of EFV. However, the detailed mechanisms are still unknown. In this study, we investigated the effects of long-term EFV treatment on cognitive functions and the potential underlying mechanisms in mice. We maintained C57BL/6 mice aged 2 months with treatment containing 40 or 80 mg/kg/day EFV for 5 months, while control group treated with saline. The cognitive functions were evaluated by novel object recognition test, Barnes maze test and Morris water maze. The results showed significant short-term memory impairment in 40 and 80 mg/kg groups, and notable spatial learning and memory impairments in 80 mg/kg group, without any spontaneous activity alteration. Moreover, EFV induced impairments in dendritic integrity and synaptic plasticity in hippocampus. Furthermore, Significant increases were observed in the expression levels of pro-IL-1β, a similar tendency of TNF-α and phosphorylation of p65 of the 80 mg/kg group compared with control group. These results imply that long-term EFV treatment causes synaptic dysfunction resulting in cognitive deficits, which might be induced by the enhanced pro-inflammatory cytokines IL-1β and TNF-α via activating NF-κB pathway.

Keywords: Cognitive deficits; Efavirenz (EFV); Pro-inflammatory cytokines; Spatial learning; Synaptic dysfunction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkynes / toxicity*
  • Animals
  • Benzoxazines / toxicity*
  • Cognition / drug effects*
  • Cognition / physiology
  • Cognitive Dysfunction / chemically induced
  • Cognitive Dysfunction / physiopathology*
  • Cyclopropanes / toxicity*
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Humans
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Memory Disorders / chemically induced
  • Memory Disorders / physiopathology*
  • Mice
  • Mice, Inbred C57BL
  • Neuroinflammatory Diseases / chemically induced
  • Neuroinflammatory Diseases / physiopathology*
  • Reverse Transcriptase Inhibitors / toxicity
  • Spatial Learning / drug effects
  • Spatial Learning / physiology
  • Synapsins / metabolism
  • Synaptophysin / metabolism
  • Synaptotagmin I / metabolism
  • Time Factors

Substances

  • Alkynes
  • Benzoxazines
  • Cyclopropanes
  • Reverse Transcriptase Inhibitors
  • Synapsins
  • Synaptophysin
  • Synaptotagmin I
  • efavirenz