Experimental autoimmune encephalopathy (EAE)-induced hippocampal neuroinflammation and memory deficits are prevented with the non-opioid TLR2/TLR4 antagonist (+)-naltrexone.

Abstract

Multiple sclerosis (MS) is associated with burdensome memory impairments and preclinical literature suggests that these impairments are linked to neuroinflammation. Previously, we have shown that toll-like receptor 4 (TLR4) antagonists, such as (+)-naltrexone [(+)-NTX], block neuropathic pain and associated spinal inflammation in rats. Here we extend these findings to first demonstrate that (+)-NTX blocks TLR2 in addition to TLR4. Additionally, we examined in two rat strains whether (+)-NTX could attenuate learning and memory disturbances and associated neuroinflammation using a low-dose experimental autoimmune encephalomyelitis (EAE) model of MS. EAE is the most commonly used experimental model for the human inflammatory demyelinating disease, MS. This low-dose model avoided motor impairments that would confound learning and memory measurements. Fourteen days later, daily subcutaneous (+)-NTX or saline injections began and continued throughout the study. Contextual and auditory-fear conditioning were conducted at day 21 to assess hippocampal and amygdalar function. With this low-dose model, EAE impaired long-term, but not short-term, contextual fear memory; both long-term and short-term auditory-cued fear memory were spared. This was associated with increased mRNA for hippocampal interleukin-1β (IL-1β), TLR2, TLR4, NLRP3, and IL-17 and elevated expression of the microglial marker Iba1 in CA1 and DG regions of the hippocampus, confirming the neuroinflammation observed in higher-dose EAE models. Importantly, (+)-NTX completely prevented the EAE-induced memory impairments and robustly attenuated the associated proinflammatory effects. These findings suggest that (+)-NTX may exert therapeutic effects on memory function by dampening the neuroinflammatory response in the hippocampus through blockade of TLR2/TLR4. This study suggests that TLR2 and TLR4 antagonists may be effective at treating MS-related memory deficits.

• Authors: Andrew J Kwilasz, Laurel S Todd, Julissa C Duran-Malle, Anouk E W Schrama, Eric H Mitten, Tracey A Larson, Madison A Clements, Kevin M Harris, Scott T Litwiler, Xiaohui Wang, Anne-Marie Van Dam, Steven F Maier, Kenner C Rice, Linda R Watkins, Ruth M Barrientos
• Journal: Behavioural brain research (Behav Brain Res) Vol. 396 Pg. 112896 (01 01 2021) ISSN: 1872-7549 [Electronic] Netherlands
• PMID: 32905811 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Narcotic Antagonists
• Toll-Like Receptor 2
• Toll-Like Receptor 4
• Naltrexone

Topics

• Animals
• Behavior, Animal (drug effects, physiology)
• Cells, Cultured
• Conditioning, Classical (drug effects, physiology)
• Encephalomyelitis, Autoimmune, Experimental (complications)
• Fear (drug effects, physiology)
• Hippocampus (drug effects, immunology)
• Inflammation (etiology, prevention & control)
• Male
• Memory Disorders (etiology, prevention & control)
• Mice
• Microglia (drug effects, immunology)
• Multiple Sclerosis (complications)
• Naltrexone (administration & dosage, pharmacology)
• Narcotic Antagonists (administration & dosage, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Toll-Like Receptor 2 (antagonists & inhibitors)
• Toll-Like Receptor 4 (antagonists & inhibitors)