Evidence map›Paper›PMID 32905811›Full record

ArticleBehavioural brain research2021

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

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 and 5 more

Registry-linked trialOpen access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Behavioural brain research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05685225 (Safety and Efficacy of Naltrexone/Acetaminophen for the Acute Treatment of Migraine), which is not on this map. Cited by 15 papers.

0numbers the graph read from it
0cells of the map it votes in
15citing papers in PubMed
1.5field-weighted citation impact, top 17% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT05685225 phase2withdrawnnot on this mapstarted 2025, after this paper: background citation

Safety and Efficacy of Naltrexone/Acetaminophen for the Acute Treatment of Migraine: A Single-Site, Phase 2 Randomized Trial

TypeinterventionalSponsorAllodynic Therapeutics, IncRan2025 to 2025Enrolled0ConditionsMigraineArmsStage 1: Naltrexone/Acetaminophen, Stage 1: Naltrexone, Stage 1: Acetaminophen, Stage1: Placebo, Stage 2: Naltrxone/Acetaminophen high dose
3 · Its place in the literature

Who cites it

15 citing papers in PubMed, 25 citations in OpenAlex.

  1. Article
  2. Review
  3. Long-term isoflurane anesthesia induces cognitive deficits via AQP4 depolarization mediated blunted glymphatic inflammatory proteins clearance.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2024
    Article
  4. Article
  5. Article
  6. CD8Brain, behavior, and immunity · 2023
    Article
  7. Article
  8. Article
  9. Review
  10. Article
  11. Article
  12. Review
  13. Article
  14. Article
  15. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors at 4 institutions in 3 countries.

Andrew J KwilaszDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA; The Center for Neuroscience, University of Colorado, Boulder, CO, USA.
Laurel S ToddDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA; The Center for Neuroscience, University of Colorado, Boulder, CO, USA.
Julissa C Duran-MalleDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA; The Center for Neuroscience, University of Colorado, Boulder, CO, USA.
Anouk E W SchramaDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA; The Center for Neuroscience, University of Colorado, Boulder, CO, USA.
Eric H MittenDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA; The Center for Neuroscience, University of Colorado, Boulder, CO, USA.
Tracey A LarsonDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA; The Center for Neuroscience, University of Colorado, Boulder, CO, USA.
Madison A ClementsDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA; The Center for Neuroscience, University of Colorado, Boulder, CO, USA.
Kevin M HarrisDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA; The Center for Neuroscience, University of Colorado, Boulder, CO, USA.
Scott T LitwilerDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA; The Center for Neuroscience, University of Colorado, Boulder, CO, USA.
Xiaohui WangLaboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of the Sciences, Changchun, Jilin 130022, China.
Anne-Marie Van DamDepartment of Anatomy and Neurosciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Steven F MaierDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA; The Center for Neuroscience, University of Colorado, Boulder, CO, USA.
Kenner C RiceDrug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
Linda R WatkinsDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA; The Center for Neuroscience, University of Colorado, Boulder, CO, USA.
Ruth M BarrientosDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA; The Center for Neuroscience, University of Colorado, Boulder, CO, USA; Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, USA; Department of Psychiatry and Behavioral Health, The Ohio State University, Columbus, OH, USA; Chronic Brain Injury Program, Discovery Themes Initiative, The Ohio State University, Columbus, OH, USA; Department of Neuroscience, The Ohio State University, Columbus, OH, USA. Electronic address: ruth.barrientos@osumc.edu.
University of Colorado Boulder · USAmsterdam University Medical Centers · NLChangchun Institute of Applied Chemistry · CNNational Institute on Drug Abuse · US

Funding

Neuroinflammation, Inflammatory Challenge, and MemoryR01AG028271 · NIA · UNIVERSITY OF COLORADO · PI MAIER, STEVEN F · 2006 to 2016
$3.8M
Neuroinflammation, Inflammatory Challenge, and MemoryRF1AG028271 · NIA · UNIVERSITY OF COLORADO · PI BARRIENTOS, RUTH M, MAIER, STEVEN F · 2018 to 2021
$2.4M
Targeting toll like receptor 4 (TLR4) and TLR2 to resolve EAE-associated paralysis, pain and cognitive deficits: efficacy of a clinically-relevant blood brain barrier permeable TLR4/TLR2 antagonistR01NS097313 · NINDS · UNIVERSITY OF COLORADO · PI WATKINS, LINDA · 2016 to 2020
$1.7M
NIA NIH HHS R01 AG028271NIA NIH HHS RF1 AG028271NINDS NIH HHS R01 NS097313
6 · The paper itself

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.

Indexed as

AnimalsBehavior, AnimalCells, CulturedConditioning, ClassicalEncephalomyelitis, Autoimmune, ExperimentalFearHippocampusInflammationMaleMemory DisordersMiceMicrogliaMultiple SclerosisNaltrexoneNarcotic AntagonistsRatsNaltrexoneNarcotic AntagonistsToll-Like Receptor 2Toll-Like Receptor 4Auditory fear conditioningContextual fear conditioningExperimental autoimmune encephalomyelitisHippocampusMultiple sclerosisRatsToll-like receptors

Identifiers

PMID32905811
PMCPMC7572683
OpenAlexW3083456037

What OpenQuestion holds

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LicenceTDM
Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.