# 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 antagonist

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 2020 · $336,875

## Abstract

PROJECT SUMMARY
 Multiple sclerosis (MS) is a life-long, debilitating disease in both males and females. Symptoms include
loss of motor function, neuropathic pain, cognitive impairments, and impaired social interaction. MS is
furthermore associated with elevations in circulating and central (spinal cord and brain) levels of pro-
inflammatory cytokines and decreased levels of anti-inflammatory cytokines, suggesting a dysregulation of
immune and glial processes resulting in chronic inflammation. This ongoing inflammation is important in
demyelination, chronic glial activation, and neuronal death characteristic of the disease.
 Targeted suppression of spinal cord neuroinflammation using anti-inflammatory strategies dramatically
improves symptoms of experimental autoimmune encephalomyelitis (EAE), a rat model of MS. Looking forward
toward translation, what is needed is not our current approaches that are injected intrathecally, but rather a
means to effectively treat EAE/MS via a clinically relevant, orally available, blood-brain barrier permeable small
molecule that targets EAE/MS pathology driven by neuroinflammation.
 We have discovered, and extensively characterized, such a small molecule. This drug (the non-opioid
(+)-isomer of naltrexone; (+)-naltrexone) is rapidly moving toward FDA application for Investigational New Drug
status. This is a selective antagonist at toll-like receptor 4 (TLR4) and TLR2. As it fails to bind classical opioid
receptors, (+)-naltrexone does not interfere with the efficacy of opioids for pain control or normal functioning of
opioid receptor systems. Targeting TLR2 and TLR4 arises from an extensive literature demonstrating the
importance of these receptors in the neuroinflammatory processes and EAE/MS symptoms to be studied here.
 A complimentary series of behavioral and immunohistochemistry studies are proposed in males and
females which will explore the ability of (+)-naltrexone to suppress EAE-induced (a) paresis/paralysis, (b)
neuropathic pain, (c) cognitive impairment, and (d) social interaction impairment, as well as (e) improve
survival, when (+)-naltrexone is systemically administered across days, comparing dosing early vs. late in the
EAE timecourse. The IHC studies will analyze brain and spinal cord tissues collected after early vs. late (+)-
naltrexone treatment (mapping onto the behavioral studies) to define whether (+)-naltrexone suppresses glial
activation, neuronal cell death, and demyelination, as well as stimulates remyelination, as predicted.
 These studies create two complimentary Aims. Aim 1 explores a novel means of positively intervening in
EAE-induced motor dysfunction, neuropathic pain, deficits in social interaction and cognition, and loss of life by
targeting TLR4/TLR2 by systemic administration of (+)-naltrexone. Aim 2 transitions to an initial exploration of
potential mechanisms underlying pathophysiology, focusing on the impact of TLR4/TLR2 blockade on
demyelination and remyelination, neuro...

## Key facts

- **NIH application ID:** 9938698
- **Project number:** 5R01NS097313-05
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** LINDA WATKINS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $336,875
- **Award type:** 5
- **Project period:** 2016-06-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938698

## Citation

> US National Institutes of Health, RePORTER application 9938698, 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 antagonist (5R01NS097313-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9938698. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*