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, Anne-Marie Van Dam, Steven F Maier, Kenner C Rice, Linda R Watkins, Ruth M Barrientos, 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
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.
Keywords: Auditory fear conditioning; Contextual fear conditioning; Experimental autoimmune encephalomyelitis; Hippocampus; Multiple sclerosis; Rats; Toll-like receptors.
Copyright © 2020 Elsevier B.V. All rights reserved.
Figures
![Figure 1.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7572683/bin/nihms-1628518-f0001.jpg)
![Figure 2.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7572683/bin/nihms-1628518-f0002.jpg)
Figure 3.
Long-term memory in Dark Agouti…
Figure 3.
Long-term memory in Dark Agouti (A-C) and Sprague Dawley (D-F) control or rats…
Figure 4.
Short-term memory in control or…
Figure 4.
Short-term memory in control or rats with EAE that were treated with (+)-NTX…
Figure 5.
Assessment of IL-1β mRNA in…
Figure 5.
Assessment of IL-1β mRNA in (A) hippocampus and (B) amygdala of naïve rats…
Figure 6.
Microglial (Iba1) and astrocyte (GFAP)…
Figure 6.
Microglial (Iba1) and astrocyte (GFAP) cell immunoreactivity of hippocampal CA1 and DG of…
Figure 7.
Gene expression of the pattern…
Figure 7.
Gene expression of the pattern recognition receptors (A) TLR2 and (B) TLR4, (C)…
Figure 8.
Increased serum anti-MOG IgG antibody…
Figure 8.
Increased serum anti-MOG IgG antibody concentration in rats with EAE that were treated…
Figure 9.
Assessment of (+)-NTX administration on…
Figure 9.
Assessment of (+)-NTX administration on motor disturbances in Dark Agouti (DA) and Sprague-Dawley…
- Involvement of TLR2-TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis.Kwilasz AJ, Clements MA, Larson TA, Harris KM, Litwiler ST, Woodall BJ, Todd LS, Schrama AEW, Mitten EH, Maier SF, Van Dam AM, Rice KC, Watkins LR. Kwilasz AJ, et al. Front Pain Res (Lausanne). 2022 Sep 13;3:932530. doi: 10.3389/fpain.2022.932530. eCollection 2022. Front Pain Res (Lausanne). 2022. PMID: 36176709 Free PMC article.
- Toll-like receptor 2 and 4 antagonism for the treatment of experimental autoimmune encephalomyelitis (EAE)-related pain.Kwilasz AJ, Green Fulgham SM, Duran-Malle JC, Schrama AEW, Mitten EH, Todd LS, Patel HP, Larson TA, Clements MA, Harris KM, Litwiler ST, Harvey LO Jr, Maier SF, Chavez RA, Rice KC, Van Dam AM, Watkins LR. Kwilasz AJ, et al. Brain Behav Immun. 2021 Mar;93:80-95. doi: 10.1016/j.bbi.2020.12.016. Epub 2021 Jan 7. Brain Behav Immun. 2021. PMID: 33358978 Free PMC article.
- Neurodegeneration and inflammation in hippocampus in experimental autoimmune encephalomyelitis induced in rats by one--time administration of encephalitogenic T cells.Kurkowska-Jastrzębska I, Swiątkiewicz M, Zaremba M, Cudna A, Piechal A, Pyrzanowska J, Widy-Tyszkiewicz E, Członkowska A. Kurkowska-Jastrzębska I, et al. Neuroscience. 2013 Sep 17;248:690-8. doi: 10.1016/j.neuroscience.2013.06.025. Epub 2013 Jun 24. Neuroscience. 2013. PMID: 23806721
- Opioid growth factor and low-dose naltrexone impair central nervous system infiltration by CD4 + T lymphocytes in established experimental autoimmune encephalomyelitis, a model of multiple sclerosis.Hammer LA, Waldner H, Zagon IS, McLaughlin PJ. Hammer LA, et al. Exp Biol Med (Maywood). 2016 Jan;241(1):71-8. doi: 10.1177/1535370215596384. Epub 2015 Jul 22. Exp Biol Med (Maywood). 2016. PMID: 26202376 Free PMC article.
- The Toll-like Receptor 2 (TLR2)-related Immunopathological Responses in the Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis.Jafarzadeh A, Nemati M, Khorramdelazad H, Mirshafiey A. Jafarzadeh A, et al. Iran J Allergy Asthma Immunol. 2019 Jun 8;18(3):230-250. doi: 10.18502/ijaai.v18i3.1117. Iran J Allergy Asthma Immunol. 2019. PMID: 31522431 Review.
- CD8+ T cells contribute to diet-induced memory deficits in aged male rats.Butler MJ, Sengupta S, Muscat SM, Amici SA, Biltz RG, Deems NP, Dravid P, Mackey-Alfonso S, Ijaz H, Bettes MN, Godbout JP, Kapoor A, Guerau-de-Arellano M, Barrientos RM. Butler MJ, et al. Brain Behav Immun. 2023 Mar;109:235-250. doi: 10.1016/j.bbi.2023.02.003. Epub 2023 Feb 9. Brain Behav Immun. 2023. PMID: 36764399
- Involvement of TLR2-TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis.Kwilasz AJ, Clements MA, Larson TA, Harris KM, Litwiler ST, Woodall BJ, Todd LS, Schrama AEW, Mitten EH, Maier SF, Van Dam AM, Rice KC, Watkins LR. Kwilasz AJ, et al. Front Pain Res (Lausanne). 2022 Sep 13;3:932530. doi: 10.3389/fpain.2022.932530. eCollection 2022. Front Pain Res (Lausanne). 2022. PMID: 36176709 Free PMC article.
- A behavioral and molecular study; ameliorated anxiety-like behavior and cognitive dysfunction in a rat model of chronic unpredictable stress treated with oregano extract.Mohseni-Moghaddam P, Dogani M, Hatami M, Roohollahi S, Amiresmaeli A, Askari N. Mohseni-Moghaddam P, et al. Brain Behav. 2022 Aug;12(8):e2727. doi: 10.1002/brb3.2727. Epub 2022 Jul 27. Brain Behav. 2022. PMID: 35898162 Free PMC article.
- Application and prospect of targeting innate immune sensors in the treatment of autoimmune diseases.Liu J, Zhang H, Su Y, Zhang B. Liu J, et al. Cell Biosci. 2022 May 26;12(1):68. doi: 10.1186/s13578-022-00810-w. Cell Biosci. 2022. PMID: 35619184 Free PMC article. Review.
- Dietary DHA prevents cognitive impairment and inflammatory gene expression in aged male rats fed a diet enriched with refined carbohydrates.Butler MJ, Deems NP, Muscat S, Butt CM, Belury MA, Barrientos RM. Butler MJ, et al. Brain Behav Immun. 2021 Nov;98:198-209. doi: 10.1016/j.bbi.2021.08.214. Epub 2021 Aug 20. Brain Behav Immun. 2021. PMID: 34425209 Free PMC article.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Animals
- Behavior, Animal / drug effects
- Behavior, Animal / physiology
- Cells, Cultured
- Conditioning, Classical / drug effects
- Conditioning, Classical / physiology
- Encephalomyelitis, Autoimmune, Experimental / complications*
- Fear / drug effects
- Fear / physiology
- Hippocampus / drug effects*
- Hippocampus / immunology*
- Inflammation / etiology*
- Inflammation / prevention & control*
- Male
- Memory Disorders / etiology*
- Memory Disorders / prevention & control*
- Mice
- Microglia / drug effects
- Microglia / immunology
- Multiple Sclerosis / complications*
- Naltrexone / administration & dosage
- Naltrexone / pharmacology*
- Narcotic Antagonists / administration & dosage
- Narcotic Antagonists / pharmacology*
- Rats
- Rats, Sprague-Dawley
- Toll-Like Receptor 2 / antagonists & inhibitors
- Toll-Like Receptor 4 / antagonists & inhibitors
- Narcotic Antagonists
- Toll-Like Receptor 2
- Toll-Like Receptor 4
- Naltrexone
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 3.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7572683/bin/nihms-1628518-f0003.jpg)
Figure 4.
Short-term memory in control or…
Figure 4.
Short-term memory in control or rats with EAE that were treated with (+)-NTX…
Figure 5.
Assessment of IL-1β mRNA in…
Figure 5.
Assessment of IL-1β mRNA in (A) hippocampus and (B) amygdala of naïve rats…
Figure 6.
Microglial (Iba1) and astrocyte (GFAP)…
Figure 6.
Microglial (Iba1) and astrocyte (GFAP) cell immunoreactivity of hippocampal CA1 and DG of…
Figure 7.
Gene expression of the pattern…
Figure 7.
Gene expression of the pattern recognition receptors (A) TLR2 and (B) TLR4, (C)…
Figure 8.
Increased serum anti-MOG IgG antibody…
Figure 8.
Increased serum anti-MOG IgG antibody concentration in rats with EAE that were treated…
Figure 9.
Assessment of (+)-NTX administration on…
Figure 9.
Assessment of (+)-NTX administration on motor disturbances in Dark Agouti (DA) and Sprague-Dawley…
- Involvement of TLR2-TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis.Kwilasz AJ, Clements MA, Larson TA, Harris KM, Litwiler ST, Woodall BJ, Todd LS, Schrama AEW, Mitten EH, Maier SF, Van Dam AM, Rice KC, Watkins LR. Kwilasz AJ, et al. Front Pain Res (Lausanne). 2022 Sep 13;3:932530. doi: 10.3389/fpain.2022.932530. eCollection 2022. Front Pain Res (Lausanne). 2022. PMID: 36176709 Free PMC article.
- Toll-like receptor 2 and 4 antagonism for the treatment of experimental autoimmune encephalomyelitis (EAE)-related pain.Kwilasz AJ, Green Fulgham SM, Duran-Malle JC, Schrama AEW, Mitten EH, Todd LS, Patel HP, Larson TA, Clements MA, Harris KM, Litwiler ST, Harvey LO Jr, Maier SF, Chavez RA, Rice KC, Van Dam AM, Watkins LR. Kwilasz AJ, et al. Brain Behav Immun. 2021 Mar;93:80-95. doi: 10.1016/j.bbi.2020.12.016. Epub 2021 Jan 7. Brain Behav Immun. 2021. PMID: 33358978 Free PMC article.
- Neurodegeneration and inflammation in hippocampus in experimental autoimmune encephalomyelitis induced in rats by one--time administration of encephalitogenic T cells.Kurkowska-Jastrzębska I, Swiątkiewicz M, Zaremba M, Cudna A, Piechal A, Pyrzanowska J, Widy-Tyszkiewicz E, Członkowska A. Kurkowska-Jastrzębska I, et al. Neuroscience. 2013 Sep 17;248:690-8. doi: 10.1016/j.neuroscience.2013.06.025. Epub 2013 Jun 24. Neuroscience. 2013. PMID: 23806721
- Opioid growth factor and low-dose naltrexone impair central nervous system infiltration by CD4 + T lymphocytes in established experimental autoimmune encephalomyelitis, a model of multiple sclerosis.Hammer LA, Waldner H, Zagon IS, McLaughlin PJ. Hammer LA, et al. Exp Biol Med (Maywood). 2016 Jan;241(1):71-8. doi: 10.1177/1535370215596384. Epub 2015 Jul 22. Exp Biol Med (Maywood). 2016. PMID: 26202376 Free PMC article.
- The Toll-like Receptor 2 (TLR2)-related Immunopathological Responses in the Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis.Jafarzadeh A, Nemati M, Khorramdelazad H, Mirshafiey A. Jafarzadeh A, et al. Iran J Allergy Asthma Immunol. 2019 Jun 8;18(3):230-250. doi: 10.18502/ijaai.v18i3.1117. Iran J Allergy Asthma Immunol. 2019. PMID: 31522431 Review.
- CD8+ T cells contribute to diet-induced memory deficits in aged male rats.Butler MJ, Sengupta S, Muscat SM, Amici SA, Biltz RG, Deems NP, Dravid P, Mackey-Alfonso S, Ijaz H, Bettes MN, Godbout JP, Kapoor A, Guerau-de-Arellano M, Barrientos RM. Butler MJ, et al. Brain Behav Immun. 2023 Mar;109:235-250. doi: 10.1016/j.bbi.2023.02.003. Epub 2023 Feb 9. Brain Behav Immun. 2023. PMID: 36764399
- Involvement of TLR2-TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis.Kwilasz AJ, Clements MA, Larson TA, Harris KM, Litwiler ST, Woodall BJ, Todd LS, Schrama AEW, Mitten EH, Maier SF, Van Dam AM, Rice KC, Watkins LR. Kwilasz AJ, et al. Front Pain Res (Lausanne). 2022 Sep 13;3:932530. doi: 10.3389/fpain.2022.932530. eCollection 2022. Front Pain Res (Lausanne). 2022. PMID: 36176709 Free PMC article.
- A behavioral and molecular study; ameliorated anxiety-like behavior and cognitive dysfunction in a rat model of chronic unpredictable stress treated with oregano extract.Mohseni-Moghaddam P, Dogani M, Hatami M, Roohollahi S, Amiresmaeli A, Askari N. Mohseni-Moghaddam P, et al. Brain Behav. 2022 Aug;12(8):e2727. doi: 10.1002/brb3.2727. Epub 2022 Jul 27. Brain Behav. 2022. PMID: 35898162 Free PMC article.
- Application and prospect of targeting innate immune sensors in the treatment of autoimmune diseases.Liu J, Zhang H, Su Y, Zhang B. Liu J, et al. Cell Biosci. 2022 May 26;12(1):68. doi: 10.1186/s13578-022-00810-w. Cell Biosci. 2022. PMID: 35619184 Free PMC article. Review.
- Dietary DHA prevents cognitive impairment and inflammatory gene expression in aged male rats fed a diet enriched with refined carbohydrates.Butler MJ, Deems NP, Muscat S, Butt CM, Belury MA, Barrientos RM. Butler MJ, et al. Brain Behav Immun. 2021 Nov;98:198-209. doi: 10.1016/j.bbi.2021.08.214. Epub 2021 Aug 20. Brain Behav Immun. 2021. PMID: 34425209 Free PMC article.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Animals
- Behavior, Animal / drug effects
- Behavior, Animal / physiology
- Cells, Cultured
- Conditioning, Classical / drug effects
- Conditioning, Classical / physiology
- Encephalomyelitis, Autoimmune, Experimental / complications*
- Fear / drug effects
- Fear / physiology
- Hippocampus / drug effects*
- Hippocampus / immunology*
- Inflammation / etiology*
- Inflammation / prevention & control*
- Male
- Memory Disorders / etiology*
- Memory Disorders / prevention & control*
- Mice
- Microglia / drug effects
- Microglia / immunology
- Multiple Sclerosis / complications*
- Naltrexone / administration & dosage
- Naltrexone / pharmacology*
- Narcotic Antagonists / administration & dosage
- Narcotic Antagonists / pharmacology*
- Rats
- Rats, Sprague-Dawley
- Toll-Like Receptor 2 / antagonists & inhibitors
- Toll-Like Receptor 4 / antagonists & inhibitors
- Narcotic Antagonists
- Toll-Like Receptor 2
- Toll-Like Receptor 4
- Naltrexone
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 4.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7572683/bin/nihms-1628518-f0004.jpg)
![Figure 5.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7572683/bin/nihms-1628518-f0005.jpg)
Figure 6.
Microglial (Iba1) and astrocyte (GFAP)…
Figure 6.
Microglial (Iba1) and astrocyte (GFAP) cell immunoreactivity of hippocampal CA1 and DG of…
Figure 7.
Gene expression of the pattern…
Figure 7.
Gene expression of the pattern recognition receptors (A) TLR2 and (B) TLR4, (C)…
Figure 8.
Increased serum anti-MOG IgG antibody…
Figure 8.
Increased serum anti-MOG IgG antibody concentration in rats with EAE that were treated…
Figure 9.
Assessment of (+)-NTX administration on…
Figure 9.
Assessment of (+)-NTX administration on motor disturbances in Dark Agouti (DA) and Sprague-Dawley…
- Involvement of TLR2-TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis.Kwilasz AJ, Clements MA, Larson TA, Harris KM, Litwiler ST, Woodall BJ, Todd LS, Schrama AEW, Mitten EH, Maier SF, Van Dam AM, Rice KC, Watkins LR. Kwilasz AJ, et al. Front Pain Res (Lausanne). 2022 Sep 13;3:932530. doi: 10.3389/fpain.2022.932530. eCollection 2022. Front Pain Res (Lausanne). 2022. PMID: 36176709 Free PMC article.
- Toll-like receptor 2 and 4 antagonism for the treatment of experimental autoimmune encephalomyelitis (EAE)-related pain.Kwilasz AJ, Green Fulgham SM, Duran-Malle JC, Schrama AEW, Mitten EH, Todd LS, Patel HP, Larson TA, Clements MA, Harris KM, Litwiler ST, Harvey LO Jr, Maier SF, Chavez RA, Rice KC, Van Dam AM, Watkins LR. Kwilasz AJ, et al. Brain Behav Immun. 2021 Mar;93:80-95. doi: 10.1016/j.bbi.2020.12.016. Epub 2021 Jan 7. Brain Behav Immun. 2021. PMID: 33358978 Free PMC article.
- Neurodegeneration and inflammation in hippocampus in experimental autoimmune encephalomyelitis induced in rats by one--time administration of encephalitogenic T cells.Kurkowska-Jastrzębska I, Swiątkiewicz M, Zaremba M, Cudna A, Piechal A, Pyrzanowska J, Widy-Tyszkiewicz E, Członkowska A. Kurkowska-Jastrzębska I, et al. Neuroscience. 2013 Sep 17;248:690-8. doi: 10.1016/j.neuroscience.2013.06.025. Epub 2013 Jun 24. Neuroscience. 2013. PMID: 23806721
- Opioid growth factor and low-dose naltrexone impair central nervous system infiltration by CD4 + T lymphocytes in established experimental autoimmune encephalomyelitis, a model of multiple sclerosis.Hammer LA, Waldner H, Zagon IS, McLaughlin PJ. Hammer LA, et al. Exp Biol Med (Maywood). 2016 Jan;241(1):71-8. doi: 10.1177/1535370215596384. Epub 2015 Jul 22. Exp Biol Med (Maywood). 2016. PMID: 26202376 Free PMC article.
- The Toll-like Receptor 2 (TLR2)-related Immunopathological Responses in the Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis.Jafarzadeh A, Nemati M, Khorramdelazad H, Mirshafiey A. Jafarzadeh A, et al. Iran J Allergy Asthma Immunol. 2019 Jun 8;18(3):230-250. doi: 10.18502/ijaai.v18i3.1117. Iran J Allergy Asthma Immunol. 2019. PMID: 31522431 Review.
- CD8+ T cells contribute to diet-induced memory deficits in aged male rats.Butler MJ, Sengupta S, Muscat SM, Amici SA, Biltz RG, Deems NP, Dravid P, Mackey-Alfonso S, Ijaz H, Bettes MN, Godbout JP, Kapoor A, Guerau-de-Arellano M, Barrientos RM. Butler MJ, et al. Brain Behav Immun. 2023 Mar;109:235-250. doi: 10.1016/j.bbi.2023.02.003. Epub 2023 Feb 9. Brain Behav Immun. 2023. PMID: 36764399
- Involvement of TLR2-TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis.Kwilasz AJ, Clements MA, Larson TA, Harris KM, Litwiler ST, Woodall BJ, Todd LS, Schrama AEW, Mitten EH, Maier SF, Van Dam AM, Rice KC, Watkins LR. Kwilasz AJ, et al. Front Pain Res (Lausanne). 2022 Sep 13;3:932530. doi: 10.3389/fpain.2022.932530. eCollection 2022. Front Pain Res (Lausanne). 2022. PMID: 36176709 Free PMC article.
- A behavioral and molecular study; ameliorated anxiety-like behavior and cognitive dysfunction in a rat model of chronic unpredictable stress treated with oregano extract.Mohseni-Moghaddam P, Dogani M, Hatami M, Roohollahi S, Amiresmaeli A, Askari N. Mohseni-Moghaddam P, et al. Brain Behav. 2022 Aug;12(8):e2727. doi: 10.1002/brb3.2727. Epub 2022 Jul 27. Brain Behav. 2022. PMID: 35898162 Free PMC article.
- Application and prospect of targeting innate immune sensors in the treatment of autoimmune diseases.Liu J, Zhang H, Su Y, Zhang B. Liu J, et al. Cell Biosci. 2022 May 26;12(1):68. doi: 10.1186/s13578-022-00810-w. Cell Biosci. 2022. PMID: 35619184 Free PMC article. Review.
- Dietary DHA prevents cognitive impairment and inflammatory gene expression in aged male rats fed a diet enriched with refined carbohydrates.Butler MJ, Deems NP, Muscat S, Butt CM, Belury MA, Barrientos RM. Butler MJ, et al. Brain Behav Immun. 2021 Nov;98:198-209. doi: 10.1016/j.bbi.2021.08.214. Epub 2021 Aug 20. Brain Behav Immun. 2021. PMID: 34425209 Free PMC article.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Animals
- Behavior, Animal / drug effects
- Behavior, Animal / physiology
- Cells, Cultured
- Conditioning, Classical / drug effects
- Conditioning, Classical / physiology
- Encephalomyelitis, Autoimmune, Experimental / complications*
- Fear / drug effects
- Fear / physiology
- Hippocampus / drug effects*
- Hippocampus / immunology*
- Inflammation / etiology*
- Inflammation / prevention & control*
- Male
- Memory Disorders / etiology*
- Memory Disorders / prevention & control*
- Mice
- Microglia / drug effects
- Microglia / immunology
- Multiple Sclerosis / complications*
- Naltrexone / administration & dosage
- Naltrexone / pharmacology*
- Narcotic Antagonists / administration & dosage
- Narcotic Antagonists / pharmacology*
- Rats
- Rats, Sprague-Dawley
- Toll-Like Receptor 2 / antagonists & inhibitors
- Toll-Like Receptor 4 / antagonists & inhibitors
- Narcotic Antagonists
- Toll-Like Receptor 2
- Toll-Like Receptor 4
- Naltrexone
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 6.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7572683/bin/nihms-1628518-f0006.jpg)
Figure 7.
Gene expression of the pattern…
Figure 7.
Gene expression of the pattern recognition receptors (A) TLR2 and (B) TLR4, (C)…
Figure 8.
Increased serum anti-MOG IgG antibody…
Figure 8.
Increased serum anti-MOG IgG antibody concentration in rats with EAE that were treated…
Figure 9.
Assessment of (+)-NTX administration on…
Figure 9.
Assessment of (+)-NTX administration on motor disturbances in Dark Agouti (DA) and Sprague-Dawley…
- Involvement of TLR2-TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis.Kwilasz AJ, Clements MA, Larson TA, Harris KM, Litwiler ST, Woodall BJ, Todd LS, Schrama AEW, Mitten EH, Maier SF, Van Dam AM, Rice KC, Watkins LR. Kwilasz AJ, et al. Front Pain Res (Lausanne). 2022 Sep 13;3:932530. doi: 10.3389/fpain.2022.932530. eCollection 2022. Front Pain Res (Lausanne). 2022. PMID: 36176709 Free PMC article.
- Toll-like receptor 2 and 4 antagonism for the treatment of experimental autoimmune encephalomyelitis (EAE)-related pain.Kwilasz AJ, Green Fulgham SM, Duran-Malle JC, Schrama AEW, Mitten EH, Todd LS, Patel HP, Larson TA, Clements MA, Harris KM, Litwiler ST, Harvey LO Jr, Maier SF, Chavez RA, Rice KC, Van Dam AM, Watkins LR. Kwilasz AJ, et al. Brain Behav Immun. 2021 Mar;93:80-95. doi: 10.1016/j.bbi.2020.12.016. Epub 2021 Jan 7. Brain Behav Immun. 2021. PMID: 33358978 Free PMC article.
- Neurodegeneration and inflammation in hippocampus in experimental autoimmune encephalomyelitis induced in rats by one--time administration of encephalitogenic T cells.Kurkowska-Jastrzębska I, Swiątkiewicz M, Zaremba M, Cudna A, Piechal A, Pyrzanowska J, Widy-Tyszkiewicz E, Członkowska A. Kurkowska-Jastrzębska I, et al. Neuroscience. 2013 Sep 17;248:690-8. doi: 10.1016/j.neuroscience.2013.06.025. Epub 2013 Jun 24. Neuroscience. 2013. PMID: 23806721
- Opioid growth factor and low-dose naltrexone impair central nervous system infiltration by CD4 + T lymphocytes in established experimental autoimmune encephalomyelitis, a model of multiple sclerosis.Hammer LA, Waldner H, Zagon IS, McLaughlin PJ. Hammer LA, et al. Exp Biol Med (Maywood). 2016 Jan;241(1):71-8. doi: 10.1177/1535370215596384. Epub 2015 Jul 22. Exp Biol Med (Maywood). 2016. PMID: 26202376 Free PMC article.
- The Toll-like Receptor 2 (TLR2)-related Immunopathological Responses in the Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis.Jafarzadeh A, Nemati M, Khorramdelazad H, Mirshafiey A. Jafarzadeh A, et al. Iran J Allergy Asthma Immunol. 2019 Jun 8;18(3):230-250. doi: 10.18502/ijaai.v18i3.1117. Iran J Allergy Asthma Immunol. 2019. PMID: 31522431 Review.
- CD8+ T cells contribute to diet-induced memory deficits in aged male rats.Butler MJ, Sengupta S, Muscat SM, Amici SA, Biltz RG, Deems NP, Dravid P, Mackey-Alfonso S, Ijaz H, Bettes MN, Godbout JP, Kapoor A, Guerau-de-Arellano M, Barrientos RM. Butler MJ, et al. Brain Behav Immun. 2023 Mar;109:235-250. doi: 10.1016/j.bbi.2023.02.003. Epub 2023 Feb 9. Brain Behav Immun. 2023. PMID: 36764399
- Involvement of TLR2-TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis.Kwilasz AJ, Clements MA, Larson TA, Harris KM, Litwiler ST, Woodall BJ, Todd LS, Schrama AEW, Mitten EH, Maier SF, Van Dam AM, Rice KC, Watkins LR. Kwilasz AJ, et al. Front Pain Res (Lausanne). 2022 Sep 13;3:932530. doi: 10.3389/fpain.2022.932530. eCollection 2022. Front Pain Res (Lausanne). 2022. PMID: 36176709 Free PMC article.
- A behavioral and molecular study; ameliorated anxiety-like behavior and cognitive dysfunction in a rat model of chronic unpredictable stress treated with oregano extract.Mohseni-Moghaddam P, Dogani M, Hatami M, Roohollahi S, Amiresmaeli A, Askari N. Mohseni-Moghaddam P, et al. Brain Behav. 2022 Aug;12(8):e2727. doi: 10.1002/brb3.2727. Epub 2022 Jul 27. Brain Behav. 2022. PMID: 35898162 Free PMC article.
- Application and prospect of targeting innate immune sensors in the treatment of autoimmune diseases.Liu J, Zhang H, Su Y, Zhang B. Liu J, et al. Cell Biosci. 2022 May 26;12(1):68. doi: 10.1186/s13578-022-00810-w. Cell Biosci. 2022. PMID: 35619184 Free PMC article. Review.
- Dietary DHA prevents cognitive impairment and inflammatory gene expression in aged male rats fed a diet enriched with refined carbohydrates.Butler MJ, Deems NP, Muscat S, Butt CM, Belury MA, Barrientos RM. Butler MJ, et al. Brain Behav Immun. 2021 Nov;98:198-209. doi: 10.1016/j.bbi.2021.08.214. Epub 2021 Aug 20. Brain Behav Immun. 2021. PMID: 34425209 Free PMC article.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Animals
- Behavior, Animal / drug effects
- Behavior, Animal / physiology
- Cells, Cultured
- Conditioning, Classical / drug effects
- Conditioning, Classical / physiology
- Encephalomyelitis, Autoimmune, Experimental / complications*
- Fear / drug effects
- Fear / physiology
- Hippocampus / drug effects*
- Hippocampus / immunology*
- Inflammation / etiology*
- Inflammation / prevention & control*
- Male
- Memory Disorders / etiology*
- Memory Disorders / prevention & control*
- Mice
- Microglia / drug effects
- Microglia / immunology
- Multiple Sclerosis / complications*
- Naltrexone / administration & dosage
- Naltrexone / pharmacology*
- Narcotic Antagonists / administration & dosage
- Narcotic Antagonists / pharmacology*
- Rats
- Rats, Sprague-Dawley
- Toll-Like Receptor 2 / antagonists & inhibitors
- Toll-Like Receptor 4 / antagonists & inhibitors
- Narcotic Antagonists
- Toll-Like Receptor 2
- Toll-Like Receptor 4
- Naltrexone
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
NCBI Literature Resources
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![Figure 7.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7572683/bin/nihms-1628518-f0007.jpg)
Figure 8.
Increased serum anti-MOG IgG antibody…
Figure 8.
Increased serum anti-MOG IgG antibody concentration in rats with EAE that were treated…
Figure 9.
Assessment of (+)-NTX administration on…
Figure 9.
Assessment of (+)-NTX administration on motor disturbances in Dark Agouti (DA) and Sprague-Dawley…
- Involvement of TLR2-TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis.Kwilasz AJ, Clements MA, Larson TA, Harris KM, Litwiler ST, Woodall BJ, Todd LS, Schrama AEW, Mitten EH, Maier SF, Van Dam AM, Rice KC, Watkins LR. Kwilasz AJ, et al. Front Pain Res (Lausanne). 2022 Sep 13;3:932530. doi: 10.3389/fpain.2022.932530. eCollection 2022. Front Pain Res (Lausanne). 2022. PMID: 36176709 Free PMC article.
- Toll-like receptor 2 and 4 antagonism for the treatment of experimental autoimmune encephalomyelitis (EAE)-related pain.Kwilasz AJ, Green Fulgham SM, Duran-Malle JC, Schrama AEW, Mitten EH, Todd LS, Patel HP, Larson TA, Clements MA, Harris KM, Litwiler ST, Harvey LO Jr, Maier SF, Chavez RA, Rice KC, Van Dam AM, Watkins LR. Kwilasz AJ, et al. Brain Behav Immun. 2021 Mar;93:80-95. doi: 10.1016/j.bbi.2020.12.016. Epub 2021 Jan 7. Brain Behav Immun. 2021. PMID: 33358978 Free PMC article.
- Neurodegeneration and inflammation in hippocampus in experimental autoimmune encephalomyelitis induced in rats by one--time administration of encephalitogenic T cells.Kurkowska-Jastrzębska I, Swiątkiewicz M, Zaremba M, Cudna A, Piechal A, Pyrzanowska J, Widy-Tyszkiewicz E, Członkowska A. Kurkowska-Jastrzębska I, et al. Neuroscience. 2013 Sep 17;248:690-8. doi: 10.1016/j.neuroscience.2013.06.025. Epub 2013 Jun 24. Neuroscience. 2013. PMID: 23806721
- Opioid growth factor and low-dose naltrexone impair central nervous system infiltration by CD4 + T lymphocytes in established experimental autoimmune encephalomyelitis, a model of multiple sclerosis.Hammer LA, Waldner H, Zagon IS, McLaughlin PJ. Hammer LA, et al. Exp Biol Med (Maywood). 2016 Jan;241(1):71-8. doi: 10.1177/1535370215596384. Epub 2015 Jul 22. Exp Biol Med (Maywood). 2016. PMID: 26202376 Free PMC article.
- The Toll-like Receptor 2 (TLR2)-related Immunopathological Responses in the Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis.Jafarzadeh A, Nemati M, Khorramdelazad H, Mirshafiey A. Jafarzadeh A, et al. Iran J Allergy Asthma Immunol. 2019 Jun 8;18(3):230-250. doi: 10.18502/ijaai.v18i3.1117. Iran J Allergy Asthma Immunol. 2019. PMID: 31522431 Review.
- CD8+ T cells contribute to diet-induced memory deficits in aged male rats.Butler MJ, Sengupta S, Muscat SM, Amici SA, Biltz RG, Deems NP, Dravid P, Mackey-Alfonso S, Ijaz H, Bettes MN, Godbout JP, Kapoor A, Guerau-de-Arellano M, Barrientos RM. Butler MJ, et al. Brain Behav Immun. 2023 Mar;109:235-250. doi: 10.1016/j.bbi.2023.02.003. Epub 2023 Feb 9. Brain Behav Immun. 2023. PMID: 36764399
- Involvement of TLR2-TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis.Kwilasz AJ, Clements MA, Larson TA, Harris KM, Litwiler ST, Woodall BJ, Todd LS, Schrama AEW, Mitten EH, Maier SF, Van Dam AM, Rice KC, Watkins LR. Kwilasz AJ, et al. Front Pain Res (Lausanne). 2022 Sep 13;3:932530. doi: 10.3389/fpain.2022.932530. eCollection 2022. Front Pain Res (Lausanne). 2022. PMID: 36176709 Free PMC article.
- A behavioral and molecular study; ameliorated anxiety-like behavior and cognitive dysfunction in a rat model of chronic unpredictable stress treated with oregano extract.Mohseni-Moghaddam P, Dogani M, Hatami M, Roohollahi S, Amiresmaeli A, Askari N. Mohseni-Moghaddam P, et al. Brain Behav. 2022 Aug;12(8):e2727. doi: 10.1002/brb3.2727. Epub 2022 Jul 27. Brain Behav. 2022. PMID: 35898162 Free PMC article.
- Application and prospect of targeting innate immune sensors in the treatment of autoimmune diseases.Liu J, Zhang H, Su Y, Zhang B. Liu J, et al. Cell Biosci. 2022 May 26;12(1):68. doi: 10.1186/s13578-022-00810-w. Cell Biosci. 2022. PMID: 35619184 Free PMC article. Review.
- Dietary DHA prevents cognitive impairment and inflammatory gene expression in aged male rats fed a diet enriched with refined carbohydrates.Butler MJ, Deems NP, Muscat S, Butt CM, Belury MA, Barrientos RM. Butler MJ, et al. Brain Behav Immun. 2021 Nov;98:198-209. doi: 10.1016/j.bbi.2021.08.214. Epub 2021 Aug 20. Brain Behav Immun. 2021. PMID: 34425209 Free PMC article.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Animals
- Behavior, Animal / drug effects
- Behavior, Animal / physiology
- Cells, Cultured
- Conditioning, Classical / drug effects
- Conditioning, Classical / physiology
- Encephalomyelitis, Autoimmune, Experimental / complications*
- Fear / drug effects
- Fear / physiology
- Hippocampus / drug effects*
- Hippocampus / immunology*
- Inflammation / etiology*
- Inflammation / prevention & control*
- Male
- Memory Disorders / etiology*
- Memory Disorders / prevention & control*
- Mice
- Microglia / drug effects
- Microglia / immunology
- Multiple Sclerosis / complications*
- Naltrexone / administration & dosage
- Naltrexone / pharmacology*
- Narcotic Antagonists / administration & dosage
- Narcotic Antagonists / pharmacology*
- Rats
- Rats, Sprague-Dawley
- Toll-Like Receptor 2 / antagonists & inhibitors
- Toll-Like Receptor 4 / antagonists & inhibitors
- Narcotic Antagonists
- Toll-Like Receptor 2
- Toll-Like Receptor 4
- Naltrexone
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
![Figure 8.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7572683/bin/nihms-1628518-f0008.jpg)
Figure 9.
Assessment of (+)-NTX administration on…
Figure 9.
Assessment of (+)-NTX administration on motor disturbances in Dark Agouti (DA) and Sprague-Dawley…
![Figure 9.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7572683/bin/nihms-1628518-f0009.jpg)
Source: PubMed