Immunotherapeutic treatment of inflammation in mice exposed to methamphetamine
IntroductionCurrently, there are no FDA-approved medications to treat methamphetamine addiction, including the inflammatory, neurotoxic, and adverse neuropsychiatric effects. We have shown that partial (p)MHC class II constructs (i.e., Recombinant T-cell receptor Ligand – RTL1000), comprised of the...
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| Format: | Article |
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Psychiatry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1259041/full |
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| author | Jennifer M. Loftis Jennifer M. Loftis Jennifer M. Loftis Jennifer M. Loftis Sankrith Ramani Evan J. Firsick Rebekah Hudson Anh Le-Cook Kevin S. Murnane Kevin S. Murnane Kevin S. Murnane Arthur Vandenbark Arthur Vandenbark Arthur Vandenbark Renee L. Shirley |
| author_facet | Jennifer M. Loftis Jennifer M. Loftis Jennifer M. Loftis Jennifer M. Loftis Sankrith Ramani Evan J. Firsick Rebekah Hudson Anh Le-Cook Kevin S. Murnane Kevin S. Murnane Kevin S. Murnane Arthur Vandenbark Arthur Vandenbark Arthur Vandenbark Renee L. Shirley |
| author_sort | Jennifer M. Loftis |
| collection | DOAJ |
| description | IntroductionCurrently, there are no FDA-approved medications to treat methamphetamine addiction, including the inflammatory, neurotoxic, and adverse neuropsychiatric effects. We have shown that partial (p)MHC class II constructs (i.e., Recombinant T-cell receptor Ligand – RTL1000), comprised of the extracellular α1 and β1 domains of MHC class II molecules linked covalently to myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide, can address the neuroimmune effects of methamphetamine addiction through its ability to bind to and down-regulate CD74 expression, block macrophage migration inhibitory factor (MIF) signaling, and reduce levels of pro-inflammatory chemokine ligand 2 (CCL2). The present study evaluated the effects of our third-generation pMHC II construct, DRmQ, on cognitive function and concentration of inflammatory cytokines in the frontal cortex, a region critical for cognitive functions such as memory, impulse control, and problem solving.MethodsFemale and male C57BL/6J mice were exposed to methamphetamine (or saline) via subcutaneous (s.c.) injections administered four times per day every other day for 14 days. Following methamphetamine exposure, mice received immunotherapy (DRmQ or ibudilast) or vehicle s.c. injections daily for five days. Cognitive function was assessed using the novel object recognition test (NORT). To evaluate the effects of immunotherapy on inflammation in the frontal cortex, multiplex immunoassays were conducted. ANOVA was used to compare exploration times on the NORT and immune factor concentrations.ResultsPost hoc analysis revealed increased novel object exploration time in MA-DRmQ treated mice, as compared to MA-VEH treated mice (non-significant trend). One-way ANOVA detected a significant difference across the groups in the concentration of macrophage inflammatory protein-2 (MIP-2) (p = 0.03). Post hoc tests indicated that mice treated with methamphetamine and DRmQ or ibudilast had significantly lower levels of MIP-2 in frontal cortex, as compared to mice treated with methamphetamine and vehicle (p > 0.05).DiscussionBy specifically targeting CD74, our DRQ constructs can block the signaling of MIF, inhibiting the downstream signaling and pro-inflammatory effects that contribute to and perpetuate methamphetamine addiction. |
| first_indexed | 2024-03-11T10:56:19Z |
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| id | doaj.art-82c8251d12ad425cbe00a081dc2253b9 |
| institution | Directory Open Access Journal |
| issn | 1664-0640 |
| language | English |
| last_indexed | 2024-03-11T10:56:19Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Psychiatry |
| spelling | doaj.art-82c8251d12ad425cbe00a081dc2253b92023-11-13T06:30:56ZengFrontiers Media S.A.Frontiers in Psychiatry1664-06402023-11-011410.3389/fpsyt.2023.12590411259041Immunotherapeutic treatment of inflammation in mice exposed to methamphetamineJennifer M. Loftis0Jennifer M. Loftis1Jennifer M. Loftis2Jennifer M. Loftis3Sankrith Ramani4Evan J. Firsick5Rebekah Hudson6Anh Le-Cook7Kevin S. Murnane8Kevin S. Murnane9Kevin S. Murnane10Arthur Vandenbark11Arthur Vandenbark12Arthur Vandenbark13Renee L. Shirley14Research and Development Service, Veterans Affairs Portland Health Care System, Portland, OR, United StatesDepartment of Psychiatry, Oregon Health & Science University, Portland, OR, United StatesDepartment of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, United StatesMethamphetamine Research Center, Oregon Health & Science University, Portland, OR, United StatesResearch and Development Service, Veterans Affairs Portland Health Care System, Portland, OR, United StatesResearch and Development Service, Veterans Affairs Portland Health Care System, Portland, OR, United StatesResearch and Development Service, Veterans Affairs Portland Health Care System, Portland, OR, United StatesResearch and Development Service, Veterans Affairs Portland Health Care System, Portland, OR, United StatesDepartment of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, United StatesLouisiana Addiction Research Center, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, United StatesDepartment of Psychiatry and Behavioral Medicine, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, United StatesResearch and Development Service, Veterans Affairs Portland Health Care System, Portland, OR, United StatesDepartment of Neurology, Oregon Health & Science University, Portland, OR, United StatesDepartment of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, United States0Virogenomics BioDevelopment, Inc., Portland, OR, United StatesIntroductionCurrently, there are no FDA-approved medications to treat methamphetamine addiction, including the inflammatory, neurotoxic, and adverse neuropsychiatric effects. We have shown that partial (p)MHC class II constructs (i.e., Recombinant T-cell receptor Ligand – RTL1000), comprised of the extracellular α1 and β1 domains of MHC class II molecules linked covalently to myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide, can address the neuroimmune effects of methamphetamine addiction through its ability to bind to and down-regulate CD74 expression, block macrophage migration inhibitory factor (MIF) signaling, and reduce levels of pro-inflammatory chemokine ligand 2 (CCL2). The present study evaluated the effects of our third-generation pMHC II construct, DRmQ, on cognitive function and concentration of inflammatory cytokines in the frontal cortex, a region critical for cognitive functions such as memory, impulse control, and problem solving.MethodsFemale and male C57BL/6J mice were exposed to methamphetamine (or saline) via subcutaneous (s.c.) injections administered four times per day every other day for 14 days. Following methamphetamine exposure, mice received immunotherapy (DRmQ or ibudilast) or vehicle s.c. injections daily for five days. Cognitive function was assessed using the novel object recognition test (NORT). To evaluate the effects of immunotherapy on inflammation in the frontal cortex, multiplex immunoassays were conducted. ANOVA was used to compare exploration times on the NORT and immune factor concentrations.ResultsPost hoc analysis revealed increased novel object exploration time in MA-DRmQ treated mice, as compared to MA-VEH treated mice (non-significant trend). One-way ANOVA detected a significant difference across the groups in the concentration of macrophage inflammatory protein-2 (MIP-2) (p = 0.03). Post hoc tests indicated that mice treated with methamphetamine and DRmQ or ibudilast had significantly lower levels of MIP-2 in frontal cortex, as compared to mice treated with methamphetamine and vehicle (p > 0.05).DiscussionBy specifically targeting CD74, our DRQ constructs can block the signaling of MIF, inhibiting the downstream signaling and pro-inflammatory effects that contribute to and perpetuate methamphetamine addiction.https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1259041/fulladdictionchemokinedrug discoveryfrontal cortexinflammationmethamphetamine |
| spellingShingle | Jennifer M. Loftis Jennifer M. Loftis Jennifer M. Loftis Jennifer M. Loftis Sankrith Ramani Evan J. Firsick Rebekah Hudson Anh Le-Cook Kevin S. Murnane Kevin S. Murnane Kevin S. Murnane Arthur Vandenbark Arthur Vandenbark Arthur Vandenbark Renee L. Shirley Immunotherapeutic treatment of inflammation in mice exposed to methamphetamine Frontiers in Psychiatry addiction chemokine drug discovery frontal cortex inflammation methamphetamine |
| title | Immunotherapeutic treatment of inflammation in mice exposed to methamphetamine |
| title_full | Immunotherapeutic treatment of inflammation in mice exposed to methamphetamine |
| title_fullStr | Immunotherapeutic treatment of inflammation in mice exposed to methamphetamine |
| title_full_unstemmed | Immunotherapeutic treatment of inflammation in mice exposed to methamphetamine |
| title_short | Immunotherapeutic treatment of inflammation in mice exposed to methamphetamine |
| title_sort | immunotherapeutic treatment of inflammation in mice exposed to methamphetamine |
| topic | addiction chemokine drug discovery frontal cortex inflammation methamphetamine |
| url | https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1259041/full |
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