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Glial Glutamate Transporter Modulation Prevents Development of Complete Freund’s Adjuvant-Induced Hyperalgesia and Allodynia in Mice
Glial glutamate transporter (GLT-1) modulation in the hippocampus and anterior cingulate cortex (ACC) is critically involved in nociceptive pain. The objective of the study was to investigate the effects of 3-[[(2-methylphenyl) methyl] thio]-6-(2-pyridinyl)-pyridazine (LDN-212320), a GLT-1 activator...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10216248/ https://www.ncbi.nlm.nih.gov/pubmed/37239279 http://dx.doi.org/10.3390/brainsci13050807 |
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author | Alotaibi, Ghallab Khan, Amna Ronan, Patrick J. Lutfy, Kabirullah Rahman, Shafiqur |
author_facet | Alotaibi, Ghallab Khan, Amna Ronan, Patrick J. Lutfy, Kabirullah Rahman, Shafiqur |
author_sort | Alotaibi, Ghallab |
collection | PubMed |
description | Glial glutamate transporter (GLT-1) modulation in the hippocampus and anterior cingulate cortex (ACC) is critically involved in nociceptive pain. The objective of the study was to investigate the effects of 3-[[(2-methylphenyl) methyl] thio]-6-(2-pyridinyl)-pyridazine (LDN-212320), a GLT-1 activator, against microglial activation induced by complete Freund’s adjuvant (CFA) in a mouse model of inflammatory pain. Furthermore, the effects of LDN-212320 on the protein expression of glial markers, such as ionized calcium-binding adaptor molecule 1 (Iba1), cluster of differentiation molecule 11b (CD11b), mitogen-activated protein kinases (p38), astroglial GLT-1, and connexin 43 (CX43), were measured in the hippocampus and ACC following CFA injection using the Western blot analysis and immunofluorescence assay. The effects of LDN-212320 on the pro-inflammatory cytokine interleukin-1β (IL-1β) in the hippocampus and ACC were also assessed using an enzyme-linked immunosorbent assay. Pretreatment with LDN-212320 (20 mg/kg) significantly reduced the CFA-induced tactile allodynia and thermal hyperalgesia. The anti-hyperalgesic and anti-allodynic effects of LDN-212320 were reversed by the GLT-1 antagonist DHK (10 mg/kg). Pretreatment with LDN-212320 significantly reduced CFA-induced microglial Iba1, CD11b, and p38 expression in the hippocampus and ACC. LDN-212320 markedly modulated astroglial GLT-1, CX43, and, IL-1β expression in the hippocampus and ACC. Overall, these results suggest that LDN-212320 prevents CFA-induced allodynia and hyperalgesia by upregulating astroglial GLT-1 and CX43 expression and decreasing microglial activation in the hippocampus and ACC. Therefore, LDN-212320 could be developed as a novel therapeutic drug candidate for chronic inflammatory pain. |
format | Online Article Text |
id | pubmed-10216248 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-102162482023-05-27 Glial Glutamate Transporter Modulation Prevents Development of Complete Freund’s Adjuvant-Induced Hyperalgesia and Allodynia in Mice Alotaibi, Ghallab Khan, Amna Ronan, Patrick J. Lutfy, Kabirullah Rahman, Shafiqur Brain Sci Article Glial glutamate transporter (GLT-1) modulation in the hippocampus and anterior cingulate cortex (ACC) is critically involved in nociceptive pain. The objective of the study was to investigate the effects of 3-[[(2-methylphenyl) methyl] thio]-6-(2-pyridinyl)-pyridazine (LDN-212320), a GLT-1 activator, against microglial activation induced by complete Freund’s adjuvant (CFA) in a mouse model of inflammatory pain. Furthermore, the effects of LDN-212320 on the protein expression of glial markers, such as ionized calcium-binding adaptor molecule 1 (Iba1), cluster of differentiation molecule 11b (CD11b), mitogen-activated protein kinases (p38), astroglial GLT-1, and connexin 43 (CX43), were measured in the hippocampus and ACC following CFA injection using the Western blot analysis and immunofluorescence assay. The effects of LDN-212320 on the pro-inflammatory cytokine interleukin-1β (IL-1β) in the hippocampus and ACC were also assessed using an enzyme-linked immunosorbent assay. Pretreatment with LDN-212320 (20 mg/kg) significantly reduced the CFA-induced tactile allodynia and thermal hyperalgesia. The anti-hyperalgesic and anti-allodynic effects of LDN-212320 were reversed by the GLT-1 antagonist DHK (10 mg/kg). Pretreatment with LDN-212320 significantly reduced CFA-induced microglial Iba1, CD11b, and p38 expression in the hippocampus and ACC. LDN-212320 markedly modulated astroglial GLT-1, CX43, and, IL-1β expression in the hippocampus and ACC. Overall, these results suggest that LDN-212320 prevents CFA-induced allodynia and hyperalgesia by upregulating astroglial GLT-1 and CX43 expression and decreasing microglial activation in the hippocampus and ACC. Therefore, LDN-212320 could be developed as a novel therapeutic drug candidate for chronic inflammatory pain. MDPI 2023-05-16 /pmc/articles/PMC10216248/ /pubmed/37239279 http://dx.doi.org/10.3390/brainsci13050807 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Alotaibi, Ghallab Khan, Amna Ronan, Patrick J. Lutfy, Kabirullah Rahman, Shafiqur Glial Glutamate Transporter Modulation Prevents Development of Complete Freund’s Adjuvant-Induced Hyperalgesia and Allodynia in Mice |
title | Glial Glutamate Transporter Modulation Prevents Development of Complete Freund’s Adjuvant-Induced Hyperalgesia and Allodynia in Mice |
title_full | Glial Glutamate Transporter Modulation Prevents Development of Complete Freund’s Adjuvant-Induced Hyperalgesia and Allodynia in Mice |
title_fullStr | Glial Glutamate Transporter Modulation Prevents Development of Complete Freund’s Adjuvant-Induced Hyperalgesia and Allodynia in Mice |
title_full_unstemmed | Glial Glutamate Transporter Modulation Prevents Development of Complete Freund’s Adjuvant-Induced Hyperalgesia and Allodynia in Mice |
title_short | Glial Glutamate Transporter Modulation Prevents Development of Complete Freund’s Adjuvant-Induced Hyperalgesia and Allodynia in Mice |
title_sort | glial glutamate transporter modulation prevents development of complete freund’s adjuvant-induced hyperalgesia and allodynia in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10216248/ https://www.ncbi.nlm.nih.gov/pubmed/37239279 http://dx.doi.org/10.3390/brainsci13050807 |
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