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...
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MDPI AG
2023-05-01
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| Series: | Brain Sciences |
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| Online Access: | https://www.mdpi.com/2076-3425/13/5/807 |
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| author | Ghallab Alotaibi Amna Khan Patrick J. Ronan Kabirullah Lutfy Shafiqur Rahman |
| author_facet | Ghallab Alotaibi Amna Khan Patrick J. Ronan Kabirullah Lutfy Shafiqur Rahman |
| author_sort | Ghallab Alotaibi |
| collection | DOAJ |
| 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. |
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| institution | Directory Open Access Journal |
| issn | 2076-3425 |
| language | English |
| last_indexed | 2024-03-11T03:53:44Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
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| series | Brain Sciences |
| spelling | doaj.art-67c1729f035740729eb4a3d5b8920b1a2023-11-18T00:43:08ZengMDPI AGBrain Sciences2076-34252023-05-0113580710.3390/brainsci13050807Glial Glutamate Transporter Modulation Prevents Development of Complete Freund’s Adjuvant-Induced Hyperalgesia and Allodynia in MiceGhallab Alotaibi0Amna Khan1Patrick J. Ronan2Kabirullah Lutfy3Shafiqur Rahman4Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USADepartment of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USAResearch Service, Sioux Falls VA Healthcare System, Sioux Falls, SD 57105, USACollege of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USADepartment of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USAGlial 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.https://www.mdpi.com/2076-3425/13/5/807glutamate transporterchronic painastrogliamicrogliaLDN-212320mice |
| spellingShingle | Ghallab Alotaibi Amna Khan Patrick J. Ronan Kabirullah Lutfy Shafiqur Rahman Glial Glutamate Transporter Modulation Prevents Development of Complete Freund’s Adjuvant-Induced Hyperalgesia and Allodynia in Mice Brain Sciences glutamate transporter chronic pain astroglia microglia LDN-212320 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 | glutamate transporter chronic pain astroglia microglia LDN-212320 mice |
| url | https://www.mdpi.com/2076-3425/13/5/807 |
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