Differential time course of glycogen synthase kinase-3 inhibition in experimental autoimmune encephalomyelitis
Introduction: GSK-3 is an immune regulator that plays a role in the modulation of cytokine-producing effector T cells associated with inflammation and demyelination of the CNS in EAE. Objective: This study aimed to evaluate the treatment paradigm of a single dose of GSK-3 inhibitor administration at...
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| Format: | Article |
| Language: | English |
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Malaysian Society of Pathologists
2021
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| Online Access: | http://psasir.upm.edu.my/id/eprint/96733/1/ABSTRACT.pdf |
| _version_ | 1825937756432367616 |
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| author | Al-Zaidi, Ahmed Salam Mohtarrudin, Norhafizah Hassan, Masriana |
| author_facet | Al-Zaidi, Ahmed Salam Mohtarrudin, Norhafizah Hassan, Masriana |
| author_sort | Al-Zaidi, Ahmed Salam |
| collection | UPM |
| description | Introduction: GSK-3 is an immune regulator that plays a role in the modulation of cytokine-producing effector T cells associated with inflammation and demyelination of the CNS in EAE. Objective: This study aimed to evaluate the treatment paradigm of a single dose of GSK-3 inhibitor administration at various time courses for the protection of the CNS from EAE. Materials and methods: Effects of GSK-3 inhibition on intracellular cytokine levels were evaluated from in vitro naïve CD4+ T cell cultures. Immunized C57BL/6 female mice with MOG35-55 in conjunction with CFA and Ptx were used as a chronic inflammatory EAE disease model. Tideglusib (NP12), a Thiadiazolidinone class, selective, and non-ATP competitive GSK-3 inhibitor, was injected intraperitoneally at pre-EAE, same-day of immunization or disease onset. After 30 days post-immunization, brain, and spinal cord tissues were collected for inflammation and demyelination analysis by H&E and luxol fast blue staining, respectively, whereas cytokine profiles of the serum were assessed by cytokine beads array. Results: The inhibition of GSK-3 in CD4+ T cells increased IL-10 production. The administration of Tideglusib during pre-EAE and same-day, but not during disease onset, significantly reduced clinical symptoms and delayed disease onset. Histopathological analysis of spinal cord tissues showed a significant decline in the number of inflammatory cell infiltration with a concomitant reduction in demyelination through the blocking of GSK-3, especially during pre-EAE and sameday. Upregulation of IL-10 via GSK-3 inhibition coincided with the downregulation of cytokineassociated effector T cells, including IFN-γ, IL-9, IL-17A, IL-17F, IL-21, and IL-23. Increased IL-4 production, however, was only significant in the pre-EAE group. Conclusion: The neuroprotective effects of Tideglusib against EAE are time-dependent. Downregulation of Th1 and Th17 hallmark cytokines by Tideglusib in EAE may be associated with IL-10 production. |
| first_indexed | 2024-03-06T11:04:21Z |
| format | Article |
| id | upm.eprints-96733 |
| institution | Universiti Putra Malaysia |
| language | English |
| last_indexed | 2024-03-06T11:04:21Z |
| publishDate | 2021 |
| publisher | Malaysian Society of Pathologists |
| record_format | dspace |
| spelling | upm.eprints-967332022-12-01T08:22:43Z http://psasir.upm.edu.my/id/eprint/96733/ Differential time course of glycogen synthase kinase-3 inhibition in experimental autoimmune encephalomyelitis Al-Zaidi, Ahmed Salam Mohtarrudin, Norhafizah Hassan, Masriana Introduction: GSK-3 is an immune regulator that plays a role in the modulation of cytokine-producing effector T cells associated with inflammation and demyelination of the CNS in EAE. Objective: This study aimed to evaluate the treatment paradigm of a single dose of GSK-3 inhibitor administration at various time courses for the protection of the CNS from EAE. Materials and methods: Effects of GSK-3 inhibition on intracellular cytokine levels were evaluated from in vitro naïve CD4+ T cell cultures. Immunized C57BL/6 female mice with MOG35-55 in conjunction with CFA and Ptx were used as a chronic inflammatory EAE disease model. Tideglusib (NP12), a Thiadiazolidinone class, selective, and non-ATP competitive GSK-3 inhibitor, was injected intraperitoneally at pre-EAE, same-day of immunization or disease onset. After 30 days post-immunization, brain, and spinal cord tissues were collected for inflammation and demyelination analysis by H&E and luxol fast blue staining, respectively, whereas cytokine profiles of the serum were assessed by cytokine beads array. Results: The inhibition of GSK-3 in CD4+ T cells increased IL-10 production. The administration of Tideglusib during pre-EAE and same-day, but not during disease onset, significantly reduced clinical symptoms and delayed disease onset. Histopathological analysis of spinal cord tissues showed a significant decline in the number of inflammatory cell infiltration with a concomitant reduction in demyelination through the blocking of GSK-3, especially during pre-EAE and sameday. Upregulation of IL-10 via GSK-3 inhibition coincided with the downregulation of cytokineassociated effector T cells, including IFN-γ, IL-9, IL-17A, IL-17F, IL-21, and IL-23. Increased IL-4 production, however, was only significant in the pre-EAE group. Conclusion: The neuroprotective effects of Tideglusib against EAE are time-dependent. Downregulation of Th1 and Th17 hallmark cytokines by Tideglusib in EAE may be associated with IL-10 production. Malaysian Society of Pathologists 2021 Article PeerReviewed text en http://psasir.upm.edu.my/id/eprint/96733/1/ABSTRACT.pdf Al-Zaidi, Ahmed Salam and Mohtarrudin, Norhafizah and Hassan, Masriana (2021) Differential time course of glycogen synthase kinase-3 inhibition in experimental autoimmune encephalomyelitis. Malaysian Journal of Pathology, 43 (3). pp. 413-424. ISSN 0126-8635 https://pubmed.ncbi.nlm.nih.gov/34958063/ |
| spellingShingle | Al-Zaidi, Ahmed Salam Mohtarrudin, Norhafizah Hassan, Masriana Differential time course of glycogen synthase kinase-3 inhibition in experimental autoimmune encephalomyelitis |
| title | Differential time course of glycogen synthase kinase-3 inhibition in experimental autoimmune encephalomyelitis |
| title_full | Differential time course of glycogen synthase kinase-3 inhibition in experimental autoimmune encephalomyelitis |
| title_fullStr | Differential time course of glycogen synthase kinase-3 inhibition in experimental autoimmune encephalomyelitis |
| title_full_unstemmed | Differential time course of glycogen synthase kinase-3 inhibition in experimental autoimmune encephalomyelitis |
| title_short | Differential time course of glycogen synthase kinase-3 inhibition in experimental autoimmune encephalomyelitis |
| title_sort | differential time course of glycogen synthase kinase 3 inhibition in experimental autoimmune encephalomyelitis |
| url | http://psasir.upm.edu.my/id/eprint/96733/1/ABSTRACT.pdf |
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