Differential time course of glycogen synthase kinase-3 inhibition in experimental autoimmune encephalomyelitis
A S Al-Zaidi1, N Mohtarrudin1, J Chupri1
1Universiti Putra Malaysia, Faculty of Medicine and Health Sciences, Department of Pathology, Serdang 43400, Selangor, Malaysia.
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.
Insights
Administering a GSK-3 inhibitor like Tideglusib early in experimental autoimmune encephalomyelitis (EAE) reduces neuroinflammation and demyelination. This neuroprotection is linked to increased IL-10 production and decreased pro-inflammatory cytokines.
Area of Science:
- Neuroimmunology
- Immunology
- Pharmacology
Background:
- Glycogen synthase kinase 3 (GSK-3) regulates T cells involved in CNS inflammation and demyelination in experimental autoimmune encephalomyelitis (EAE).
- Understanding GSK-3's role is crucial for developing targeted therapies for neuroinflammatory diseases.
Purpose of the Study:
- To evaluate the neuroprotective potential of a single dose of a GSK-3 inhibitor at different time points in an EAE model.
- To investigate the impact of GSK-3 inhibition on immune cell modulation and CNS pathology.
Main Methods:
- In vitro evaluation of GSK-3 inhibition on CD4+ T cell cytokine production.
- Induction of chronic EAE in mice using MOG35-55 peptide.
- Administration of Tideglusib (a selective GSK-3 inhibitor) at pre-EAE, immunization day, or disease onset.
- Assessment of clinical symptoms, histopathology (inflammation, demyelination), and serum cytokine profiles.
Main Results:
- GSK-3 inhibition in CD4+ T cells enhanced Interleukin-10 (IL-10) production.
- Tideglusib administration before or on the day of immunization significantly reduced EAE clinical symptoms and delayed onset.
- Histological analysis revealed decreased CNS inflammation and demyelination, particularly with early Tideglusib treatment.
- Early Tideglusib treatment downregulated key pro-inflammatory cytokines (IFN-γ, IL-17A/F, IL-23) and upregulated IL-4 and IL-10.
Conclusions:
- The neuroprotective effects of Tideglusib in EAE are time-dependent, with early administration being most effective.
- GSK-3 inhibition may protect the CNS by downregulating Th1/Th17 cytokines and promoting an IL-10-mediated anti-inflammatory response.
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