Role of orexin-A in experimental autoimmune encephalomyelitis
Iman Fatemi1, Ali Shamsizadeh1, Fatemeh Ayoobi1
1Physiology-Pharmacology Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
Abstract:
The aim of this study was to evaluate the effects of orexin-A (OX-A) on behavioral and pathological parameters and on gene expression of some multiple sclerosis-related peptides in a model of experimental autoimmune encephalomyelitis (EAE). EAE was induced by subcutaneous administration of MOG 35-55. Following immunization, the treatment was initiated by using SB.334867 (orexin-1 receptor antagonist) and/or OX-A. Locomotor activity and exploratory behaviors were monitored using open field and T-maze continuous alternation task (T-CAT) respectively. Pain sensitivity was assessed by hot-plate test. Histopathological assessments were performed by H&E staining. The expression of TGF-β, MBP, MMP-9, IL-12, iNOS and MCP-1 were measured using real-time PCR method in lumbar spinal cord. OX-A administration in EAE mice remarkably attenuated the clinical symptoms, increased latency response in hot plate test, inhibited infiltration of inflammatory cells, up-regulated mRNA expression of TGF-β as well as MBP and down-regulated mRNA expression of iNOS, MMP-9 and IL-12. In contrast SB.334867 administration in EAE mice deteriorated the clinical symptoms, decreased the alternation in T-CAT, increased infiltration of inflammatory cells, down-regulated mRNA expression of TGF-β and MBP and up-regulated mRNA expression of iNOS. Results of this study suggest that the orexinergic system might be involved in pathological development of EAE. These findings suggest orexinergic system as a potential target for treatment of multiple sclerosis.
Insights
Orexin-A (OX-A) treatment improved multiple sclerosis symptoms in a mouse model by reducing inflammation and altering gene expression. The orexinergic system shows potential for treating multiple sclerosis.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system.
- The orexinergic system, involving orexin-A (OX-A), plays a role in various physiological processes.
- Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model for studying MS.
Purpose of the Study:
- To investigate the therapeutic potential of orexin-A (OX-A) in a mouse model of multiple sclerosis (MS).
- To evaluate the effects of OX-A on behavioral, pathological, and molecular changes in experimental autoimmune encephalomyelitis (EAE).
Main Methods:
- EAE was induced in mice using MOG 35-55 peptide.
- Mice were treated with OX-A or an orexin-1 receptor antagonist (SB.334867).
- Behavioral tests (locomotor activity, exploratory behavior, pain sensitivity) and histopathological analyses were performed.
- Gene expression of MS-related peptides (TGF-β, MBP, MMP-9, IL-12, iNOS, MCP-1) was quantified using real-time PCR.
Main Results:
- OX-A treatment significantly attenuated EAE clinical symptoms, improved pain response, and reduced inflammatory cell infiltration.
- OX-A administration upregulated TGF-β and MBP mRNA expression while downregulating iNOS, MMP-9, and IL-12.
- Conversely, the orexin-1 receptor antagonist worsened EAE symptoms, impaired behavior, increased inflammation, and altered gene expression patterns unfavorably.
Conclusions:
- The orexinergic system is implicated in the pathological development of experimental autoimmune encephalomyelitis (EAE).
- Orexin-A demonstrates neuroprotective and anti-inflammatory effects in the EAE model.
- These findings highlight the orexinergic system as a promising therapeutic target for multiple sclerosis treatment.
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