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Activation of Glucagon-Like Peptide-1 Receptor Promotes Neuroprotection in Experimental Autoimmune Encephalomyelitis by Reducing Neuroinflammatory Responses

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Abstract

The signaling axis of glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) has been an important component in overcoming diabetes, and recent reports have uncovered novel beneficial roles of this signaling axis in central nervous system (CNS) disorders, such as Alzheimer’s disease, Parkinson’s disease, and cerebral ischemia, accelerating processes for exendin-4 repositioning. Here, we studied whether multiple sclerosis (MS) could be a complement to the CNS disorders that are associated with the GLP-1/GLP-1R signaling axis. Both components of the signaling axis, GLP-1 and GLP-1R proteins, are expressed in neurons, astrocytes, and microglia in the spinal cord of normal mice. In particular, they are abundant in Iba1-positive microglia. Upon challenge by experimental autoimmune encephalomyelitis (EAE), an animal model of MS, the mRNA expression of both GLP-1 and GLP-1R was markedly downregulated in EAE-symptomatic spinal cords, indicating attenuated activity of GLP-1/GLP-1R signaling in EAE. Such a downregulation obviously occurred in LPS-stimulated rat primary microglia, a main cell type to express both GLP-1 and GLP-1R, further indicating attenuated activity of GLP-1/GLP-1R signaling in activated microglia. To investigate whether increased activity of GLP-1R has a therapeutic benefit, exendin-4 (5 μg/kg, i.p.), a GLP-1R agonist, was administered daily to EAE-symptomatic mice. Exendin-4 administration to symptomatic EAE mice significantly improved the clinical signs of the disease, along with the reversal of histopathological sequelae such as cell accumulation, demyelination, astrogliosis, microglial activation, and morphological transformation of activated microglia in the injured spinal cord. Such an improvement by exendin-4 was comparable to that by FTY720 (3 mg/kg, i.p.), a drug for MS. The neuroprotective effects of exendin-4 against EAE were also associated with decreased mRNA expression of proinflammatory cytokines, such as interleukin (IL)-17, IL-1β, IL-6, and tumor necrosis factor (TNF)-α, all of which are usually upregulated in injured sites of the EAE spinal cord. Interestingly, exendin-4 exposure similarly reduced mRNA levels of IL-1β and TNF-α in LPS-stimulated microglia. Furthermore, exendin-4 administration significantly attenuated activation of NF-κB signaling in EAE spinal cord and LPS-stimulated microglia. Collectively, the current study demonstrates the therapeutic potential of exendin-4 for MS by reducing immune responses in the CNS, highlighting the importance of the GLP-1/GLP-1R signaling axis in the development of a novel therapeutic strategy for MS.

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Acknowledgements

This work was supported by grants from the National Research Foundation (NRF) and Ministry of Health and Welfare funded by the Korean Government to JWC [NRF-2013R1A1A1A05005520 and NRF-2014M3A9B6069339] and HSJ [HI14C1135]. The authors thank Mr. Bhakta Prasad Gaire for technical assistance with histological analysis.

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Authors and Affiliations

  1. Laboratory of Neuropharmacology, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, 406-799, South Korea

    Chi-Ho Lee, Eunjung Moon, Arjun Sapkota & Ji Woong Choi

  2. Laboratory of Immunology, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, 406-799, South Korea

    Chi-Ho Lee & Hee Sook Jun

  3. Departments of Life and Nanopharmaceutical Science and Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, 130-701, South Korea

    Se Jin Jeon, Kyu Suk Cho & Jong Hoon Ryu

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  1. Chi-Ho Lee
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Correspondence to Ji Woong Choi.

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Chi-Ho Lee, Se Jin Jeon, and Kyu Suk Cho contribute equally to this study.

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Lee, CH., Jeon, S.J., Cho, K.S. et al. Activation of Glucagon-Like Peptide-1 Receptor Promotes Neuroprotection in Experimental Autoimmune Encephalomyelitis by Reducing Neuroinflammatory Responses. Mol Neurobiol 55, 3007–3020 (2018). https://doi.org/10.1007/s12035-017-0550-2

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