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Systemic administration of orexin A ameliorates established experimental autoimmune encephalomyelitis by diminishing neuroinflammation.
J Neuroinflammation 2019; 16(1):64JN

Abstract

BACKGROUND

Orexins (hypocretins, Hcrt) A and B are GPCR-binding hypothalamic neuropeptides known to regulate sleep/wake states and feeding behavior. A few studies have shown that orexin A exhibits anti-inflammatory and neuroprotective properties, suggesting that it might provide therapeutic effects in inflammatory and neurodegenerative diseases like multiple sclerosis (MS). In MS, encephalitogenic Th1 and Th17 cells trigger an inflammatory response in the CNS destroying the myelin sheath. Here, we investigated the effects of peripheral orexin A administration to mice undergoing experimental autoimmune encephalomyelitis (EAE), a widely used model of MS.

METHODS

Mice were subcutaneously immunized with myelin oligodendrocyte glycoprotein peptide (MOG)35-55 in CFA. Mice were treated intraperitoneally for five consecutive days with either PBS or 300 μg of orexin A starting at a moderate EAE score. Molecular, cellular, and histological analysis were performed by real-time PCR, ELISA, flow cytometry, and immunofluorescence.

RESULTS

Orexin A strongly ameliorated ongoing EAE, limiting the infiltration of pathogenic CD4+ T lymphocytes, and diminishing chemokine (MCP-1/CCL2 and IP-10/CXCL10) and cytokine (IFN-γ (Th1), IL-17 (Th17), TNF-α, IL-10, and TGF-β) expressions in the CNS. Moreover, orexin A treatment was neuroprotective, decreasing demyelination, astrogliosis, and microglial activation. Despite its strong local therapeutic effects, orexin A did not impair peripheral draining lymph node cell proliferation and Th1/Th17 cytokine production in response to MOG35-55 in vitro.

CONCLUSIONS

Peripherally-administered orexin A ameliorated EAE by reducing CNS neuroinflammation. These results suggest that orexins may represent new therapeutic candidates that should be further investigated for MS treatment.

Authors+Show Affiliations

University of Rouen Normandy, INSERM U1234 PANTHER, Institute for Research and Innovation in Biomedicine (IRIB), Faculté de Médecine et Pharmacie, 22 Boulevard Gambetta, 76183, Rouen, France.University of Rouen Normandy, INSERM U1234 PANTHER, Institute for Research and Innovation in Biomedicine (IRIB), Faculté de Médecine et Pharmacie, 22 Boulevard Gambetta, 76183, Rouen, France.University of Rouen Normandy, INSERM U1234 PANTHER, Institute for Research and Innovation in Biomedicine (IRIB), Faculté de Médecine et Pharmacie, 22 Boulevard Gambetta, 76183, Rouen, France.University of Rouen Normandy, INSERM U1234 PANTHER, Institute for Research and Innovation in Biomedicine (IRIB), Faculté de Médecine et Pharmacie, 22 Boulevard Gambetta, 76183, Rouen, France.University of Rouen Normandy, INSERM U1234 PANTHER, Institute for Research and Innovation in Biomedicine (IRIB), Faculté de Médecine et Pharmacie, 22 Boulevard Gambetta, 76183, Rouen, France.University of Rouen Normandy, INSERM U1234 PANTHER, Institute for Research and Innovation in Biomedicine (IRIB), Faculté de Médecine et Pharmacie, 22 Boulevard Gambetta, 76183, Rouen, France.Paris-Diderot University, INSERM U1149, Inflammation Research Center (CRI), DHU UNITY, Faculté de Médecine Site Bichat, 16 rue H. Huchard, 75018, Paris, France.University of Rouen Normandy, INSERM U1234 PANTHER, Institute for Research and Innovation in Biomedicine (IRIB), Faculté de Médecine et Pharmacie, 22 Boulevard Gambetta, 76183, Rouen, France. Department of Immunology and Biotherapy, University of Rouen Normandy, INSERM U1234 PANTHER, IRIB, Rouen University Hospital, 22 Boulevard Gambetta, 76183, Rouen, France.University of Rouen Normandy, INSERM U1234 PANTHER, Institute for Research and Innovation in Biomedicine (IRIB), Faculté de Médecine et Pharmacie, 22 Boulevard Gambetta, 76183, Rouen, France. yossan-var.tan@univ-rouen.fr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30894198

Citation

Becquet, Laurine, et al. "Systemic Administration of Orexin a Ameliorates Established Experimental Autoimmune Encephalomyelitis By Diminishing Neuroinflammation." Journal of Neuroinflammation, vol. 16, no. 1, 2019, p. 64.
Becquet L, Abad C, Leclercq M, et al. Systemic administration of orexin A ameliorates established experimental autoimmune encephalomyelitis by diminishing neuroinflammation. J Neuroinflammation. 2019;16(1):64.
Becquet, L., Abad, C., Leclercq, M., Miel, C., Jean, L., Riou, G., ... Tan, Y. V. (2019). Systemic administration of orexin A ameliorates established experimental autoimmune encephalomyelitis by diminishing neuroinflammation. Journal of Neuroinflammation, 16(1), p. 64. doi:10.1186/s12974-019-1447-y.
Becquet L, et al. Systemic Administration of Orexin a Ameliorates Established Experimental Autoimmune Encephalomyelitis By Diminishing Neuroinflammation. J Neuroinflammation. 2019 Mar 20;16(1):64. PubMed PMID: 30894198.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Systemic administration of orexin A ameliorates established experimental autoimmune encephalomyelitis by diminishing neuroinflammation. AU - Becquet,Laurine, AU - Abad,Catalina, AU - Leclercq,Mathilde, AU - Miel,Camille, AU - Jean,Laetitia, AU - Riou,Gaëtan, AU - Couvineau,Alain, AU - Boyer,Olivier, AU - Tan,Yossan-Var, Y1 - 2019/03/20/ PY - 2018/11/07/received PY - 2019/02/26/accepted PY - 2019/3/22/entrez PY - 2019/3/22/pubmed PY - 2019/7/16/medline KW - EAE KW - Multiple sclerosis KW - Neuro-immunomodulation KW - Neuroinflammation KW - Neuropeptide KW - Orexin A SP - 64 EP - 64 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 16 IS - 1 N2 - BACKGROUND: Orexins (hypocretins, Hcrt) A and B are GPCR-binding hypothalamic neuropeptides known to regulate sleep/wake states and feeding behavior. A few studies have shown that orexin A exhibits anti-inflammatory and neuroprotective properties, suggesting that it might provide therapeutic effects in inflammatory and neurodegenerative diseases like multiple sclerosis (MS). In MS, encephalitogenic Th1 and Th17 cells trigger an inflammatory response in the CNS destroying the myelin sheath. Here, we investigated the effects of peripheral orexin A administration to mice undergoing experimental autoimmune encephalomyelitis (EAE), a widely used model of MS. METHODS: Mice were subcutaneously immunized with myelin oligodendrocyte glycoprotein peptide (MOG)35-55 in CFA. Mice were treated intraperitoneally for five consecutive days with either PBS or 300 μg of orexin A starting at a moderate EAE score. Molecular, cellular, and histological analysis were performed by real-time PCR, ELISA, flow cytometry, and immunofluorescence. RESULTS: Orexin A strongly ameliorated ongoing EAE, limiting the infiltration of pathogenic CD4+ T lymphocytes, and diminishing chemokine (MCP-1/CCL2 and IP-10/CXCL10) and cytokine (IFN-γ (Th1), IL-17 (Th17), TNF-α, IL-10, and TGF-β) expressions in the CNS. Moreover, orexin A treatment was neuroprotective, decreasing demyelination, astrogliosis, and microglial activation. Despite its strong local therapeutic effects, orexin A did not impair peripheral draining lymph node cell proliferation and Th1/Th17 cytokine production in response to MOG35-55 in vitro. CONCLUSIONS: Peripherally-administered orexin A ameliorated EAE by reducing CNS neuroinflammation. These results suggest that orexins may represent new therapeutic candidates that should be further investigated for MS treatment. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/30894198/Systemic_administration_of_orexin_A_ameliorates_established_experimental_autoimmune_encephalomyelitis_by_diminishing_neuroinflammation_ L2 - https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-019-1447-y DB - PRIME DP - Unbound Medicine ER -