Crotalphine Attenuates Pain and Neuroinflammation Induced by Experimental Autoimmune Encephalomyelitis in Mice.

Aline C Giardini,Gisele Picolo,Orlando G Ribeiro,Bianca G Evangelista,Barbara B Martins,Morena B Sant’Anna,Vanessa O Zambelli,Rosana L Pagano,Adriano P Ciena,Marucia Chacur,Carmen L P Lancellotti

doi:10.3390/toxins13110827

Abstract

Multiple sclerosis (MS) is a demyelinating disease of inflammatory and autoimmune origin, which induces sensory and progressive motor impairments, including pain. Cells of the immune system actively participate in the pathogenesis and progression of MS by inducing neuroinflammation, tissue damage, and demyelination. Crotalphine (CRO), a structural analogue to a peptide firstly identified in Crotalus durissus terrificus snake venom, induces analgesia by endogenous opioid release and type 2 cannabinoid receptor (CB2) activation. Since CB2 activation downregulates neuroinflammation and ameliorates symptoms in mice models of MS, it was presently investigated whether CRO has a beneficial effect in the experimental autoimmune encephalomyelitis (EAE). CRO was administered on the 5th day after immunization, in a single dose, or five doses starting at the peak of disease. CRO partially reverted EAE-induced mechanical hyperalgesia and decreased the severity of the clinical signs. In addition, CRO decreases the inflammatory infiltrate and glial cells activation followed by TNF-α and IL-17 downregulation in the spinal cord. Peripherally, CRO recovers the EAE-induced impairment in myelin thickness in the sciatic nerve. Therefore, CRO interferes with central and peripheral neuroinflammation, opening perspectives to MS control.

Highlights

Licensee MDPI, Basel, Switzerland.Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease which affects more than 2.8 million people worldwide [1]
CRO (10, 50, or 100 μg/Kg) or saline was first administered on the fifth day after imCRO (10, 50, or 100 μg/Kg) or saline was first administered on the fifth day after munization, in a single dose
The hypernociception tion remained until the last day of evaluation. i.e., 10th day, when the assessment of the remained until the last day of evaluation. i.e., 10th day, when the assessment of the pain pain threshold was stopped due to the onset of motor dysfunctions

Summary

Introduction

Licensee MDPI, Basel, Switzerland.Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease which affects more than 2.8 million people worldwide [1]. The autoimmune inflammation that affects the central nervous system (CNS) progressively results in oligodendrocyte injury and demyelination. The inflammatory response is mainly mediated by T helper (Th) cells, which play an essential role in the course of MS [10]. Pro-inflammatory cytokines such as interleukin (IL)-6, IL-17, IL-21, IL-22, IL-23, and tumor necrosis factor (TNF)-α are produced by Th17 cells [10,11,12,13]. Th1 cells mediate CNS inflammation by stimulating macrophage infiltration and producing important cytokines including interferon (IFN)-γ, which plays a relevant role in spinal neuroinflammation [10]. B-lymphocytes play a critical role in tissue damage, propagating inflammation, and spinal demyelination in MS [16,17]

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