Crotoxin down-modulates pro-inflammatory cells and alleviates pain on the MOG(35-55)-induced experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis

Author(s)

Teixeira, N. B. ^[1] ; Sant'Anna, M. B. ^[1] ; Giardini, A. C. ^[1] ; Araujo, L. P. ^[2] ; Fonseca, L. A. ^[1] ; Basso, A. S. ^[2] ; Cury, Y. ^[1] ; Picolo, G. ^[1]

Affiliation

^[1] Butantan Inst, Lab Pain & Signaling, Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Paulista Sch Med, Dept Microbiol Immunol & Parasitol, UNIFESP, Sao Paulo - Brazil

• Document type: Journal article
• Source: BRAIN BEHAVIOR AND IMMUNITY; v. 84, p. 253-268, FEB 2020.
• Web of Science Citations: 0

Abstract

Multiple sclerosis (MS) is a Central Nervous System inflammatory demyelinating disease that has as primary symptoms losses of sensory and motor functions, including chronic pain. To date, however, few studies have investigated the mechanisms of chronic pain in animal models of MS since locomotor impairments render difficult its evaluation. It was previously demonstrated that in the MOG(35-55)-induced EAE, an animal model of MS, the hypernociception appears before the onset of motor disability, allowing for the study of these two phenomena separately. Here, we evaluated the effect of crotoxin (CTX), a neurotoxin isolated from the Crotalus durissus terrificus snake venom that displays, at non-toxic dose, antinociceptive, anti-inflammatory and immunomodulatory effects, in the pain and in symptoms progression of EAE. The pain threshold of female C57BL/6 mice decreased at the 4th day after immunization, while the first sign of disease appeared around the 11st-12nd days, coinciding with the onset of motor abnormalities. CTX (40 mu g/kg, s.c.) administered in a single dose on the 5th day after immunization, induced a long-lasting analgesic effect (5 days), without interfering with the clinical signs of the disease. On the other hand, when crotoxin was administered for 5 consecutive days, from 5th-9th day after immunization, it induced analgesia and also reduced EAE progression. The antinociceptive effect of crotoxin was blocked by Boc-2 (0.5 mg/kg, i.p.), a selective antagonist of formyl peptide receptors, by NDGA (30 mu g/kg, i.p.), a lipoxygenase inhibitor and by atropine sulfate (10 mg/kg, i.p.), an antagonist of muscarinic receptors, administered 30 min before CTX. CTX was also effective in decreasing EAE clinical signs even when administered after its onset. Regarding the interactions between neurons and immunocompetent cells, CTX, in vitro, was able to reduce T cell proliferation, decreasing Th1 and Th17 and increasing Treg cell differentiation. Furthermore, in EAE model, the treatment with 5 consecutive doses of CTX inhibited IFN-gamma-producing T cells, GM-CSF-producing T cells, reduced the frequency of activated microglia/macrophages within the CNS and decreased the number of migrating cell to spinal cord and cerebellum at the peak of the disease. These results suggest that CTX is a potential treatment not only for pain alteration but also for clinical progression induced by the disease as well as an useful tool for the development of new therapeutic approaches for the multiple sclerosis control. (AU)

• FAPESP's process: 11/17974-2 - Effect of crotoxin in the pain and in the clinical signs observed in animals with experimental autoimmune encephalomyelitis, a model of multiple sclerosis
• Grantee: Gisele Picolo
• Support Opportunities: Regular Research Grants
• FAPESP's process: 10/12903-7 - Effect of crotoxin in the Experimental Autoimmune Encephalomyelitis, a model of multiple sclerosis: Evaluation of the nociception and clinical symptoms.
• Grantee: Nathália Bernardes Teixeira
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 13/07467-1 - CeTICS - Center of Toxins, Immune-Response and Cell Signaling
• Grantee: Hugo Aguirre Armelin
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC