Inhalation of Dimethyl Fumarate encapsulated-nanoparticles attenuates clinical signs and central nervous system inflammation of Experimental Autoimmune Encephalomyelitis animals’ models

Winner Young Investigator Award
Young Investigator
Bárbara Pinto
Universidade Federal de Minas Gerais
05
Belo Horizonte, Brazil

Abstract

Introduction:
Multiple sclerosis (MS) is a chronic disabling autoimmune disease characterized by inflammatory response, gliosis, demyelination and neuroaxonal degeneration in the central nervous system. Dimethyl fumarate (DMF) has been approved as an oral drug for MS treatment based on its immunomodulatory activities, including neuroprotective and anti-inflammatory effects. However, the drug when administered orally causes serious adverse effects, mainly related to the gastrointestinal system, impairing the patient's adherence to therapy. Objective: Here, we investigated the potential effects of solid lipid nanoparticles (SLN) containing DMF, administered by inhalation in mice with experimental autoimmune encephalomyelitis (EAE).

Methods:
EAE was induced with a subcutaneous administration of an emulsion containing MOG35-55, Mycobacterium tuberculosis and complete Freund's adjuvant in female C57BL/6J mice. Pertussis toxin (i.p.) was injected at the induction day and 48 hours later. Mice were treated via inhalatory route with DMF-encapsulated nanoparticles (CTRL/SLN/DMF and EAE/SLN/DMF), empty nanoparticles (CTRL/SLN and EAE/SLN) and saline solution (CTRL/saline and EAE/saline) each 72 hours for 21 days. Clinical score, body weight, brain and spinal cord vascular permeability, spinal cord inflammatory infiltration, in vivo leukocyte endothelial interactions, cerebral cytokines levels (IL-10, TNF-α, IL-17, IL-1β and IL-6) and FOXp3 spinal cord level cells were evaluated.

Results:
EAE mice treated with DMF-encapsulated in SLN, when compared to EAE/saline, showed decreased in clinical score and weight loss, reduction in brain and spinal cord vascular permeability and in spinal cord inflammatory cellularity, as well as, an increased in leucocyte rolling and adhesion. It was also observed a decrease in cerebral levels of TNF-α and IL-17 and an increased in FOXp3 cells in spinal cord. Conclusion: Our study suggests that inhalation of DMF encapsulated in SLN is an effective therapeutic protocol which reduces CNS inflammatory process and disability progression characteristic of EAE disease.

Keywords: Multiple Sclerosis, EAE, Dimethyl Fumarate, Solid Lipid Nanoparticles, Airway administration, Neuroinflammation.

Inhalation of Dimethyl Fumarate encapsulated-nanoparticles attenuates clinical signs and central nervous system inflammation of Experimental Autoimmune Encephalomyelitis animals’ models

Bárbara Fernandes Pinto1,2, Lorena Natasha Brito Ribeiro1, Gisela Bevilacqua Rolfsen Ferreira da Silva3,4, Lucas Kraemer2,5, Gabryella Soares Pinheiro dos Santos6, Samantha Ribeiro Béla6, Fábio de Lima Leite3, Anselmo Gomes de Oliveira4, Maura Regina Silva da Páscoa Vilela1, Onésia Cristina Oliveira Lima7, Ricardo Toshio Fujiwara5, Alexander Birbrair6, Remo Castro Russo2* and Juliana Carvalho-Tavares1*
1Neuroscience Group, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.
2Laboratory of Pulmonary Immunology and Mechanics, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.
3Nanoneurobiophysics Research Group, Department of Physics, Chemistry and Mathematics, Federal University of São Carlos (UFSCAR), Sorocaba, São Paulo, Brazil.
4Department of Drugs and Medicine, School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, São Paulo, Brazil.
5Laboratory of Immunology and Genomics of Parasites, Department of Parasitology, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.
6Department of Pathology, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.
7Department of Pharmacology, Institute of Biological Sciences, Federal University of Goiás (UFG), Goiânia, GO, Brazil.
*These authors contributed equally to this work.