Inhalation of dimethyl fumarate-encapsulated solid lipid nanoparticles attenuate clinical signs of experimental autoimmune encephalomyelitis and pulmonary inflammatory dysfunction in mice

Made available in DSpace on 2022-04-29T08:38:47Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-01-01 Rationale: The FDA-approved Dimethyl Fumarate (DMF) as an oral drug for Multiple Sclerosis (MS) treatment based on its immunomodulatory activities. However, it also caused severe adverse effects mainly related to the gastrointestinal system. Objective: Investigated the potential effects of solid lipid nanoparticles (SLNs) containing DMF, administered by inhalation on the clinical signs, central nervous system (CNS) inflammatory response, and lung function changes in mice with experimental autoimmune encephalomyelitis (EAE). Materials and methods: EAE was induced using MOG35-55 peptide in female C57BL/6J mice and the mice were treated via inhalation with DMF-encapsulated SLN (CTRL/SLN/DMF and EAE/SLN/DMF), empty SLN (CTRL/SLN and EAE/SLN), or saline solution (CTRL/saline and EAE/saline), every 72 h during 21 days. Results: After 21 days post-induction, EAE mice treated with DMF-loaded SLN, when compared with EAE/saline and EAE/SLN, showed decreased clinical score and weight loss, reduction in brain and spinal cord injury and inflammation, also related to the increased influx of Foxp3+ cells into the spinal cord and lung tissues. Moreover, our data revealed that EAE mice showed signs of respiratory disease, marked by increased vascular permeability, leukocyte influx, production of TNF-α and IL-17, perivascular and peribronchial inflammation, with pulmonary mechanical dysfunction associated with loss of respiratory volumes and elasticity, which DMF-encapsulated reverted in SLN nebulization. Conclusion: Our study suggests that inhalation of DMF-encapsulated SLN is an effective therapeutic protocol that reduces not only the CNS inflammatory process and disability progression, characteristic of EAE disease, but also protects mice from lung inflammation and pulmonary dysfunction. Neuroscience Group Department of Physiology and Biophysics Institute of Biological Sciences Federal University of Minas Gerais (UFMG), MG Nanoneurobiophysics Research Group Department of Physics Chemistry and Mathematics Federal University of Sao Carlos (UFSCAR), Sao Paulo State of Sao Paulo University (UNESP) Drugs and Medicines Department School of Pharmaceutical Sciences, Sao Paulo Laboratory of Pulmonary Immunology and Mechanics Department of Physiology and Biophysics Institute of Biological Sciences Federal University of Minas Gerais (UFMG), MG Laboratory of Immunology and Genomics of Parasites Department of Parasitology Institute of Biological Sciences Federal University of Minas Gerais (UFMG), MG Center for Technology and Research in Magneto-Resonance (CTPMAG) Federal University of Minas Gerais (UFMG), MG Department of Pathology Institute of Biological Sciences Federal University of Minas Gerais (UFMG), MG Laboratory of Functional Genetics Department of Genetics Ecology and Evolution Institute of Biological Sciences Federal University of Minas Gerais (UFMG), MG Department of Pharmacology Institute of Biological Sciences Federal University of Goias (UFG), GO State of Sao Paulo University (UNESP) Drugs and Medicines Department School of Pharmaceutical Sciences, Sao Paulo