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