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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

Our working hypothesis is that constant interpulse interval (IPI) electrical stimulation would resonate with endogenous epileptogenic reverberating circuits, inducing seizures, whereas a random interinterval electrical stimulation protocol would promote desynchronization of such neural networks, producing an anticonvulsant effect. Male Wistar rats were stereotaxically implanted with a bipolar electrical stimulation electrode in the amygdala. Pentylenetetrazole (10 mg/ml/min) was continuously infused through an intravenous catheter to induce seizures while four different patterns of temporally coded electrical stimulation were applied: periodic stimulation (PS), pseudo-randomized IPI stimulation (LH), restrictively randomized IPI stimulation (IH), and bursts of 20-ms IPIs (burst). PS decreased the pentylenetetrazole threshold to forelimb clonus, whereas IH increased the threshold to forelimb clonus and to generalized tonic–clonic seizures. We hypothesize that PS facilitates forelimb clonus by reverberating with epileptogenic circuits in the limbic system, whereas IH delays forelimb clonus and generalized tonic–clonic seizures by desynchronizing the epileptic neural networks in the forebrain–midbrain–hindbrain circuits.

In the PTZ animal model of epilepsy, electrical stimulation applied to the amygdaloid complex may result in either pro-convulsive or anticonvulsant effect, depending on the temporal pattern used (i.e. periodic-PS and non-periodic-NPS electrical stimulation). Our hypothesis is that the anatomical target is a determinant factor for the differential effect of temporally-coded patterns on seizure outcome. The threshold dose of PTZ to elicit forelimb clonus and generalized tonic–clonic seizure behavior was measured. The effect of amygdaloid complex PS on forelimb clonus threshold showed a pro-convulsive effect while NPS was anticonvulsant. NPS also significantly increased generalized tonic–clonic threshold; while PS, although at lower threshold levels, did not present statistical significance. Thalamus stimulation did not affect forelimb clonus threshold and showed similar anticonvulsant profiles for both PS and NPS on generalized tonic–clonic threshold. In summary, the anatomical target is a determinant factor on whether temporally-coded ES differentially modulates seizure outcome.