Preliminary results of PBA-loaded nanoparticles development and the effect on oxidative stress and neuroinflammation in rats submitted to a chemically induced chronic model of MSUD

• Published in: Metabolic brain disease 2021-06, Vol.36 (5), p.1015-1027
• Main Authors: Mescka, Caroline Paula, de Moura Coelho, Daniella, Sitta, Angela, Catarino, Felipe, Donida, Bruna, Rosa, Andrea Pereira, Gonzalez, Esteban Alberto, Pinheiro, Camila Vieira, Poletto, Fernanda, Baldo, Guilherme, Dutra-Filho, Carlos Severo, Vargas, Carmen Regla
• Format: Article
• Language: English
• Subjects: Amino acids; Amino Acids, Branched-Chain - blood; Animals; Brain damage; Brain injury; Caspase-3; Catalase; Catalase - metabolism; Cell death; Central nervous system; Cerebral cortex; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Chain branching; Damage prevention; Genetic disorders; Glial fibrillary acidic protein; Glutathione; Glutathione peroxidase; Glutathione Peroxidase - metabolism; Glutathione reductase; Inflammation; Intellectual disabilities; Isoleucine; Leucine; Lipid membranes; Lipids; Low protein diet; Maple syrup; Maple syrup urine disease; Maple Syrup Urine Disease - blood; Maple Syrup Urine Disease - chemically induced; Maple Syrup Urine Disease - metabolism; Metabolites; Nanoparticles; Nanoparticles - administration & dosage; Nutrient deficiency; Oxidative stress; Oxidative Stress - drug effects; Peroxidase; Phenylbutyrates - administration & dosage; Phenylbutyric acid; Proteins; Rats; Rats, Wistar; Reductases; Signs and symptoms; Superoxide dismutase; Superoxide Dismutase - metabolism; Syrup; Valine
• ISSN: 0885-7490; 1573-7365; 1573-7365
• DOI: 10.1007/s11011-021-00686-8

Maple syrup urine disease (MSUD) is a genetic disorder that leads the accumulation of branched-chain amino acids (BCAA) leucine (Leu), isoleucine, valine and metabolites. The symptomatology includes psychomotor delay and mental retardation. MSUD therapy comprises a lifelong protein strict diet with low BCAA levels and is well established that high concentrations of Leu and/or its ketoacid are associated with neurological symptoms. Recently, it was demonstrated that the phenylbutyrate (PBA) have the ability to decrease BCAA concentrations. This work aimed the development of lipid-based nanoparticles loaded with PBA, capable of targeting to the central nervous system in order to verify its action mechanisms on oxidative stress and cell death in brain of rats subjected to a MSUD chronic model. PBA-loaded nanoparticles treatment was effective in significantly decreasing BCAA concentration in plasma and Leu in the cerebral cortex of MSUD animals. Furthermore, PBA modulate the activity of catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase enzymes, as well as preventing the oxidative damage to lipid membranes and proteins. PBA was also able to decrease the glial fibrillary acidic protein concentrations and partially decreased the reactive species production and caspase-3 activity in MSUD rats. Taken together, the data indicate that the PBA-loaded nanoparticles could be an efficient adjuvant in the MSUD therapy, protecting against oxidative brain damage and neuroinflammation.