Administration of branched‐chain amino acids increases the susceptibility to lipopolysaccharide‐induced inflammation in young Wistar rats

Abstract

Maple Syrup Urine Disease (MSUD) is an inborn error of the metabolism caused by defects in the branched a‐ketoacid dehydrogenase complex (BCKDC), leading to the accumulation of branched chain amino acids (BCAAs) (leucine, isoleucine and valine). Patients with MSUD present a series of neurological dysfunction. Recent studies have been associated the brain damage in the MSUD with inflammation and immune system activation. MSUD patients die within a few months of life due to recurrent metabolic crises and neurologic deterioration, often precipitated by infection or other stresses. In this regard, our previous results showed that the inflammatory process, induced by lipopolysaccharide (LPS), associated with high levels of BCAAs causes blood‐brain barrier (BBB) breakdown due to hyperactivation of MMPs. Thus, we hypothesize that the synergistic action between high concentrations of BCAAs (H‐BCAAs) and LPS on BBB permeability and hyperactivation of MMPs could be through an increase in the production of cytokines and RAGE protein levels. We observed that high levels of BCAA in infant rats are related to increased brain inflammation induced by LPS administration. In addition, BCAA exposure led to an increase on brain RAGE expression of young rats. The brain inflammation was characterized by enhanced levels of interleukin 1 β (IL‐1β), interleukin 6 (IL‐6), tumor necrosis factor‐α (TNF‐α) and Interferon‐ γ (IFN‐γ), and decreased content of interleukin‐10 (IL‐10). Therefore, MSUD is associated with a more intense neuroinflammation induced by LPS infection.

The Amino Acid-mTORC1 Pathway Mediates APEC TW-XM-Induced Inflammation in bEnd.3 Cells

“…Due to amino acids' involvement in the interaction between bacteria and host, Ser and Glu have always been the focus of research [17,41]. Ser and Glu have increasingly been involved in promoting central nervous system diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis [42][43][44][45][46][47].…”

"Ultrastructure of the Mitochondrial Membrane and Respiratory Ensembles"

“…the asymmetric organization of individual enzymes or entire ensembles in the membrane. The vector properties of respiratory ensembles [52] formed the basis of Mitchell's concept of the anisotropic localization of respiratory enzymes in the mitochondrial membrane and the vector action of membrane enzymes, which is opposed to the scalar (direction-independent) action of soluble enzymes. Many, if not all, enzymatic reactions are asymmetric with respect to the active center of the enzyme, but the vector characteristic cannot be expressed as movement in one direction unless some barrier restricts the rotational and vibrational diffusion of enzyme molecules [53].…”

Intravenous branched-chain amino-acid-free solution for the treatment of metabolic decompensation episodes in Spanish pediatric patients with maple syrup urine disease

“…The elevated blood level of BCAAs impairs cerebral uptake of large neutral amino acids thought the blood-brain barrier, decreasing their concentration in brain ( 1 ). In the pathogenesis of neurological damage in MSUD, an increasingly role of the neurotoxic properties of the BCAA and BCKA is recognized ( 1 ), disturbing brain bioenergetics and redox homeostasis ( 2 ), inducing neuroinflammation ( 3 ) and contributing to a reduction of brain glutamate, glutamine, and gamma-aminobutyrate concentrations ( 4 ). Leucine and KIC are considered the main neurotoxins in this disorder.…”