Coadministration of Branched-Chain Amino Acids and Lipopolysaccharide Causes Matrix Metalloproteinase Activation and Blood–Brain Barrier Breakdown

Abstract

Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by a severe deficiency in the activity of the branched-chain α-keto acid dehydrogenase complex, leading to accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine. Infections have a significant role in precipitating acute metabolic decompensation in patients with MSUD; however, the mechanisms underlying the neurotoxicity in this disorder are poorly understood. In this study, we subjected rats to the coadministration of lipopolysaccharide (LPS), which is a major component of gram-negative bacteria cell walls, and high concentrations of BCAA (H-BCAA) to determine their effects on the permeability of the blood-brain barrier (BBB) and on the levels of matrix metalloproteinases (MMP-2 and MMP-9). Our results demonstrated that the coadministration of H-BCAA and LPS causes breakdown of the BBB and increases the levels of MMP-2 and MMP-9 in the hippocampus of these rats. On the other hand, examination of the cerebral cortex of the 10- and 30-day-old rats revealed a significant difference in Evan's Blue content after coadministration of H-BCAA and LPS, as MMP-9 levels only increased in the cerebral cortex of the 10-day-old rats. In conclusion, these results suggest that the inflammatory process associated with high levels of BCAA causes BBB breakdown. Thus, we suggest that BBB breakdown is relevant to the perpetuation of brain inflammation and may be related to the brain dysfunction observed in MSUD patients.

The preterm cervix reveals a transcriptomic signature in the presence of premature prelabor rupture of membranes

“…Consistent with our hypothesis, MMP-2 and MMP-9 increase in response to exogenous BCAAs in the hippocampus of rats 60 and bone Report of the GO terms containing the features PRAM1, FGD3, CEACAM3, and NDRG2 among other genes that mapped to significant features at adjusted value of P < .01 (continued) Original Research OBSTETRICS ajog.org marrowederived cells have been also shown to secrete MMPs. [61][62][63] A similar mechanism for cervical remodeling in TL and PPROM involving bone marrowerecruited cells can be further evidenced by KEGG analysis, in which the osteoclast differentiation pathway is enriched not only in PPROM-PTL comparison (Table 2) but also in TL-PTL (Supplemental Table 3).…”

Effects of Long Term Consumption of Animal Proteins in the High Calorie Diet

“…Thus, the coadministration of branched chain amino acids and LPS not only induces breakdown of the BBB, but also increases the levels of MMP-2 and MMP-9 in the hippocampus of these rats. These studies support the view that MMP-mediated neuroinfl ammation is closely associated with BBB breakdown (Scaini et al 2014 ). Among branched chain amino acids, leucine is the most effective amino acid in inducing protein synthesis by stimulating the intracellular energy-sensing mammalian target of mTORC1 pathway (Proud 2007 ;Laplante and Sabatini 2012 ;Andre and Cota 2012 ).…”

Lipopolysaccharide-Induced Middle Ear Inflammation Disrupts the cochlear Intra-Strial Fluid–Blood Barrier through Down-Regulation of Tight Junction Proteins

“…For example, LPS-induced blood-brain-barrier (BBB) damage is associated with pro- and anti-inflammatory cytokine expression of interleukin-1 (IL-1), IL-2, IL8, toll-like receptor 4 (TLR4), nuclear transcription factor kappa-B (NF-κB), p50, and tumor necrosis factor alpha (TNFα). These cytokines activate matrix metalloproteinases, alter transporter function, and markedly affect vascular permeability [ 5 , 14 , 15 ].…”