No abstract

Acute leucine intoxication and neurologic deterioration can develop rapidly at any age as a result of net protein degradation precipitated by infection or psychological stress in patients with maple syrup urine disease (MSUD). Here, we investigated the effects of acute and chronic Hyper-BCAA (H-BCAA) administration on pro- and anti-inflammatory cytokines in the brains of rats. For acute administration, Wistar rats (10 and 30 days) received three injections of BCAA pool (15.8 μL/g at 1-h intervals) or saline, subcutaneously. For chronic administration, Wistar rats (7 days) received of BCAA pool or saline twice a day for 21 days, subcutaneously. Our results showed that acute administration of H-BCAA increased IL-1β (∼ 78%; p ≤ 0.009) and TNF-α (∼ 155%; p ≤ 0.026) levels in the cerebral cortex but not in the hippocampus of infant rats. Moreover, IL-6 levels were increased in the hippocampus (∼ 135%; p ≤ 0.009) and cerebral cortex (∼ 417%; p ≤ 0.008), whereas IL-10 levels were decreased only in the hippocampus (∼ 42%; p ≤ 0.009). However, repeated administration of H-BCAA decreased IL-1β (∼ 59%; p ≤ 0.047), IL-6 (∼ 70%; p ≤ 0.009) and IFN-γ (∼ 70%; p ≤ 0.008) levels in the cerebral cortex, whereas the IL-6 (∼ 67%; p ≤ 0.009), IL-10 (∼ 58%; p ≤ 0.01) and IFN-γ (∼ 67%; p ≤ 0.009) levels were decreased in the hippocampus. These findings suggest that a better understanding of the inflammatory response in MSUD patients may be useful to develop therapeutic strategies to modulate the hyperinflammatory/hypoinflammatory axis.

Maple syrup urine disease (MSUD) is a rare metabolic disorder associated with acute and chronic brain dysfunction. This condition has been shown to lead to macroscopic cerebral alterations that are visible on imaging studies. Cerebral oedema is widely considered to be detrimental for MSUD patients; however, the mechanisms involved are still poorly understood. Therefore, we investigated whether acute administration of branched-chain amino acids (BCAA) causes cerebral oedema, modifies the Na(+),K(+)-ATPase activity, affects the permeability of the blood-brain barrier (BBB) and alters the levels of cytokines in the hippocampus and cerebral cortex of 10-day-old rats. Additionally, we investigated the influence of concomitant administration of dexamethasone on the alterations caused by BCAA. Our results showed that the animals submitted to the model of MSUD exhibited an increase in the brain water content, both in the cerebral cortex and in the hippocampus. By investigating the mechanism of cerebral oedema, we discovered an association between H-BCAA and the Na(+),K(+)-ATPase activity and the permeability of the BBB to small molecules. Moreover, the H-BCAA administration increases Il-1β, IL-6 and TNF-α levels in the hippocampus and cerebral cortex, whereas IL-10 levels were decreased in the hippocampus. Interestingly, we showed that the administration of dexamethasone successfully reduced cerebral oedema, preventing the inhibition of Na(+),K(+)-ATPase activity, BBB breakdown and the increase in the cytokines levels. In conclusion, these findings suggest that dexamethasone can improve the acute cerebral oedema and brain injury associated with high levels of BCAA, either through a direct effect on brain capillary Na(+),K(+)-ATPase or through a generalized effect on the permeability of the BBB to all compounds.