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. 2023 Jun;38(5):1573-1579.
doi: 10.1007/s11011-023-01193-8. Epub 2023 Mar 10.

Acute effects of intracerebroventricular administration of α-ketoisocaproic acid in young rats on inflammatory parameters

Franciele Rabelo  1 , Isabela da S Lemos  1 , Camila P Dal Toé  1 , Débora D Casagrande  1 , Maria Luisa S Freitas  1 , Micaela R Quadra  1 , Igor R Lima  2 , Jaqueline S Generoso  3 , Monique Michels  2 , Paulo C L Silveira  2 , Felipe Dal Pizzol  2 , Emilio Luiz Streck  4
Affiliations

Acute effects of intracerebroventricular administration of α-ketoisocaproic acid in young rats on inflammatory parameters

Franciele Rabelo et al. Metab Brain Dis. 2023 Jun.

Abstract

Maple Syrup Urine Disease (MSUD) is an autosomal recessive inborn error of metabolism (IEM), responsible for the accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, in addition to their α-keto acids α-ketoisocaproic acid (KIC), α-keto-β-methylvaleric acid (KMV), and α-ketoisovaleric acid (KIV) in the plasma and urine of patients. This process occurs due to a partial or total blockage of the dehydrogenase enzyme activity of branched-chain α-keto acids. Oxidative stress and inflammation are conditions commonly observed on IEM, and the inflammatory response may play an essential role in the pathophysiology of MSUD. We aimed to investigate the acute effect of intracerebroventricular (ICV) administration of KIC on inflammatory parameters in young Wistar rats. For this, sixteen 30-day-old male Wistar rats receive ICV microinjection with 8 µmol KIC. Sixty minutes later, the animals were euthanized, and the cerebral cortex, hippocampus, and striatum structures were collected to assess the levels of pro-inflammatory cytokines (INF-γ; TNF-α, IL-1β). The acute ICV administration of KIC increased INF-γ levels in the cerebral cortex and reduced the levels of INF-γ and TNF-α in the hippocampus. There was no difference in IL-1β levels. KIC was related to changes in the levels of pro-inflammatory cytokines in the brain of rats. However, the inflammatory mechanisms involved in MSUD are poorly understood. Thus, studies that aim to unravel the neuroinflammation in this pathology are essential to understand the pathophysiology of this IEM.

Keywords: Alpha-ketoisocaproic acid; Inflammation; Maple syrup urine disease; Neuroinflammation.

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