• RibeiroRafael TeixeiraRTPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil., Bianca Seminotti, Ângela Zanatta, Francine Hehn de Oliveira, Alexandre Umpierrez Amaral, Guilhian Leipnitz, and Moacir Wajner.
• Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
• Neuroscience. 2021 Sep 1; 471: 115-132.

AbstractD-2-hydroxyglutaric acid (D-2-HG) accumulates and is the biochemical hallmark of D-2-hydroxyglutaric acidurias (D-2-HGA) types I and II, which comprehend two inherited neurometabolic diseases with severe cerebral abnormalities. Since the pathogenesis of these diseases is poorly established, we tested whether D-2-HG could be neurotoxic to neonatal rats. D-2-HG intracerebroventricular administration caused marked vacuolation in cerebral cortex and striatum. In addition, glial fibrillary acidic protein (GFAP), S-100 calcium binding protein B (S100B) and ionized calcium-binding adapter molecule 1 (Iba-1) staining was increased in both brain structures, suggesting glial reactivity and microglial activation. D-2-HG also provoked a reduction of NeuN-positive cells in cerebral cortex, signaling neuronal death. Considering that disturbances in redox homeostasis and energy metabolism may be involved in neuronal damage and glial reactivity, we assessed whether D-2-HG could induce oxidative stress and bioenergetics impairment. D-2-HG treatment significantly augmented reactive oxygen and nitrogen species generation, provoked lipid peroxidation and protein oxidative damage, diminished glutathione concentrations and augmented superoxide dismutase and catalase activities in cerebral cortex. Increased reactive oxygen species generation, lipoperoxidation and protein oxidation were also found in striatum. Furthermore, the antagonist of NMDA glutamate receptor MK-801 and the antioxidant melatonin were able to prevent most of D-2-HG-induced pro-oxidant effects, implying the participation of these receptors in D-2-HG-elicited oxidative damage. Our results also demonstrated that D-2-HG markedly reduced the respiratory chain complex IV and creatine kinase activities. It is presumed that these deleterious pathomechanisms caused by D-2-HGA may be involved in the brain abnormalities characteristic of early-infantile onset D-2-HGA.Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.

11 keywords...

hide…