1. Protective effects of the PPAR agonist bezafibrate against disruption of redox and energy homeostasis, neuronal death, astroglial reactivity, and neuroinflammation induced in vivo by D-2-hydroxyglutaric acid in rat brain.
- Author
-
Ribeiro RT, Marcuzzo MB, Carvalho AVS, Palavro R, Castro ET, Pinheiro CV, Bobermin LD, Amaral AU, Leipnitz G, Netto CA, and Wajner M
- Subjects
- Animals, Rats, Male, Brain drug effects, Brain metabolism, Brain pathology, Rats, Wistar, Peroxisome Proliferator-Activated Receptors agonists, Peroxisome Proliferator-Activated Receptors metabolism, Mitochondria drug effects, Mitochondria metabolism, Cell Death drug effects, Neuroinflammatory Diseases drug therapy, Neuroinflammatory Diseases metabolism, Neuroinflammatory Diseases pathology, Neuroprotective Agents pharmacology, Neuroprotective Agents therapeutic use, Oxidative Stress drug effects, Bezafibrate pharmacology, Oxidation-Reduction drug effects, Astrocytes drug effects, Astrocytes metabolism, Astrocytes pathology, Homeostasis drug effects, Neurons drug effects, Neurons metabolism, Neurons pathology, Glutarates pharmacology, Glutarates metabolism, Energy Metabolism drug effects
- Abstract
The biochemical hallmark of D-2-hydroxyglutaric aciduria is brain accumulation of D-2-hydroxyglutaric acid (D2HG). Patients present predominantly neurological manifestations, whose pathogenesis is still unknown. Thus, we examined the impact of elevated brain levels of D2HG, induced by intracerebral injection of this metabolite in juvenile rats, on redox and mitochondrial homeostasis and histochemical landmarks in the cerebral cortex. D2HG administration disrupted redox homeostasis by increasing the levels of reactive oxygen species and lipid peroxidation and the activities of superoxide dismutase, glutathione peroxidase, and glutathione reductase and decreasing reduced glutathione levels. Furthermore, the complex IV and mitochondrial creatine kinase activities, as well as the protein contents of voltage-dependent anion channel 1, translocase of outer mitochondrial membrane 20, and peroxisome proliferator-activated receptor-γ coactivator 1-α, were diminished by D2HG, indicating bioenergetics dysfunction and disrupted mitochondrial biogenesis. D2HG also reduced neuronal nuclear protein content and augmented cleaved caspase-3, S100 calcium-binding protein B, glial fibrillary acidic protein, and ionized calcium-binding adaptor molecule 1, indicating neuronal loss, apoptosis, astrogliosis, and microglial activation, respectively. The tumor necrosis factor alpha expression was also significantly augmented, reflecting an increased inflammatory response. We also evaluated whether bezafibrate (BEZ) pretreatment could prevent the alterations induced by D2HG. BEZ normalized most of the D2HG-induced deleterious effects. Therefore, bioenergetics and redox status disruption caused by D2HG, associated with neuronal death, glial reactivity, and increased inflammatory response, may potentially represent pathomechanisms of brain damage in D-2-HGA. Finally, it is proposed that BEZ may be potentially used as therapy for D-2-HGA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.) more...
- Published
- 2025
- Full Text
- View/download PDF