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

• Published in: European journal of pharmacology 2025-01, Vol.987, p.177186, Article 177186
• Main Authors: Ribeiro, Rafael Teixeira, Marcuzzo, Manuela Bianchin, Carvalho, Andrey Vinícios Soares, Palavro, Rafael, Castro, Ediandra Tissot, Pinheiro, Camila Vieira, Bobermin, Larissa Daniele, Amaral, Alexandre Umpierrez, Leipnitz, Guilhian, Netto, Carlos Alexandre, Wajner, Moacir
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes - drug effects; Astrocytes - metabolism; Astrocytes - pathology; Bezafibrate; Bezafibrate - pharmacology; Brain - drug effects; Brain - metabolism; Brain - pathology; Cell Death - drug effects; D-2-hydroxyglutaric acid; D-2-hydroxyglutaric aciduria; Energy Metabolism - drug effects; Glial reactivity; Glutarates - metabolism; Glutarates - pharmacology; Homeostasis - drug effects; Male; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial metabolism; Neuroinflammatory Diseases - drug therapy; Neuroinflammatory Diseases - metabolism; Neuroinflammatory Diseases - pathology; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Oxidation-Reduction - drug effects; Oxidative Stress - drug effects; Peroxisome Proliferator-Activated Receptors - agonists; Peroxisome Proliferator-Activated Receptors - metabolism; Rats; Rats, Wistar; Redox homeostasis
• ISSN: 0014-2999; 1879-0712; 1879-0712
• DOI: 10.1016/j.ejphar.2024.177186

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. Intracerebroventricular (icv) administration of D-2-hydroxyglutaric acid (D2HG) impairs mitochondrial bioenergetics, redox homeostasis, and induces glial reactivity, neuroinflammation and neuronal damage: neuroprotective role of the pan-PPAR agonist bezafibrate (BEZ) against D2HG-induced neurotoxicity. [Display omitted] •D-2-hydroxyglutaric acid (D2HG) brain accumulation in D-2-hydroxyglutaric aciduria.•D2HG disturbs redox and energy homeostasis in rat brain.•D2HG causes neuronal loss, astrogliosis, microglial activation and neuroinflammation.•Bezafib