Ribeiro Rafael Teixeira, Carvalho Andrey Vinícios Soares, Palavro Rafael, Durán-Carabali Luz Elena, Zemniaçak Ângela Beatris, Amaral Alexandre Umpierrez, Netto Carlos Alexandre, Wajner Moacir
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.
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Rua Ramiro Barcelos, Porto Alegre, RS, 260090035-003, Brazil.
Neurotox Res. 2023 Apr;41(2):119-140. doi: 10.1007/s12640-022-00625-0. Epub 2022 Dec 29.
L-2-Hydroxyglutaric aciduria (L-2-HGA) is an inherited neurometabolic disorder caused by deficient activity of L-2-hydroxyglutarate dehydrogenase. L-2-Hydroxyglutaric acid (L-2-HG) accumulation in the brain and biological fluids is the biochemical hallmark of this disease. Patients present exclusively neurological symptoms and brain abnormalities, particularly in the cerebral cortex, basal ganglia, and cerebellum. Since the pathogenesis of this disorder is still poorly established, we investigated the short-lived effects of an intracerebroventricular injection of L-2-HG to neonatal rats on redox homeostasis in the cerebellum, which is mostly affected in this disorder. We also determined immunohistochemical landmarks of neuronal viability (NeuN), astrogliosis (S100B and GFAP), microglia activation (Iba1), and myelination (MBP and CNPase) in the cerebral cortex and striatum following L-2-HG administration. Finally, the neuromotor development and cognitive abilities were examined. L-2-HG elicited oxidative stress in the cerebellum 6 h after its injection, which was verified by increased reactive oxygen species production, lipid oxidative damage, and altered antioxidant defenses (decreased concentrations of reduced glutathione and increased glutathione peroxidase and superoxide dismutase activities). L-2-HG also decreased the content of NeuN, MBP, and CNPase, and increased S100B, GFAP, and Iba1 in the cerebral cortex and striatum at postnatal days 15 and 75, implying long-standing neuronal loss, demyelination, astrocyte reactivity, and increased inflammatory response, respectively. Finally, L-2-HG administration caused a delay in neuromotor development and a deficit of cognition in adult animals. Importantly, the antioxidant melatonin prevented L-2-HG-induced deleterious neurochemical, immunohistochemical, and behavioral effects, indicating that oxidative stress may be central to the pathogenesis of brain damage in L-2-HGA.
L-2-羟基戊二酸尿症（L-2-HGA）是一种遗传性神经代谢紊乱疾病，由L-2-羟基戊二酸脱氢酶活性不足引起。L-2-羟基戊二酸（L-2-HG）在大脑和生物体液中的蓄积是该疾病的生化标志。患者仅表现出神经症状和脑部异常，尤其是在大脑皮层、基底神经节和小脑。由于这种疾病的发病机制仍未完全明确，我们研究了向新生大鼠脑室内注射L-2-HG对小脑氧化还原稳态的短期影响，小脑在这种疾病中受影响最为严重。我们还确定了在给予L-2-HG后，大脑皮层和纹状体中神经元活力（NeuN）、星形胶质细胞增生（S100B和GFAP）、小胶质细胞活化（Iba1）和髓鞘形成（MBP和CNPase）的免疫组化标志物。最后，检测了神经运动发育和认知能力。注射L-2-HG后6小时，小脑出现氧化应激，这通过活性氧生成增加、脂质氧化损伤以及抗氧化防御改变（还原型谷胱甘肽浓度降低，谷胱甘肽过氧化物酶和超氧化物歧化酶活性增加）得到证实。在出生后第15天和第75天，L-2-HG还降低了大脑皮层和纹状体中NeuN、MBP和CNPase的含量，并增加了S100B、GFAP和Iba1的含量，分别意味着长期的神经元丢失、脱髓鞘、星形胶质细胞反应性增加和炎症反应增强。最后，给予L-2-HG导致成年动物神经运动发育延迟和认知缺陷。重要的是，抗氧化剂褪黑素可预防L-2-HG诱导的有害神经化学、免疫组化和行为学效应，表明氧化应激可能是L-2-HGA脑损伤发病机制的核心。
