In vivo intracerebral administration of L-2-hydroxyglutaric acid provokes oxidative stress and histopathological alterations in striatum and cerebellum of adolescent rats

Rosa, Marcelo Prado Amaral; Ribeiro, César Augusto João; Seminotti, Bianca; Ribeiro, Rafael Teixeira; Amaral, Alexandre Umpierrez; Coelho, Daniella de Moura; Oliveira, Francine Hehn de; Leipnitz, Guilhian

doi:10.1016/j.freeradbiomed.2015.02.008

Cited by 25 publications

(10 citation statements)

References 43 publications

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“…Increased levels of L2HG in the brain are associated with oxidative stress through impaired antioxidant defences and increased reactive oxygen species generation, resulting in reactive astrogliosis and a decreased neuronal population (Latini and others 2003, da Rosa and others 2015). In developing rats, cerebellar mitochondrial creatine kinase activity is inhibited by L2HG, potentially resulting in impaired ATP utilisation/production in this region of the brain (da Silva and others 2003).…”

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confidence: 99%

“…L‐2‐Hydroxyglutaric aciduria (L‐2‐HGA) is an uncommon metabolic disorder characterised by accumulation of L‐2‐hydroxyglutaric acid (L2HG) within various tissues, including urine, cerebrospinal fluid and plasma (Duran and others 1980, Abramson and others 2003). Increased levels of L2HG in the brain are associated with oxidative stress through impaired antioxidant defences and increased reactive oxygen species generation, resulting in reactive astrogliosis and a decreased neuronal population (Latini and others 2003, da Rosa and others 2015). In developing rats, cerebellar mitochondrial creatine kinase activity is inhibited by L2HG, potentially resulting in impaired ATP utilisation/production in this region of the brain (da Silva and others 2003).…”

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confidence: 99%

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Clinical features and disease progression of L‐2‐hydroxyglutaric aciduria in 27 Staffordshire bull terriers

Shea

Risio

Carruthers³

et al. 2016

Veterinary Record

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To describe the development of clinical signs (CS) and outcome of L-2-hydroxyglutaric aciduria (L-2-HGA), owners of 119 Staffordshire bull terriers positive for the known L-2-hydroxyglutarate dehydrogenase autosomal-recessive mutations were requested to complete a questionnaire regarding their pet's CS. Questionnaires were returned for 27 dogs, all with neurological abnormalities-not all questions were answered in all cases. The mean age of CS onset was 12 months (range 2.5-60). Gait dysfunction was reported in 26/26 dogs, with stiffness of all four limbs the most common (24/26) and earliest recognised abnormality. Kyphosis (19/26), body and/or head tremors (19/26) and hypermetria (15/26) were frequent. Behavioural changes were present in 24/27 dogs; most commonly staring into space (21/24), signs of dementia (17/24) and loss of training (15/24). Eighteen dogs demonstrated paroxysmal seizure-like/dyskinetic episodes. Nineteen (70 per cent) dogs were alive at a mean survival time of 76.6 months (12-170) after onset of CS. L-2-HGA was the cause of euthanasia in six dogs. Euthanasia occurred at a mean survival time of 44 months (8.5-93) after onset of CS, with 2/8 dogs euthanased within 12 months. L-2-HGA is considered a progressive neurological disease; however, CS can be successfully managed with affected dogs potentially living a normal lifespan.

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confidence: 99%

mentioning

confidence: 99%

Clinical features and disease progression of L‐2‐hydroxyglutaric aciduria in 27 Staffordshire bull terriers

Shea

Risio

Carruthers³

et al. 2016

Veterinary Record

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“…alcohol dehydrogenase, iron containing 1 ( ADHFE1 ) overexpression or D-2-hydroxyglutarate dehydrogenase ( D2HGDH ) downregulation) [41]. Intracerebral 2HG injection in rats (both D-2HG and L-2HG) has resulted in increased oxidative damage on lipids, proteins, and DNA, paralleled by the suppression of antioxidative defense mechanisms [58, 59]. As mentioned above, both D-2HG and L-2HG have been shown to inhibit αKG-dependent dioxygenases, including prolyl hydroxylase domain (PHD) enzymes (which usually help degrade HIF1α), histone demethylases, and the ten-eleven translocation (TET) enzyme family [60].…”

Section: The Interplay Between 2hg Myc and Glutamine Catabolismmentioning

confidence: 99%

On metabolic reprogramming and tumor biology: A comprehensive survey of metabolism in breast cancer

et al. 2016

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Altered metabolism in tumor cells has been a focus of cancer research for as long as a century but has remained controversial and vague due to an inhomogeneous overall picture. Accumulating genomic, metabolomic, and lastly panomic data as well as bioenergetics studies of the past few years enable a more comprehensive, systems-biologic approach promoting deeper insight into tumor biology and challenging hitherto existing models of cancer bioenergetics. Presenting a compendium on breast cancer-specific metabolome analyses performed thus far, we review and compile currently known aspects of breast cancer biology into a comprehensive network, elucidating previously dissonant issues of cancer metabolism. As such, some of the aspects critically discussed in this review include the dynamic interplay or metabolic coupling between cancer (stem) cells and cancer-associated fibroblasts, the intratumoral and intertumoral heterogeneity and plasticity of cancer cell metabolism, the existence of distinct metabolic tumor compartments in need of separate yet simultaneous therapeutic targeting, the reliance of cancer cells on oxidative metabolism and mitochondrial power, and the role of pro-inflammatory, pro-tumorigenic stromal conditioning. Comprising complex breast cancer signaling networks as well as combined metabolomic and genomic data, we address metabolic consequences of mutations in tumor suppressor genes and evaluate their contribution to breast cancer predisposition in a germline setting, reasoning for distinct personalized preventive and therapeutic measures. The review closes with a discussion on central root mechanisms of tumor cell metabolism and rate-limiting steps thereof, introducing essential strategies for therapeutic targeting.

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“…No cerebelo foram encontradas vacuolização e infiltração linfocítica e macrofágica. Esses achados, em que o L-2-HG provoca dano in vivo cerebelar e estriatal, podem estar relacionados à indução de estresse oxidativo 40 . Relatos de casos na literatura mostraram os efeitos tóxicos do L-2-HG no cérebro.…”

Section: Toxicidade Do áCido L-2-hidroxiglutáricounclassified

“…Além disso, houve aumento de ERO, que foi determinado por oxidação de DCFH e produção de H 2 O 2 , além do aumento de MDA, que reflete dano lipídico. Cabe salientar que essas alterações na homeostase redox causadas pelo L-2-HGA foram seletivas, tendo em vista que foi utilizado um análogo estruturalmente similar (ácido L-2-hidroxi-3-metil-valérico), o qual não alterou nenhum desses parâmetros 40 . Além disso, esses resultados em modelo animal estão de acordo com um estudo realizado em pacientes portadores de L-2-HGA, no qual foram medidos alguns parâmetros em plasma.…”

Section: áCido L-2-hidroxiglutárico E O Envolvimento No Estresse Oxidunclassified

Acidúrias D-2-hidroxiglutárica e L-2-hidroxiglutárica: uma revisão da literatura

Rodrigues¹,

Vargas²

2016

cbr

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RESUMOAs acidúrias D-2-hidroxiglutárica (D-2-HGA) e L-2-hidroxiglutárica (L-2-HGA) são raras doenças neurometabólicas que constituem um grupo de erros inatos do metabolismo. Essas doenças são causadas pela deficiência das atividades enzimáticas da D-2-hidroxiglutarato desidrogenase na D-2-HGA do tipo I ou isocitrato desidrogenase na D-2-HGA do tipo II, e da L-2-hidroxiglutarato desidrogenase na L-2-HGA. Os principais achados clínicos nos pacientes caracterizam-se por sintomas neurológicos, como convulsões, coma e atrofia cerebral. Também ocorrem lesões cerebrais nos gânglios da base (D-2-HGA, L-2-HGA) e cerebelo (L-2-HGA). Bioquimicamente, essas acidúrias caracterizam-se por acúmulo em tecidos e elevada excreção urinária dos ácidos D-2-hidroxiglutárico (na D-2-HGA) e L-2-hidroxiglutárico (na L-2-HGA). Ainda, uma terceira variante bioquímica da acidúria, a D,L-2-hidroxiglutárica (D,L-2-HGA), é caracterizada por excreção aumentada de ambos enantiômeros do ácido 2-hidroxiglutárico. Em modelo animal, estudos de toxicidade dos ácidos D e L-2-hidroxiglutárico mostraram injúria cerebral, mas não foi elucidado o mecanismo exato causador do dano. Além disso, altos níveis dos ácidos D e L-2-hidroxiglutárico foram encontrados em tumores cerebrais. No entanto, a relação entre a acidúria e o câncer ainda precisa ser esclarecida. Tendo em vista a gravidade da doença, este trabalho teve como objetivo fazer uma revisão bibliográfica acerca do tema, enfatizando as consequências do metabolismo, principalmente para o tecido cerebral, bem como apontar possíveis abordagens terapêuticas. Palavras-chave: ácido D-2-hidroxiglutárico; acidúria D-2-hidroxiglutárica; dano cerebral; ácido L-2-hidroxiglutárico; acidúria L-2-hidroxiglutárica; tumor ABSTRACTThe D-2-hydroxyglutaric (D-2-HGA) and L-2-hydroxyglutaric acidurias (L-2-HGA) are rare neurometabolic diseases that form a group of inborn errors of metabolism. They are caused by a deficiency on the enzyme activities of D-2-hydroxyglutarate dehydrogenase in D-2-HGA type I or isocitrate dehydrogenase in D-2-HGA type II, and L-2-hydroxyglutarate dehydrogenase in L-2-HGA. The main clinical findings in affected patients are related to neurological symptoms, such as convulsions, coma and brain atrophy. Brain injuries also occur in the basal ganglia (D-2-HGA, L-2-HGA) and cerebellum (L-2-HGA). These acidurias are biochemically characterized by the accumulation in tissues and increased urinary excretion of D-2-hydroxyglutaric acid (in D-2-HGA) and L-2-hydroxyglutaric acid (in L-2-HGA). Still, a third biochemical variant of aciduria, called D,L-2-hydroxyglutaric (D,L-2-HGA), is characterized by increased excretion of both enantiomers of 2-hydroxyglutaric acid. In an animal model, toxicity studies on D-and L-2-hydroxyglutaric acids showed brain injury, but the exact mechanism of brain damage was not elucidated. Furthermore, high levels of D-and L-2-hydroxyglutaric acids were found in brain tumors. However, the relationship between cancer and aciduria still needs to be clarified. In view of the seve...

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In vivo intracerebral administration of L-2-hydroxyglutaric acid provokes oxidative stress and histopathological alterations in striatum and cerebellum of adolescent rats

Cited by 25 publications

References 43 publications

Clinical features and disease progression of L‐2‐hydroxyglutaric aciduria in 27 Staffordshire bull terriers

Clinical features and disease progression of L‐2‐hydroxyglutaric aciduria in 27 Staffordshire bull terriers

On metabolic reprogramming and tumor biology: A comprehensive survey of metabolism in breast cancer

Acidúrias D-2-hidroxiglutárica e L-2-hidroxiglutárica: uma revisão da literatura

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