Glutaric Acid Neurotoxicity: Mechanisms and Actions

Amaral, Alexandre Umpierrez; Ferreira, Gustavo C.; Seminotti, Bianca; Leipnitz, Guilhian; Wajner, Moaçir

doi:10.1007/978-3-030-71519-9_186-1

Cited by 3 publications

(2 citation statements)

References 86 publications

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“…23 Glutaric acid is known to be neurotoxic, albeit in the context of glutaric aciduria type I with a more pronounced accumulation of this metabolite. 24 Conversely, glycolic acid has been described as neuroprotective, preventing ischemiainduced neuronal death in in vitro and in vivo models of stroke. 25 Despite the less distinct increases, all three metabolites could be of interest for our understanding of SSADHD pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

“…Glutaric acid and glycolic acid were so far only described as urine biomarkers for SSADHD 23 . Glutaric acid is known to be neurotoxic, albeit in the context of glutaric aciduria type I with a more pronounced accumulation of this metabolite 24 . Conversely, glycolic acid has been described as neuroprotective, preventing ischemia‐induced neuronal death in in vitro and in vivo models of stroke 25 .…”

Section: Discussionmentioning

confidence: 99%

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Succinic semialdehyde dehydrogenase deficiency in mice and in humans: An untargeted metabolomics perspective

Peters,

Engelke,

de Boer

et al. 2023

J of Inher Metab Disea

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Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare neurometabolic disorder caused by disruption of the gamma‐aminobutyric acid (GABA) pathway. A more detailed understanding of its pathophysiology, beyond the accumulation of GABA and gamma‐hydroxybutyric acid (GHB), will increase our understanding of the disease and may support novel therapy development. To this end, we compared biochemical body fluid profiles from SSADHD patients with controls using next‐generation metabolic screening (NGMS). Targeted analysis of NGMS data from cerebrospinal fluid (CSF) showed a moderate increase of aspartic acid, glutaric acid, glycolic acid, 4‐guanidinobutanoic acid, and 2‐hydroxyglutaric acid, and prominent elevations of GHB and 4,5‐dihydroxyhexanoic acid (4,5‐DHHA) in SSADHD samples. Remarkably, the intensities of 4,5‐DHHA and GHB showed a significant positive correlation in control CSF, but not in patient CSF. In an established zebrafish epilepsy model, 4,5‐DHHA showed increased mobility that may reflect limited epileptogenesis. Using untargeted metabolomics, we identified 12 features in CSF with high biomarker potential. These had comparable increased fold changes as GHB and 4,5‐DHHA. For 10 of these features, a similar increase was found in plasma, urine and/or mouse brain tissue for SSADHD compared to controls. One of these was identified as the novel biomarker 4,5‐dihydroxyheptanoic acid. The intensities of selected features in plasma and urine of SSADHD patients positively correlated with the clinical severity score of epilepsy and psychiatric symptoms of those patients, and also showed a high mutual correlation. Our findings provide new insights into the (neuro)metabolic disturbances in SSADHD and give leads for further research concerning SSADHD pathophysiology.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Succinic semialdehyde dehydrogenase deficiency in mice and in humans: An untargeted metabolomics perspective

Peters,

Engelke,

de Boer

et al. 2023

J of Inher Metab Disea

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Does glutaric aciduria type 1 affect hearing function?

et al. 2022

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Antiproliferative activity of antimicrobial peptides and bioactive compounds from the mangrove Glutamicibacter mysorens

et al. 2023

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The Glutamicibacter group of microbes is known for antibiotic and enzyme production. Antibiotics and enzymes produced by them are important in the control, protection, and treatment of chronic human diseases. In this study, the Glutamicibacter mysorens (G. mysorens) strain MW647910.1 was isolated from mangrove soil in the Mangalore region of India. After optimization of growth conditions for G. mysorens on starch casein agar media, the micromorphology of G. mysorens was found to be spirally coiled spore chain, each spore visualized as an elongated cylindrical hairy appearance with curved edges visualized through Field Emission Scanning Electron Microscopy (FESEM) analysis. The culture phenotype with filamentous mycelia, brown pigmentation, and ash–colored spore production was observed. The intracellular extract of G. mysorens characterized through GCMS analysis detected bioactive compounds reported for pharmacological applications. The majority of bioactive compounds identified in intracellular extract when compared to the NIST library revealed molecular weight ranging below 1kgmole−1. The Sephadex G-10 could result in 10.66 fold purification and eluted peak protein fraction showed significant anticancer activity on the prostate cancer cell line. Liquid Chromatography–Mass Spectrometry (LC–MS) analysis revealed Kinetin-9-ribose and Embinin with a molecular weight below 1 kDa. This study showed small molecular weight bioactive compounds produced from microbial origin possess dual roles, acting as antimicrobial peptides (AMPs) and anticancer peptides (ACPs). Hence, the bioactive compounds produced from microbial origin are a promising source of future therapeutics.

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Glutaric Acid Neurotoxicity: Mechanisms and Actions

Cited by 3 publications

References 86 publications

Succinic semialdehyde dehydrogenase deficiency in mice and in humans: An untargeted metabolomics perspective

Succinic semialdehyde dehydrogenase deficiency in mice and in humans: An untargeted metabolomics perspective

Does glutaric aciduria type 1 affect hearing function?

Antiproliferative activity of antimicrobial peptides and bioactive compounds from the mangrove Glutamicibacter mysorens

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