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3-Hydroxyglutaric Acid as a Neurotoxin

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Handbook of Neurotoxicity

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Abstract

3-Hydroxyglutaric acid (3HGA) accumulates predominantly in the brain and biological fluids of individuals affected by glutaric acidemia type 1 (GA 1), being considered the most reliable biochemical marker for the diagnosis of this disease. GA 1 is a hereditary neurometabolic disease clinically characterized by acute episodes of encephalopathy resembling intoxication, which are associated with extensive striatal damage and followed by a complex movement disorder. Progressive striatal and extrastriatal abnormalities associated with white matter changes attributed to defective myelination are also common in this disease. Although brain concentrations of 3HGA in GA 1 are still unknown, an important characteristic of this organic acid is that, once produced mainly from lysine, it cannot leave the central nervous system because of very limited efflux, therefore, accumulating in this tissue. The pathogenesis of the brain damage of GA 1 is still poorly established, although neurotoxic effects have been attributed to 3HGA. In this particular, experimental data indicate that 3HGA (i) induces excitotoxicity, possibly due to its similar chemical structure to glutamate, the main excitatory neurotransmitter; (ii) disrupts redox homeostasis, increasing production of mitochondrial reactive species, decreasing cellular antioxidant defenses, and inducing oxidative damage to biomolecules; (iii) impairs bioenergetics, by inhibition of mitochondrial respiration and compromising the citric acid cycle activity; (iv) promotes reactive astrogliosis; and (v) causes blood-brain barrier breakage and cerebral vascular alterations. However, the pathophysiological relevance of the aforementioned deleterious effects on the neuropathology of GA 1 should be taken cautiously since some of these data were obtained with supraphysiological concentrations of 3HGA.

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Abbreviations

3HGA:

3-Hydroxyglutaric acid

3-MGH:

3-Methylglutaconyl-CoA hydratase

AMPA:

α-Amino-3-hydroxy-5-methylisoxazole propionic acid

BBB :

Blood-brain barrier

C5DC :

Glutarylcarnitine

CNS :

Central nervous system

CPT 1 :

Carnitine palmitoyltransferase 1

CSF :

Cerebrospinal fluid

EC:

Enzyme Commission

GA :

Glutaric acid

GA 1 :

Glutaric acidemia type I

GABA :

γ-Aminobutyric acid

GCDH :

Glutaryl-CoA dehydrogenase

Gcdh−/− :

Homozygous glutaryl-CoA dehydrogenase deficient mice

GFAP :

Glial fibrillary acidic protein

GluRs:

Glutamatergic receptors

GPx :

Glutathione peroxidase

GSH :

Reduced glutathione

HADH:

3-Hydroxy-acyl-CoA dehydrogenase

LCAD:

Long-chain acyl-CoA dehydrogenase

L-NAME:

Nω-Nitro-L-arginine

Lys:

Lysine

MCAD :

Medium-chain acyl-CoA dehydrogenase

MDA :

Malondialdehyde

MK-801:

(5R,10S)-(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-10-imine

NaC3 :

Sodium dicarboxylate cotransporter 3

NBQX:

2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline

NMDA :

N-Methyl-D-aspartate

NO:

Nitric oxide

NOS:

Nitric oxide synthase

OAT :

Organic anion transporter

OMIM :

Online Mendelian Inheritance in Man

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

RS:

Reactive species

S100B:

S100 calcium-binding protein B

VEGF:

Vascular endothelial growth factor

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Authors and Affiliations

  1. Department of Biochemistry, Institute of Basic Sciences and Health, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil

    Bianca Seminotti, Guilhian Leipnitz & Moacir Wajner

  2. Department of Biochemistry, Center for Biological Sciences, Federal University of Santa Catarina, Florianópolis, SC, Brazil

    Alexandra Latini

  3. Department of Biological Sciences, Integrated Regional University of High Uruguay and Missions, Erechim, RS, Brazil

    Alexandre U. Amaral

  4. Medical Genetics Service, Clinical Hospital of Porto Alegre, Porto Alegre, RS, Brazil

    Moacir Wajner

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  1. Bianca Seminotti
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  2. Alexandra Latini
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  3. Alexandre U. Amaral
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  4. Guilhian Leipnitz
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Correspondence to Moacir Wajner .

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  1. Department of Biomedical Sciences, Quillen College of Medicine East Tennessee State University, Johnson City, TN, USA

    Richard M. Kostrzewa

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Seminotti, B., Latini, A., Amaral, A.U., Leipnitz, G., Wajner, M. (2022). 3-Hydroxyglutaric Acid as a Neurotoxin. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-031-15080-7_229

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