3-Hydroxyglutaric Acid as a Neurotoxin

Seminotti, Bianca; Latini, Alexandra; Amaral, Alexandre U.; Leipnitz, Guilhian; Wajner, Moacir

doi:10.1007/978-3-030-71519-9_229-1

Bianca Seminotti²,
Alexandra Latini³,
Alexandre U. Amaral⁴,
Guilhian Leipnitz² &
…
Moacir Wajner^2,5

70 Accesses

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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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
Department of Biochemistry, Center for Biological Sciences, Federal University of Santa Catarina, Florianópolis, SC, Brazil
Alexandra Latini
Department of Biological Sciences, Integrated Regional University of High Uruguay and Missions, Erechim, RS, Brazil
Alexandre U. Amaral
Medical Genetics Service, Clinical Hospital of Porto Alegre, Porto Alegre, RS, Brazil
Moacir Wajner

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Bianca Seminotti
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Alexandra Latini
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Alexandre U. Amaral
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Guilhian Leipnitz
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Moacir Wajner
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Department of Biomedical Sciences, 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. (2021). 3-Hydroxyglutaric Acid as a Neurotoxin. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-030-71519-9_229-1

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DOI: https://doi.org/10.1007/978-3-030-71519-9_229-1
Received: 02 June 2021
Accepted: 29 June 2021
Published: 25 September 2021
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-71519-9
Online ISBN: 978-3-030-71519-9
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