Glutaric Acid-Mediated Apoptosis in Primary Striatal Neurons

Tian, Fang; Fu, Xi; Gao, Jinzhi; Ying, Yanqin; Hou, Ling; Qin, Ning; Luo, Xiaoping

doi:10.1155/2014/484731

Cited by 11 publications

(7 citation statements)

References 40 publications

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“…The hypothesis tested in this study was further supported by the potentiatory effect of glutaric acid on the toxic response to low levels of azaspiracid. Glutaric acid has been very recently reported to have an apoptotic effect in neurons 39 , targeting similar cellular structures to azaspiracids such as mitochondria and cell morphology 19 . A combined neurotoxicity of azaspiracid with glutaric acid has been demonstrated for the first time.…”

Section: Discussionmentioning

confidence: 99%

New insights into the causes of human illness due to consumption of azaspiracid contaminated shellfish

Chevallier

Graham

Albrecht

et al. 2015

Sci Rep

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Azaspiracid (AZA) poisoning was unknown until 1995 when shellfish harvested in Ireland caused illness manifesting by vomiting and diarrhoea. Further in vivo/vitro studies showed neurotoxicity linked with AZA exposure. However, the biological target of the toxin which will help explain such potent neurological activity is still unknown. A region of Irish coastline was selected and shellfish were sampled and tested for AZA using mass spectrometry. An outbreak was identified in 2010 and samples collected before and after the contamination episode were compared for their metabolite profile using high resolution mass spectrometry. Twenty eight ions were identified at higher concentration in the contaminated samples. Stringent bioinformatic analysis revealed putative identifications for seven compounds including, glutarylcarnitine, a glutaric acid metabolite. Glutaric acid, the parent compound linked with human neurological manifestations was subjected to toxicological investigations but was found to have no specific effect on the sodium channel (as was the case with AZA). However in combination, glutaric acid (1mM) and azaspiracid (50nM) inhibited the activity of the sodium channel by over 50%. Glutaric acid was subsequently detected in all shellfish employed in the study. For the first time a viable mechanism for how AZA manifests itself as a toxin is presented.

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Section: Discussionmentioning

confidence: 99%

New insights into the causes of human illness due to consumption of azaspiracid contaminated shellfish

Chevallier

Graham

Albrecht

et al. 2015

Sci Rep

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“…Approximately 90% of patients develop GA-I in early childhood, and the remaining 10% of patients show mild symptoms or no symptoms ( 3 ). In recent years, GA-I in the Chinese population has gained increasing interest ( 4 – 7 ). However, a large number of children do not receive a timely diagnosis and proper treatment clinically.…”

Section: Introductionmentioning

confidence: 99%

Clinical and laboratory analysis of late-onset glutaric aciduria type I (GA-I) in Uighur: A report of two cases

Zhang

Luo

2016

Experimental and Therapeutic Medicine

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The aim of the present study was to investigate the clinical, biochemical and genetic mutation characteristics of two cases of late-onset glutaric aciduria type I (GA-I) in Uighur. The clinical data and glutaryl-CoA dehydrogenase (GCDH) genetic test results of two cases of late-onset GA-I in Uighur were collected and analyzed, and reviewed with relevant literature. One patient with late-onset GA-I primarily exhibited clinical intermittent headache, while the other patient was asymptomatic. The urinary organic acid analysis detected a large number of glutaric acid and 3-hydroxy glutaric acid, 3-hydroxy-propionic acid. One patient exhibited white matter degeneration in cranial magnetic resonance imaging (MRI) and the other patient showed no abnormality. The two patients both exhibited c. 1204C >T, p.R402W, heterozygous mutation, and c. 532G >A, p.G178R, heterozygous mutation. Besides central nervous system infectious diseases, patients with clinical headache, cranial MRI-suggested bilateral temporal lobe arachnoid cyst and abnormal signals in the basal ganglia should be highly suspected as late-onset GA-I. Early diagnosis and correct treatment are key to improve its prognosis.

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“…Our compromise was to select a compound with two terminal carboxylic acids and a non-ridgid carbon chain to allow for free rotation about its axis. Glutaric acid, an NMDAR agonist (53, 54), is a five carbon chain molecule with two terminal carboxylic acid functional groups (structurally similar to glutamate with no amine); it displayed higher simulated binding affinity compared to AP5 (−5.4 vs −5.2 kcal/mol), suggesting that two molecules of acetate may outcompete AP5. While we cannot definitively say that acetate actively binds at the glutamate binding pocket in NMDAR, our experimental findings and computational data support this possiblity.…”

Section: Discussionmentioning

confidence: 99%

Local Metabolism of Ethanol to Acetic Acid/Acetate in the Central Nucleus of Amygdala Elicits Sympathoexcitatory Responses through Activation of NMDAR in Sprague Dawley Rats

Chapp

Huber

Driscoll

et al. 2020

Preprint

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Short chain fatty acid (SCFA) regulation of neuronal function remains an interesting but poorly understood area of research. The SCFA, acetic acid, the main component of vinegar and the major metabolite of ethanol has been directly linked to altering neuronal function. However, the underlying mechanisms as it relates to alcohol consumption and SCFA regulation of neuronal function have yet to be elucidated. Here we show that local metabolism of ethanol to acetic acid/acetate in the central nucleus of amygdala (CeA) activates glutamatergic N-methyl-D-aspartate receptors (NMDAR) in vivo causing a sympathoexcitatory response. External acetate and intracellular loading of acetic acid in CeA neurons increased neuronal excitability through activation of NMDAR. Furthermore, cultured neurons exposed to acetate showed increased cytosolic calcium which response was abolished by NMDAR antagonist and decreased pH. These findings suggest that acetic acid/acetate is an underestimated bioactive metabolite of ethanol that mediates some effects via an NMDAR-dependent mechanism in the brain. The link between the SCFA, acetic acid/acetate on increased neuronal excitability at least partially through NMDAR may provide a novel avenue for understanding alcohol, metabolic, cardiovascular and neurodegenerative disorders related to alterations in SCFA concentrations in the brain.

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Glutaric Acid-Mediated Apoptosis in Primary Striatal Neurons

Cited by 11 publications

References 40 publications

New insights into the causes of human illness due to consumption of azaspiracid contaminated shellfish

New insights into the causes of human illness due to consumption of azaspiracid contaminated shellfish

Clinical and laboratory analysis of late-onset glutaric aciduria type I (GA-I) in Uighur: A report of two cases

Local Metabolism of Ethanol to Acetic Acid/Acetate in the Central Nucleus of Amygdala Elicits Sympathoexcitatory Responses through Activation of NMDAR in Sprague Dawley Rats

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