Glutaric aciduria type I and methylmalonic aciduria: simulation of cerebral import and export of accumulating neurotoxic dicarboxylic acids in in vitro models of the blood-brain barrier and the choroid plexus.

@article{Sauer2010GlutaricAT,
  title={Glutaric aciduria type I and methylmalonic aciduria: simulation of cerebral import and export of accumulating neurotoxic dicarboxylic acids in in vitro models of the blood-brain barrier and the choroid plexus.},
  author={Sven Wolfgang Sauer and Silvana Opp and Anne Mahringer and Marcin M. Kamiński and Christian Thiel and J{\"u}rgen G{\"u}nther Okun and Gert Fricker and Marina A Morath and Stefan K{\"o}lker},
  journal={Biochimica et biophysica acta},
  year={2010},
  volume={1802 6},
  pages={
          552-60
        }
}
Intracerebral accumulation of neurotoxic dicarboxylic acids (DCAs) plays an important pathophysiological role in glutaric aciduria type I and methylmalonic aciduria. Therefore, we investigated the transport characteristics of accumulating DCAs - glutaric (GA), 3-hydroxyglutaric (3-OH-GA) and methylmalonic acid (MMA) - across porcine brain capillary endothelial cells (pBCEC) and human choroid plexus epithelial cells (hCPEC) representing in vitro models of the blood-brain barrier (BBB) and the… Expand
Toxic synergism between quinolinic acid and organic acids accumulating in glutaric acidemia type I and in disorders of propionate metabolism in rat brain synaptosomes: Relevance for metabolic acidemias
TLDR
It is suggested that early damaging events elicited by organic acids involved in metabolic acidemias can be magnified by toxic synergism with QUIN, and this process is mostly mediated by oxidative stress, and in a lesser extent by excitotoxicity and nitrosative stress. Expand
The unsolved puzzle of neuropathogenesis in glutaric aciduria type I.
TLDR
There is evidence that during a metabolic crisis GA and its metabolites are produced endogenously in the CNS and accumulate because of limiting transport mechanisms across the blood-brain barrier and delineate possible pathogenetic models and approaches for future studies. Expand
Therapeutic modulation of cerebral L-lysine metabolism in a mouse model for glutaric aciduria type I.
TLDR
This study provides for the first time a biochemical proof of principle for metabolic treatment in glutaric aciduria type I and suggests that further optimization of treatment could be achieved by exploitation of competition between L-lysine and L-arginine at physiological barriers and enhancement of peroxisomal L- Elysine oxidation and glutARic acid breakdown. Expand
1H-MRS in glutaric aciduria type 1: impact of biochemical phenotype and age on the cerebral accumulation of neurotoxic metabolites
TLDR
GA and 3-OH-GA are detectable by in vivo 1H-MRS, which might finally allow biochemical follow-up monitoring of intracerebrally accumulating neurotoxic metabolites in GA1. Expand
Brain damage in methylmalonic aciduria: 2-methylcitrate induces cerebral ammonium accumulation and apoptosis in 3D organotypic brain cell cultures
TLDR
Local accumulation of ammonium in CNS, that may remain undetected in plasma and urine, may therefore play a key role in the neuropathogenesis of methylmalonic aciduria both during acute decompensations and in chronic phases. Expand
Elevated glutaric acid levels in Dhtkd1-/Gcdh- double knockout mice challenge our current understanding of lysine metabolism.
TLDR
Biochemical results suggest that DHTKD1 inhibition alone is not sufficient to treat GA-I, but instead a more complex strategy is needed, and provides evidence for a so far unknown mechanism leading to glutaryl-CoA. Expand
Ethylmalonic acid impairs bioenergetics by disturbing succinate and glutamate oxidation and induces mitochondrial permeability transition pore opening in rat cerebellum
TLDR
In vitro and in vivo data indicate that EMA‐induced impairment of glutamate and succinate oxidation and MPT may contribute to the pathogenesis of the cerebellum abnormalities in EE. Expand
Immunolocalization of glutaryl-CoA dehydrogenase (GCDH) in adult and embryonic rat brain and peripheral tissues
TLDR
The differential cellular localization of GCDH in adult rat brain and peripheral organs as well as its spatiotemporal expression pattern are described to explain the evolving phenotype in GA-I patients. Expand
2‐Methylcitric acid impairs glutamate metabolism and induces permeability transition in brain mitochondria
TLDR
Data strongly indicate that 2MCA behaves as a potent inhibitor of glutamate oxidation by inhibiting glutamate dehydrogenase activity and as a permeability transition inducer, disturbing mitochondrial energy homeostasis. Expand
In vivo intracerebral administration of L-2-hydroxyglutaric acid provokes oxidative stress and histopathological alterations in striatum and cerebellum of adolescent rats.
TLDR
It is presumed that L-2-HG provokes striatal and cerebellar damage in vivo possibly through oxidative stress induction and antioxidants may serve as adjuvant therapy allied to the current treatment based on a protein-restricted diet and riboflavin and L-carnitine supplementation in patients affected by L- 2-HGA. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 53 REFERENCES
Transport and distribution of 3-hydroxyglutaric acid before and during induced encephalopathic crises in a mouse model of glutaric aciduria type 1.
TLDR
The data demonstrate that under conditions mimicking encephalopathic crises the blood-brain barrier appears to remain intact. Expand
Organic anion transporters OAT1 and OAT4 mediate the high affinity transport of glutarate derivatives accumulating in patients with glutaric acidurias
TLDR
The data provide a model for the concerted action of OAT1 and NaDC3 mediating the basolateral uptake, and OAT4 mediating apical secretion of GA derivatives from proximal tubule cells and therefore contribute to the renal clearance of these compounds. Expand
Intracerebral accumulation of glutaric and 3‐hydroxyglutaric acids secondary to limited flux across the blood–brain barrier constitute a biochemical risk factor for neurodegeneration in glutaryl‐CoA dehydrogenase deficiency
TLDR
It is proposed that an intracerebral de’novo synthesis and subsequent trapping of GA and 3‐OH‐GA should be considered as a biochemical risk factor for neurodegeneration in GCDH deficiency. Expand
Contribution of Organic Anion Transporter 3 (Slc22a8) to the Elimination of p-Aminohippuric Acid and Benzylpenicillin across the Blood-Brain Barrier
TLDR
Results suggest that rOat3 is responsible for the elimination of PAH and PCG from the brain across the blood-brain barrier (BBB), and cimetidine and pravastatin, which are also substrates and inhibitors of r Oat3, significantly inhibited the efflux of PAh and PCGs from the cerebrum. Expand
Neurodegeneration in Methylmalonic Aciduria Involves Inhibition of Complex II and the Tricarboxylic Acid Cycle, and Synergistically Acting Excitotoxicity*
TLDR
It is reported that MMA induces neuronal damage in cultures of embryonic rat striatal cells at a concentration range encountered in affected patients, and the involvement of secondary excitotoxic mechanisms in MMA-induced cell damage is suggested. Expand
Rat Organic Anion Transporter 3 (rOAT3) is Responsible for Brain-to-Blood Efflux of Homovanillic Acid at the Abluminal Membrane of Brain Capillary Endothelial Cells
  • S. Mori, H. Takanaga, +4 authors T. Terasaki
  • Biology, Medicine
  • Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
  • 2003
TLDR
Results provide the first evidence that rOAT3 is expressed at the abluminal membrane of the rat BBB and is involved in the brain-to-blood transport of HVA, and this HVA efflux transport system is likely to play an important role in controlling the level of Hva in the CNS. Expand
The aetiology of neurological complications of organic acidaemias—A role for the blood–brain barrier
TLDR
It is hypothesized that, as a result of the very limited efflux, in certain organic acidaemias there is pathological accumulation of DCAs in the brain secondary to the metabolic block, and at high concentrations some of these compounds may become neurotoxic. Expand
Analysis of the expression of murine glutaryl-CoA dehydrogenase: in vitro and in vivo studies.
TLDR
It is concluded that the specific neuropathology associated with GCD deficiency in GAI cannot be accounted for by its expression pattern, and GCD is ubiquitously expressed. Expand
New aspects of the blood-brain barrier transporters; its physiological roles in the central nervous system.
  • S. Ohtsuki
  • Biology, Medicine
  • Biological & pharmaceutical bulletin
  • 2004
TLDR
Clarifying the physiological roles of BBB transport systems should give important information allowing the development of better CNS drugs and improving the understanding of the relationship between CNS disorders and BBB function. Expand
Cerebral dicarboxylate transport and metabolism studied with isotopically labelled fumarate, malate and malonate
TLDR
A very low transport capacity for four‐carbon dicarboxylates across the blood–brain barrier is suggested and a role for exogenous fumarate as a cerebral energy substrate is ruled out. Expand
...
1
2
3
4
5
...