Delta‐aminolevulinic Acid Uptake by Rabbit Brain Cerebral Cortex

Becker, David M.; Kramer, S. D.; Viljoen, J. D.

doi:10.1111/j.1471-4159.1974.tb10754.x

Cited by 26 publications

(7 citation statements)

References 22 publications

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“…In this context however it is noteworthy that Becker et al reported that brain tissue preparations could concentrate ALA when added to the surrounding medium. 29 The Valsalva manoeuvre has been previously reported to be a good indicator of parasympathetic dysfunction in diabetic patients, and in this study was found to be abnormal in latent acute intermittent porphyria. This observation is in keeping with the subclinical sensorimotor neuropathy often present in these latent acute intermittent porphyria cases as detected by nerve conduction studies.30 Yet the Valsalva manoeuvre remained normal in the acute intermittent porphyria patients in remission whereas heart-rate variation during deep breathing was significantly reduced.…”

Section: Discussionsupporting

confidence: 56%

Autonomic neuropathy in acute intermittent porphyria.

Laiwah¹,

Macphee²,

Boyle³

et al. 1985

Journal of Neurology, Neurosurgery & Psychiatry

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SUMMARY Autonomic function was assessed in subjects with acute intermittent porphyria and age-and sex-matched controls using five different bedside tests of cardiovascular reflexes. During the acute attack both parasympathetic and sympathetic tests were impaired, but subsequently improved during remission. Early parasympathetic dysfunction was also detected during remission and in latent asymptomatic acute intermittent porphyria.Acute intermittent porphyria is an autosomal dominant inborn error of metabolism characterised by a partial deficiency in the activity of the haem biosynthetic enzyme, porphobilinogen deaminase (PBG). Consequently the porphyrin precursors delta-aminolaevulinic acid (ALA) and porphobilinogen (PBG) accumulate in blood and are excreted in excessive amounts in the urine.' 2The clinical manifestations of acute intermittent porphyria have been attributed to a widespread neurological dysfunction caused by the block in haem biosynthesis.34 Abdominal pain is the commonest and often the most troublesome symptom which occurs in more than 90% of cases.5 It has been explained on the basis of splanchnic autonomic dysfunction, thus providing a mechanism for the intestinal dilatation and stasis occasionally noted radiologically and at laparotomy in patients suffering from an acute attack.6 Indeed, many of the accompanying features of an acute attack are suggestive of autonomic neuropathy; namely, the inappropriate sinus tachycardia, labile hypertension, postural hypotension, excessive sweating, severe vomiting, constipation and occasional diarrhoea and sphincteric bladder problems.5 78 Ridley et al have reported that tachycardia invariably preceded the development of peripheral neuropathy and respiratory paralysis, and they postulated that the tachycardia of porphyria might be due to autonomic cardioneuropathy.5 The transient and labile hypertension which commonly accompanies the acute attack has also been given a neurogenic explanation follow-

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Section: Discussionsupporting

confidence: 56%

Autonomic neuropathy in acute intermittent porphyria.

Laiwah¹,

Macphee²,

Boyle³

et al. 1985

Journal of Neurology, Neurosurgery & Psychiatry

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“…Other forms of experimentation (e.g., PEPT2 knockout mice) are needed to verify whether there are indeed two transporters. Previous studies on other tissues have suggested that 5‐ALA interacts with GABA, glutamate, and PAH transporters (McGeer et al, 1961 ; Becker et al, 1974 ; McLoughlin and Cantrill, 1984 ; Cheeks and Wedeen, 1986 ; Garcia et al, 1998). Evidence (effects of Na + removal or ouabain) indicates that there are Na + ‐dependent transporters for these three compounds at the choroid plexus (Holloway and Cassin, 1972 ; Kim et al, 1996 ; Ramanathan et al, 1997 ; J. Xiang and R. F. Keep, unpublished observations on glutamate and PAH).…”

Section: Discussionmentioning

confidence: 96%

“…The mechanism(s) involved in choroid plexus transport have not been examined. In a number of other tissues, 5‐ALA uptake has been shown to be energy dependent, and there is evidence that 5‐ALA can interact with a number of transport systems, including those for GABA (McGeer et al, 1961 ; Becker et al, 1974 ; Garcia et al, 1998), glutamate (McLoughlin and Cantrill, 1984), p ‐aminohippurate (PAH) (Cheeks and Wedeen, 1986), and the di‐/tripeptide transporters PEPT1 and PEPT2 (Doring et al, 1998), although for glutamate there is question over whether 5‐ALA is merely an inhibitor rather than a substrate for the transporter (Brennan and Cantrill, 1979).…”

mentioning

confidence: 99%

Mechanisms of 5‐Aminolevulinic Acid Uptake at the Choroid Plexus

Novotny¹,

Xiang²,

Stummer³

et al. 2000

Journal of Neurochemistry

104

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5-Aminolevulinic acid (5-ALA) is a precursor of porphyrins and heme that has been implicated in the neuropsychiatric symptoms associated with porphyrias. It is also being used clinically to delineate malignant gliomas. The blood-CSF barrier may be an important interface for 5-ALA transport between blood and brain as in vivo studies have indicated 5-ALA is taken up by the choroid plexuses whereas the normal blood-brain barrier appears to be relatively impermeable. This study examines the mechanisms of 5-[ 3 H]ALA uptake into isolated rat lateral ventricle choroid plexuses. Results suggest that there are two uptake mechanisms. The first was a Na ϩ -independent uptake system that was pH dependent (being stimulated at low pH). Uptake was inhibited by the dipeptide Gly-Gly and by cefadroxil, an ␣-amino-containing cephalosporin. These properties are the same as the proton-dependent peptide transporters PEPT1 and PEPT2, which have recently been shown to transport 5-ALA in frog oocyte expression experiments. Choroid plexus uptake was not inhibited by captopril, a PEPT1 inhibitor, suggesting PEPT2-mediated uptake. The presence of PEPT2 and absence of PEPT1 in the choroid plexus were confirmed by western blotting. The second potential mechanism was both Na ϩ and HCO 3 Ϫ dependent and appears to be an organic anion transporter, although it is possible that removal of Na ϩ and HCO 3 Ϫ may indirectly affect PEPT2 by affecting intracellular pH. The presence of PEPT2 and a putative Na ϩ /HCO 3 Ϫ -dependent organic anion transporter is important not only for an understanding of 5-ALA movement between blood and brain but also because these transporters may affect the distribution of a number of drugs between blood and CSF.

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“…[4-I4C]ALA has previously been shown to be taken up into rabbit brain slices by a process which is temperature-and Na+ -dependent and inhibited by 2,4-dinitrophenol (Becker et al, 1974). But, in addition, ALA uptake into brain slices was found to be saturable and significantly inhibited by ouabain and KCN, which suggested that it involved an active transport system (Becker et al, 1974). The discrepancy may be attributed to the fact that cells in culturr, are less differentiated than in the adult brain.…”

Section: Discussionmentioning

confidence: 99%

“…Metabolism of [4J4C]ALA by the cultures was not estimated and, although Becker et al (1974) demonstrated that rabbit cortex slices did not metabolise [14C]ALA, the possibility that the less differentiated cells in culture metabolise [14C]ALA cannot be excluded. [4-14C]ALA uptake into neurons and glia was linear for 20 min (Fig.…”

Section: Ala Uptake Into Neurons and Gliamentioning

confidence: 99%

δ‐Aminolaevulinic Acid Uptake, Toxicity, and Effect on [¹⁴C]γ‐Aminobutyric Acid Uptake into Neurons and Glia in Culture

Percy

Lamm

Taljaard

1981

Journal of Neurochemistry

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delta-Aminolaevulinic acid (ALA) uptake into neurons and glia in primary culture as well as ALA toxicity and its effects on gamma-aminobutyric acid (GABA) uptake were examined. [4-14C]ALA uptake into neurons and glia was nonsaturable, partially Na+- and temperature-dependent, and appeared to comprise mainly diffusion into the cell. 2,4-Dinitrophenol caused some inhibition of [4-14C]ALA uptake whereas ouabain, KCN, or amino acids at 1 mM concentration were without effect. ALA (1 mM) caused a slight inhibition of [U-14C]GABA uptake into neurons (14%) and glia (9%), but was without effect at lower concentrations. It is unlikely that, in acute porphyria, ALA reaches sufficiently high levels in nervous tissue to interfere with the reuptake of GABA into neurons or glia. ALA was shown to be toxic, judged by the loss of cells, to both neurons and glia at concentrations as low as 10 microM. Such a concentration of ALA may be expected to occur in the CSF of porphyric patients in the acute attack. However, results obtained with dispersed cells in culture may not necessarily reflect the situation in vivo where the cell may have a far greater resistance to the effects of toxic agents.

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Delta‐aminolevulinic Acid Uptake by Rabbit Brain Cerebral Cortex

Cited by 26 publications

References 22 publications

Autonomic neuropathy in acute intermittent porphyria.

Autonomic neuropathy in acute intermittent porphyria.

Mechanisms of 5‐Aminolevulinic Acid Uptake at the Choroid Plexus

δ‐Aminolaevulinic Acid Uptake, Toxicity, and Effect on [¹⁴C]γ‐Aminobutyric Acid Uptake into Neurons and Glia in Culture

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Delta‐aminolevulinic Acid Uptake by Rabbit Brain Cerebral Cortex

Cited by 26 publications

References 22 publications

Autonomic neuropathy in acute intermittent porphyria.

Autonomic neuropathy in acute intermittent porphyria.

Mechanisms of 5‐Aminolevulinic Acid Uptake at the Choroid Plexus

δ‐Aminolaevulinic Acid Uptake, Toxicity, and Effect on [14C]γ‐Aminobutyric Acid Uptake into Neurons and Glia in Culture

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δ‐Aminolaevulinic Acid Uptake, Toxicity, and Effect on [¹⁴C]γ‐Aminobutyric Acid Uptake into Neurons and Glia in Culture