Research reportTransport of 5-aminolevulinic acid between blood and brain
Introduction
5-Aminolevulinic acid (δ-aminolevulinic acid; ALA) is a precursor of porphyrins and heme, and is important in some CNS disease states. An accumulation of the porphyrin precursors, ALA and/or porphobilinogen, has been suggested as the cause of the neuropsychiatric symptoms that occur in hereditary hepatic porphyrias [28]. Oral administration of ALA has also been used clinically to delineate malignant gliomas [23]. Such oral administration results in a highly selective accumulation of protoporphyrin IX (PpIX) in the glioma which can then be detected by fluorescence microscopy in the operating theater [23], [25].
Despite the physiological and pathophysiological importance of ALA, there is still uncertainty about the degree and mechanisms by which it is transported between blood and brain. Some studies indicate that there is little transport at the blood–brain barrier (BBB), formed by the cerebral capillaries [7], [26], whereas McGillion et al. [12] found relatively rapid transport. Evidence from autoradiography [26] and PpIX fluorescence [24] indicate that there is selective uptake of ALA into the choroid plexus, the site of the blood–CSF barrier, after systemic administration. Studies on isolated choroid plexus also indicate that this tissue is capable of ALA transport [14], but the extent to which transport of ALA from blood to CSF is an important entry mechanism for ALA into brain has not been established.
Because of these uncertainties over blood–brain ALA transport in vivo, the present study in rats was designed to examine: (1) Is the movement of ALA blood to brain or blood to CSF via diffusion or carrier-mediated transport? (2) Is there an saturable clearance mechanism removing ALA from the brain or CSF? (3) Is the movement of ALA from blood to brain altered early in development when brain growth might entail greater heme synthesis?
Section snippets
Materials and methods
These experiments were divided into six parts. The first used a graphical analysis in adult rats to determine the duration over which [14C]ALA uptake into various brain tissues is unidirectional. On establishing that [14C]ALA uptake was unidirectional for 20 min, the second set of experiments used a single time point to examine whether blood to brain [14C]ALA uptake is inhibited by loading with non-radioactive ALA or probenecid. The third set of experiments examined [14C]ALA transport at the
Results
Graphical analyses of [14C]ALA uptake into brain, CSF and choroid plexus after an intravenous injection are shown in Fig. 2 where the influx rate constants for uptake into these tissues is given by the slopes of the lines. The influx rate constants for cerebral cortex and diencephalon were the same, and Fig. 1 shows the combined data with an average blood to brain Ki of 0.18±0.03 μl/g per min. The influx rate constant for [14C]ALA entry into CSF was somewhat higher (0.32±0.4 μl/g per min) than
Discussion
The current study indicates that the permeability of ALA at the BBB is very low and that there is probably no carrier-mediated transport of ALA from blood to brain across the BBB. In contrast, there is saturable transport at the blood–CSF barrier situated at the choroid plexuses. However, it appears that the normal net effect of such transport is to keep ALA concentrations in the CSF low compared to plasma.
Acknowledgements
This work was supported by grants R01 NS034709 and P01 HL018575 (R.F.K.) and R01 GM035498 (D.E.S.) from the National Institutes of Health.
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