Article pubs.acs.org/crt
Elimination Kinetics of Domoic Acid from the Brain and Cerebrospinal Fluid of the Pregnant Rat Jennifer Maucher Fuquay, Noah Muha, Zhihong Wang, and John S. Ramsdell* Marine Biotoxins Program, Center for Coastal Environmental Health and Biomolecular Research, NOAA, National Ocean Service, 219 Fort Johnson Road, Charleston, South Carolina 29412, United States ABSTRACT: Domoic acid (DA) causes neurological effects in multiple species upon exposure, including status epilepticus in pregnant sea lions and an epileptic disease state that commonly develops in juveniles. This study aims to define brain toxicokinetic parameters in the pregnant rat in the larger context of maternal-fetal toxin transfer. Specifically, Sprague− Dawley rats were exposed to a low observable effect level of 1.0 mg DA/kg intravenously at gestational day 20, and plasma, brain, and cerebrospinal fluid (CSF) samples were taken at discrete time points over 24 h. Domoic acid concentrations were determined by a tandem LC/MS method recently optimized for brain tissue and CSF. Data showed that 6.6% of plasma DA reached the brain, 5.3% reached the CSF, and DA levels were nearly identical in both brain and CSF for 12 h, remaining above the threshold to activate isolated hippocampal neurons for 2 h. The calculated terminal half-life of CSF was 4 h, consistent with the time for complete CSF regeneration, suggesting that CSF acts as a mechanism to clear DA from the brain.
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death.3 Learning and memory deficits that arise following DA exposure are well documented in mice and rats.4,5 More recently, it was shown that a single bout of DA induced status epilepticus leads to epilepsy in young rats,6 which were used to model a similar disease state seen in California sea lions.7 The mechanism by which DA enters the brain is not well understood, but DA is known to cross the blood−brain barrier (BBB) in both adult and fetal rats.8−11 The BBB acts as a central nervous system (CNS) barrier with many functions, including ion regulation, transport of water-soluble nutrients, control of protein and neurotransmitter levels, and protection from neurotoxic substances.12 Transfer rates for DA across the BBB are low in adult rats.9 The blood−cerebrospinal fluid barrier (BCSFB) is also a CNS barrier formed by the epithelial cells of the choroid plexus, which produces the cerebrospinal fluid (CSF). CSF is responsible for the protection of the brain, transport of hormones, and excretion of waste products such as harmful metabolites, drugs, and other substances through one way flow from CSF to blood.12 Studies on other substances have shown that CSF levels can be more closely indicative of what brain target tissue concentrations are rather than plasma levels,13,14 and we explore this in the context of our study results. We have shown in previous studies that DA crosses the BBB in both pregnant rats and their fetuses,10,11 but the elimination kinetics of DA from the brain and CSF have not yet been described. The purpose of this study was to determine
INTRODUCTION Domoic acid (DA), a marine toxin produced by the diatom Pseudonitzschia spp., is a small, polar molecule (Figure 1) that is
Figure 1. Predicted predominant charge of domoic acid at physiological pH.
a persistent partial agonist of certain subtypes of ionotropic glutamatergic receptors. It directly targets AMPA-kainate subtype receptors, depolarizing pre- and postsynaptic membranes and releasing glutamate, which activates NMDA glutamatergic receptors and subsequently leads to neuronal excitotoxicity.1,2 This makes neurons the physiological targets of DA poisoning and ultimately leads to neurological symptoms such as stereotypic scratching, ataxia, aggression, seizures, and © 2012 American Chemical Society
Received: October 26, 2012 Published: November 7, 2012 2805
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toxicokinetic (TK) parameters for the first time in both CSF and the brains of pregnant rats. A comparison between the maternal TK parameters and those of their fetal pups11 are also discussed to determine risk levels in the pregnant rat model.
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triple quadruple mass spectrometer equipped with a Turbo V source (AB Sciex, Foster City, CA, USA). LC separations were done with a Luna C18(2) column (150 × 2 mm, 5 μm; Phenomenex, Torrance, CA, USA) using a gradient of water (A) and acetonitrile (B), with 0.1% formic acid as an additive. The LC gradient was 2 min of 5% B, linear gradient to 35% B at 16 min, 90% B at 18 min, held for 5 min, then returned to the initial conditions at 24 min and held for 5 min before the next injection; the injection volume was 10 μL. The LC eluant was diverted to waste except for the 6 min window bracketing the retention time of DA that was sent to the MS. The detection of DA by MS was achieved by multiple reaction monitoring (MRM; m/z 312 → 266, m/z 312 → 248, m/z 312 → 193, m/z 312 → 161) in positive ion mode. Toxicokinetic Analysis. Parameters for brains and CSF were fit via noncompartmental analysis (NCA) using WinNonLin, version 6.1 (Pharsight, Mountain View, CA). An iterative weighed least-squares (1/y2) weighting scheme was used in all analyses. The limit of detection value (0.2 ng/mL) was used as the 24 h concentration for CSF in the NCA analyses in order to calculate the lambda (terminal) phase parameters. The maximal concentration (Cmax) and the corresponding time (tmax) were the highest observed values for each. The toxicokinetic parameters are reported as the mean ± the standard error. Statistical analyses were calculated using nonparametric tests (Kruskall−Wallis) (GraphPad Prism software, v. 4.0; La Jolla, CA).
EXPERIMENTAL PROCEDURES
Animals. All experiments were reviewed and approved by the Center for Coastal Environmental Health and Biomolecular Research (CCEHBR) Institutional Animal Care and Use Committee and conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals (NIH Publication No. 86-23, revised 1996). A dose of 1.0 mg/kg domoic acid (DA) was administered by intravenous (i.v.) bolus to pregnant Sprague−Dawley female rats (Charles River) on gestational day (GD) 20, with 2 dams each designated for collection of blood, brain, and CSF samples at specific time points (5, 15, 30, 45, 60, 120 (n = 1), 240, 480, 720, or 1440 min) after exposure. This sub-lethal dose was chosen based on those previously used, which showed minimal symptoms in the dams. I.V. injection was done using a 30 gauge needle inserted into the right jugular vein while the animal was under anesthesia by a 3% mixture of isoflurane and oxygen. Dams were euthanized in a rodent induction chamber (Braintree Scientific) maintained with a 70% CO 2 concentration; transcardial exsanguination was used to collect blood samples and as a secondary method of euthanasia. CSF samples were obtained by transecting the interscutularis muscle to expose the occipital crest and the cisterna magna. Using a No. 2 dental bur, a hole was carefully made at the point of the occipital crest through the skull but not through the dura mater. A sterile 27 gauge needle was lowered approximately 5 mm through the hole in the skull, and 0.1 mL of CSF was aspirated into the syringe and stored at −80 °C. Brains were snap frozen whole in liquid nitrogen and stored at −80 °C until analysis. Sample Preparation. DA was extracted from brains according to the protocol of Maucher and Ramsdell.10 CSF was not extracted. Plasma was prepared from blood collected in a heparinized Vacutainer (registered trademark of Becton, Dickinson and Company) by centrifugation at 1890g (IEC Centra CL2 Benchtop centrifuge, Thermo Electron Corporation,Waltham, MA) and was stored at −80 °C. Brains were removed and homogenized in an equal volume of 10 mM phosphate buffered saline with 10% methanol and 0.05% Tween 20 (sample buffer). Tissues were then extracted by the addition of three times homogenate volume of 50% methanol in water and homogenized with a hand-held Teflon homogenizer in a 0.5 mL microcentrifuge tube or a 1 mL hand-held glass homogenizer (KimbleKontes, Vineland, NJ). Extracts were centrifuged at 3,000g (IEC Centra CL2 Benchtop centrifuge, Thermo Electron Corporation, Waltham, MA), and the supernatant was removed and kept at −20 °C until solid phase extraction (SPE) clean up. All extracted brain samples and nonextracted CSF and plasma samples were subjected to SPE immediately prior to analysis as described in Wang et al.15 Brain sample extracts were diluted and acidified to yield ≤5% methanol and 1% formic acid in the final 5 mL volume of solution. After centrifugation at 3,000g, the supernatants were loaded onto Agilent Bond Elut C18 (40 μm, 200 mg, 3 mL) SPE columns (Agilent, CA) and preconditioned with 100% methanol and then water. The sample tubes were washed with 3 mL of 0.5% formic acid, centrifuged, and transferred to the SPE cartridges. DA was eluted with 1 mL of 50% methanol/water (50:50, v/v). Samples were stored at +4 °C until analysis. CSF and plasma samples were acidified with an equal volume of 1% formic acid. Sample solutions (≤1 mL) were centrifuged for 6 to 10 min at ≥10,000g, and the supernatants were loaded onto an Agilent Bond Elut C18 (40 μm, 50 mg) solid phase extraction (SPE) column (Agilent Technologies, Santa Clara, CA) preconditioned with 100% methanol and then water. The sample tubes were then washed with 3 mL of 0.5% formic acid, centrifuged, and supernatants transferred to the SPE cartridges. DA was eluted with 1 mL of 50% methanol/water (50:50, v/v). Samples were stored at +4 °C until LC/MS analysis. LC/MS Analysis. DA was quantified in all samples according to the method of Wang et al.15 using a HP1100 binary LC system (Agilent Technologies, Santa Clara, CA) coupled to an AB Sciex API 4000
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RESULTS The toxicokinetic parameters in the CSF and brain of pregnant rats were determined for the time period between 5 min and 24 h following a 1.0 mg/kg i.v. bolus dose of DA. Estimates derived using noncompartmental analysis (NCA) are listed in Table 1, and the concentration with time curves are shown in Table 1. Brain and CSF Toxicokinetic Parametersa CSF parameter
estimate
Rsq Tmax Cmax HL_λz AUC24h AUCINF MRT24h MRTINF
0.98 15 0.123 240 9.8 9.8 200 212
brain units
estimate
units
min μg/mL min min·μg/mL min·μg/mL min min
0.88 15 0.154 1156 12.1 15.7 297 933
min μg/g min min·μg/g min·μg/g min min
a
The noncompartmental toxicokinetic parameters were calculated using the software WinNonlin Phoenix. AUC24h = area under the curve up to 24 h; AUCINF = area under the curve to infinity; HL_λz = terminal half-life (ln 2/λz); MRT24h = mean residence time up to 24 h; MRTINF = mean residence time to infinity.
Figure 2. The corresponding toxicokinetic parameters for DA in plasma in the pregnant rats were reported as part of a maternal−fetal study. 11 DA quickly entered both the brain and CSF from plasma, reaching maximal concentrations (Cmax) of 0.154 μg/g and 0.123 μg/mL at 15 min (Tmax), respectively, with their concentrations being very similar to each other over the first 12 h. There were no significant differences (Kruskall− Wallis; p > 0.05) between tissue concentrations with time; however, this is most likely due to the small sample size per time point (n = 2). Between 12 and 24 h, CSF concentrations were cleared below the detection limit of 0.2 ng/mL, the value used as the last time point at 24 h. The terminal half-life for the brain was nearly 5 times higher than that of CSF, and brain concentrations were still quantifiable at 24 h. The mean residence time to infinity (MRTinf) for the brain (15.5 h) was 2806
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which ultimately leads to NMDA mediated excitoxicity.2 DA, as a small polar acid, must pass through the BBB before it can enter the ISF to reach its target, and the flow of substances in the ISF is usually from the brain to the CSF,17 meaning that flow is usually from the plasma to the ISF to the CSF. The fluid dynamics of this source−sink relationship is seen in the apparent higher initial rates of plasma transfer of DA to the brain than the CSF and the elimination of DA to below the limit of analytical detection in the CSF by 24 h. Plasma levels are usually higher than brain ISF levels because of the BBB,13 whereas CSF is separate from the blood and is in direct contact with brain tissues.14 Fluids within the brain make up a substantial amount of the total brain weight, with plasma being 3%, CSF 6%, and ISF 15−20% of the total brain weight,18,19 making ISF the most relevant fluid to determine target tissue toxicity. As ISF is an extremely difficult matrix to sample, CSF would then be more indicative of ISF toxin concentration than plasma. Liu et al.13,14 confirmed this with several experiments showing CSF to be more representative of ISF levels than plasma, usually within 3- to 5-fold of actual concentrations for most tested compounds.17,20 Although for compounds that have an AUCcsf/AUCunbound plasma ratio of less than one, as in our case, the CSF may not accurately reflect the brain concentration;17 however, our data show nearly identical values for the brain and CSF for most of the 24 h time course. Interestingly, the calculated terminal half-life of CSF was 4 h, which is approximately the same amount of time (3−4 h) for complete CSF regeneration in adult rats.17 The DA clearance from CSF actually occurs slightly faster than that from plasma.11 These results support the physiologically based pharmacokinetic (PBPK) analysis of Kim et al.8 where CSF acted as a mechanism to clear DA from the brain. The plasma values11 ranged from 4.5 μg/mL (±0.7 μg/mL) at 5 min post-exposure to 1 ng/mL (±0.05 ng/mL) at 24 h post-exposure. Between the initial dosing and 1.5 h postexposure, plasma concentrations were between more than 11− 120 times higher than CSF values for the same time points. Plasma concentrations continued to be higher than CSF during the terminal phase as well (2 h to 12 h) but at a lower magnitude (between 1.5 and 6 times higher), with the closest values between the two matrices occurring at 4 h post-exposure. Although the CSF is apparently cleared of DA sometime between 12 and 24 h, while still having low detectable amounts in the brain and plasma (2 ng/g and 1 ng/mL, respectively), overall CSF is much more likely than plasma to give a more accurate assessment of potential toxicity at the physiological target during exposure to DA. The DA concentrations measured in the brain and CSF of these pregnant rats is physiologically relevant. The dose of 1.0 mg/kg was chosen as it causes minimal symptoms in the pregnant rat but does cause neurological effects to fetuses later in life.21,22 Studies with cerebellar granule cell cultures indicate that DA induces calcium entry and NMDA-dependent excitotoxicity at ED50 values of 190 and 469 ng/mL, respectively.23,24 These values exceed the Cmax of 123 ng/mL in CSF; however, the concentration of 93 ng/mL appeared as a threshold for minimal calcium entry and NMDA-dependent excitotoxicity.23,24 Xi and Ramsdell25 conducted FURA imaging studies on individual hippocampal pyramidal cells and determined that 16 ng/mL DA is sufficient to induce calcium entry, which is within the range of DA concentrations we find in CSF over the first two hours; however, by 8 h CSF levels of DA had fallen 8-fold below this threshold.
Figure 2. Log concentration with time curves for the CSF and brain over 24 h. The last time point for CSF is the detection limit of 0.2 ng/ mL.
over 4 times longer than that for CSF (3.5 h), although the MRT at 24 h (MRT24h) was similar for both. Using the matching area under the curve (AUC) values for the brain and CSF versus plasma at each time point, we calculated the transfer rates of DA from the plasma to the brain and CSF. The AUCbrain/AUCplasma ratio, which represents the brain toxin exposure, showed that 6.6% of DA was present in the brain compared to plasma concentrations. Similarly, a slightly lower level, 5.3%, was transferred to the CSF (Figure 3). Concentrations of DA in the brain were quantifiable at 24 h
Figure 3. Calculated transfer rates from plasma to tissue as a percentage based on area under the curve ratios (AUCtissue/AUCplasma) for CSF (yellow square) and the brain (red triangle).
post-exposure, and the 1 h time point values were comparable to those found in an earlier, non-TK study that administered a slightly lower dose of 0.6 mg DA/kg.10 CSF, however, cleared to levels below the detection limit between 12 and 24 h.
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DISCUSSION The toxicokinetics of domoic acid in the brain and CSF of the pregnant rat have been determined here for the first time and corroborate previous experiments that show DA quickly clears from fluids such as the plasma10,11,16 and now CSF (this study); however, it is retained in brain tissue for a period of at least 24 h. The usefulness of CSF as a more reliable indicator of DA levels in brain interstitial fluid (ISF) rather than plasma is discussed, as well as the comparative risk of neurological damage in maternal versus fetal brains. What remains unknown following exposure to DA is the actual DA concentration in the ISF of the brain, which is a more physiologically relevant value compared to plasma, as the ISF bathes the exterior of the neurons. The toxicity of DA arises indirectly from its action at the molecular target, the AMPA receptors on pre- and post- synaptic neuronal membranes, 2807
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Atmospheric Administration (NOAA). No reference shall be made to NOAA, or this publication furnished by NOAA, to any advertising or sales promotion which would indicate or imply that NOAA recommends or endorses any proprietary product mentioned herein, or which has as its purpose an interest to cause the advertised product to be used or purchased because of this publication. The authors declare no competing financial interest.
Several studies have shown that prenatal and neonatal rats are more sensitive to DA induced neurotoxicity than adults, thus putting them at potentially higher risk of developmental problems such as neuronal damage and learning deficits.21,22,26−28 Although initial maternal brain levels are 33 times higher, fetal brain concentrations remained relatively constant with little evidence for clearance at 24 h postexposure,11 whereas maternal the brain does show DA being cleared via the CSF. The discrepancy in fetal and maternal brain concentrations is not due to the lack of development of either the BBB or the BCSFB, as all tight junctions for both barriers are complete in rats by GD15.29,30 Fetal brain concentrations had persistent levels of DA, with an average of 8 ng/g over the 24 h period and seemingly little elimination compared to that in the maternal brain. At 24 h post-exposure, the fetal brain had over 3 times as much DA present11 as concurrent maternal brain levels. Although we do not have any fetal CSF values to compare to the maternal values here, it does imply that the fetal brain would also have similar measurable amounts of DA in the CSF. According to AlSarraf et al.,31 glutamate and aspartate, also excitatory amino acids, showed greater clearance from the CSF in adult rats than neonatal rats. Compounding this is the hindrance of fetal clearance of DA due to fetal recirculation of amniotic fluid,11 which increased their overall exposure time compared to that of the mother. This would render the neonate much more susceptible to DA effects than adults. When compared to plasma levels11 the MRT was more than two times longer in CSF compared to that in plasma. Thus, the overall exposure duration at the target is longer than would be indicated by using the plasma parameter. Of course in a healthy rat, brain DA is cleared rapidly by the CSF. However, any condition that may affect that clearance, such as advanced or very young age, kidney disease, or impediments of the BCSFB, would increase the time of exposure at the target with greater subsequent neurological impact.30,32,33 As the fetal unit has poor clearance and longer exposure time due to recirculation of DA via amniotic fluid,11 they are at much higher risk for neurological damage than the mother. The TK parameters of this study show that DA is quickly eliminated from the brain of pregnant rats through CSF clearance, thus limiting exposure in healthy pregnant animals. In the context of overall maternal−fetal transfer, the fetal unit is at much higher risk than the mother due to lower clearance and longer overall exposure time. Continued research in this maternal−fetal model should now begin to determine the toxicodynamics of DA. These new TK parameters will also contribute to the development of a PBPK model in order to extrapolate this model to species, such as the California sea lion, that are at high risk for in utero DA poisoning.34
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ABBREVIATIONS AUC, area under the curve; BBB, blood−brain barrier; BCSFB, blood−cerebrospinal fluid barrier; CSF, cerebrospinal fluid; DA, domoic acid; GD, gestational day; ISF, interstitial fluid; I.V., intravenous; NCA, noncompartmental analysis; PBPK, physiologically based pharmacokinetics; TK, toxicokinetics
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AUTHOR INFORMATION
Corresponding Author
*Tel: +1-843-762-8510. Fax: +1-843-762-8700. E-mail: john.
[email protected]. Funding
This work was supported by the National Oceanic and Atmospheric Administration. Notes
This publication does not constitute an endorsement of any commercial product or intend to be an opinion beyond scientific or other results obtained by the National Oceanic and 2808
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