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TOXICOLOGY
ESR Institute of Environmental Science and Research, Auckland, New Zealand (P.S.F.); Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, Toronto, Ontario, Canada (J.T., S.J.K.); Toronto General Hospital, Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada (M.Y., P.P.L.); and Division of Microbiology, Department of Environmental and Infectious Disease Sciences, Armed Forces Institute of Pathology, Washington, DC (K.S.K.)
Received June 7, 2006; accepted July 18, 2006.
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Abstract |
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). The behavioral actions of amphetamines are related, to some extent, to the ability of the drugs to cause release in brain of the neurotransmitter dopamine (Laruelle et al., 1995). This feature probably explains in large part our post mortem brain observation of markedly decreased dopamine levels in striatum (caudate, putamen) of chronic MA users who all tested positive for the drug at the time of death (Wilson et al., 1996; Moszczynska et al., 2004).
Because of evidence from experimental animal studies that high doses of MA can harm brain dopamine nerve endings (for review, see McCann and Ricaurte, 2004), there is public health concern that the drug could damage dopamine neurones in humans, even when administered under medical supervision for the treatment of attention-deficit hyperactivity disorder (Ricaurte et al., 2005). However, the absence of Parkinsonism reported as a characteristic of chronic MA exposure in human drug users indicates that such damage to nigrostriatal dopamine neurones, if present, could not be severe (see Discussion) (Moszczynska et al., 2004). There also exists in the imaging literature reports of a variety of different structural abnormalities in the brain of some self-reported human MA users (cf. Chang et al., 2005). Although a consistent pattern of structural damage has yet to emerge from the somewhat contradictory data, findings in some drug users of changes in brain that do not receive intense dopaminergic innervation (e.g., cerebral cortex, hippocampus; Thompson et al., 2004) allow for the possibility that some aspects of MA toxicity might not be dopamine-related (Gluck et al., 2001; Yuan et al., 2001).
One approach to the question of MA neurotoxicity in human brain is the measurement of indices of oxidative stress and damage. Animal data suggest that MA-induced damage to dopamine nerve endings could be explained by excessive oxidative stress possibly related to the formation of dopamine-derived oxidation products (for review, see Davidson et al., 2001). Because short-lived reactive oxygen species cannot yet be directly measured in human brain, the question could be addressed by measurement of levels of antioxidants (which might be expected to show compensatory changes) or concentrations of oxidatively damaged proteins, lipids, or DNA or products thereof. Previously, we showed that in post mortem brain of human MA users, levels of key antioxidant defenses were relatively preserved but with some markers showing modest changes suggestive of a compensatory response to oxidative stress (Mirecki et al., 2004).
We have now extended our biochemical analyses to include measurement, in post mortem brain of MA users, of levels of 4-hydroxynonenal (HNE) and malondialdehyde (MDA), two aldehydic products of oxidatively damaged lipids that have historically served as markers for lipoperoxidation (Esterbauer et al., 1991). We hypothesized that, as in most of the experimental animal studies in which MDA or MDA-like thiobarbituric acid reactive substances (TBARS) were reported to be increased in brain of MA-treated rodents (Acikgoz et al., 1998, 2000; Jayanthi et al., 1998; Yamamoto and Zhu, 1998; Kim et al., 1999; Kita et al., 2000; Wan et al., 2000; Gluck et al., 2001; Flora et al., 2002; Iwashita et al., 2004), levels of both oxidative markers would be above-normal in the dopamine-rich caudate nucleus of human MA users but less markedly increased (if at all) in brain areas having very low (frontal and cerebellar cortices) concentrations of dopamine. Our human post mortem data provide additional support to the notion based on animal models that MA can cause oxidative damage in human brain.
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Materials and Methods |
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; Tong et al., 2003; Moszczynska et al., 2004). The regional distribution of MA and its metabolite amphetamine in autopsied brain has been reported for 12 of the 16 MA cases (Kalasinsky et al., 2001). Dopamine levels in the caudate have been reported for all of the MA cases (see Table 1 and Moszczynska et al., 2004). This study was approved by the Institutional Review Board of the Centre for Addiction and Mental Health at Toronto. There were no statistical differences in age (control, 33.6 ± 2.2 years; MA, 32.4 ± 2.0 years; mean ± S.E.M.) or post mortem intervals (PMIs; interval between death and freezing of the brain; control, 13.1 ± 1.3 h; MA, 15.3 ± 1.7 h) between the control and MA users (Student's two-tailed t tests). At autopsy, one half-brain was fixed in formalin fixative for neuropathological analysis, whereas the other half was immediately frozen until dissection for neurochemical analysis. Blood samples were obtained from all of the MA users and the control subjects for drug screening. Scalp hair samples for drug analyses could be obtained from 18 of the 21 controls and 11 of the 16 MA users. Levels of drugs of abuse in blood and other bodily fluids were measured by the local medical examiner, whereas drug analyses in brain and hair samples were conducted at the Armed Forces Institute of Pathology (Washington, DC). All MA users met the following selection criteria: presence of MA on toxicology screens in blood, autopsied brain, and, where available, sequential scalp hair samples; absence of any other drugs of abuse in these tissues (and absence of blood ethanol); evidence from the case records and structured interviews with medical examiner investigators, next of kin, and informants, of use of MA for at least 1 year before death; and absence of neurological illness or brain pathology unrelated to use of the drug. The finding of MA (and metabolite amphetamine) in sequential hair samples in the absence of other psychostimulant and opiate drugs provides the strongest evidence that the subjects did not use these non-MA drugs of abuse in the recent (months) past. Examination of the case information disclosed no report of neurological illness (i.e., Parkinsonism) in any of MA users, although formal neurological testing had not been conducted.
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All control subjects were neurologically normal and had no evidence of brain pathology on neuropathological examination. All had no history of drug use and tested negative for drugs of abuse in blood, autopsied brain, and, in the 18 subjects in which scalp hair was available, sequential scalp hair samples. The cause of death for the controls were cardiovascular disease (n = 12), trauma (n = 7), drowning (n = 1), and leukemia (n = 1).
Aldehyde Derivatization and Extraction. HNE and MDA were measured by gas chromatography (GC)-negative ion chemical ionization-mass spectrometry (MS) using minor modifications of the method of Luo et al. (1995). All samples were analyzed in replicate by an unbiased observer (M.Y.) without knowledge of the source of the brain tissues. Standard solutions of 4-hydroxy-2-trans-nonenal (Calbiochem, La Jolla, CA), malondialdehyde (Sigma, St. Louis, MO), trans-4-hydroxy-nonenal-5,5,6,6,7,7,8,8,9,9,9-d11 [HNE(d11)] (CDN Isotopes, Quebec, Canada; synthesized by the acid hydrolysis of the diethyl and dimethyl acetylated parent compound), and deuterated benzaldehyde-2,3,4,5,6-d5 (CDN Isotopes) were used as deuterated internal and nondeuterated external calibration standards.
To 50 to 70 mg of frozen brain tissue, 800 pmol each of benzaldehyde-2,3,4,5,6-d5 and HNE(d11) internal standards were added and homogenized by sonication (Bronwill Biosonik; Bronwill, Rochester, NY) on ice in 800 µl of deionized H2O containing EDTA (400 µM) (Sigma), butylated hydroxy toluene (20 µM) (Sigma), and desferal (20 µM) (Novartis, Dorval, QC, Canada). Aldehydes were derivatized by the addition of O-(2,3,4,5,6-pentafluoro-benzyl) (PFB) hydroxylamine hydrochloride (Sigma) (0.05 M, 200 µl) and incubating for 60 min at room temperature. Tissue proteins were precipitated with 1 ml of ethanol, and O-PFB-oxime aldehyde derivatives were hexane-extracted by the addition of 2 ml of hexane, vortex-mixing for 1 min, and centrifugation for 5 min at 3000 rpm. The top hexane layer was transferred into clean borosilicate tubes, and the hexane extraction was repeated. The two hexane phases were combined, and residual moisture was removed with 0.5 g of sodium sulfate. The hexane solvent was evaporated under a stream of nitrogen gas, and the residue was incubated with 50 µl of N,O-bis(trimethylsilyl)trifluoroacetamide in 1% trimethylchlorosilane (Pierce Chemical, Rockford, IL) for 15 min at 80°C, forming the trimethylsilyl (TMS) ether derivatives of HNE. Hexane (50 µl) was added to each sample, vortex-mixed, and transferred into GC auto sampler vials, and 1 µl was analyzed by GC-negative ion chemical ionization-MS.
Chromatography. Derivatized aldehydes were analyzed using a 5973N mass selective detector GC-MS (Agilent Technologies, Palo Alto, CA) equipped with an HP-5ms capillary column (0.25-mm internal diameter, 0.25-µm film thickness, 30-m length; Hewlett Packard, Palo Alto, CA). Sample introduction was conducted using pulsed-splitless mode with helium carrier gas set at a constant flow rate of 1 ml/min. Mass spectrometry was performed in the negativeion chemical ionization mode with methane (1.2 ml/min) as the reagent gas. An initial oven temperature of 50°C was maintained for 1 min followed by an increase to 240°C at 10°C/min and to 300°C at 20°C/min and maintained at 300°C for 1 min. The injector temperature was maintained at 250°C, the GC to MS transfer line was maintained at 280°C, and the source temperature was set at 150°C. Derivatized aldehyde chromatographs were acquired in single ion monitor mode by recording m/z 333.1 and 283.3 for HNE-PFB-TMS derivative, m/z 204.1 for MDA-PFB derivative, 344.1 and 294.3 for HNE(d11)-PFB-TMS derivative, and m/z 286.1 for benzaldehyde-2,3,4,5,6-d5-PFB derivative.
HNE and MDA levels in tissues were quantitated by dividing the HNE or MDA chromatographic peak area by the internal standard peak area [i.e., HNE/HNE(d11) and MDA/benzaldehyde-2,3,4,5,6-d5] and interpolating the result via comparison with a standard curve constructed from ratios of known amounts of HNE/HNE(d11) and MDA/benzaldehyde-2,3,4,5,6-d5. The matrix used to construct this seven-point curve (linearity curve) was homogenized brain tissue. To estimate recovery, a standard mixture of HNE, MDA [including internal standards HNE(d11) and benzaldehyde-2,3,4,5,6-d5] was added to brain tissue homogenate. Following the procedures described above, the levels of HNE and MDA were quantified in both tissue and spiked tissue samples, and percentage recovery was calculated.
Statistical Analyses. Statistical analyses were performed by using STATISTICA 7.1 (StatSoft, Tulsa, OK). Differences in levels of the aldehydes between control and MA cases and between the brain regions were analyzed by one- or two-way ANCOVA, with PMI as the covariate, followed by post hoc Bonferroni's tests. Differences in percentage changes of the aldehydes between the brain regions were analyzed by paired Student's t tests. Correlations were examined by Pearson product moment correlation or Spearman ranking order correlation as indicated under Results.
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Results |
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Possible Influence of Age and PMI on Brain Levels of HNE and MDA. No statistically significant correlations (Pearson correlation coefficient r) were found between the age of the subjects, either controls or MA users, and levels of either HNE or MDA. Significant correlations between levels of HNE or MDA and PMI were limited to the caudate nucleus of the control subjects (HNE, r = 0.58, p = 0.01; MDA, r = 0.54, p = 0.01) and the frontal cortex of the MA users (HNE, r = 0.51, p = 0.04).
Increased Levels of HNE and MDA in Brain of Human Chronic MA Users. Regional levels of HNE and MDA in the MA users were significantly correlated (Pearson) with each other (caudate, r = 0.60, p = 0.01; frontal cortex, r = 0.90, p < 0.001; cerebellar cortex, r = 0.84, p < 0.001), whereas in the controls, the correlation was significant for caudate (r = 0.77, p < 0.001) and cerebellar cortex (r = 0.92, p < 0.001) but not for frontal cortex (r = 0.17, p = 0.47). As shown in Table 2 and Fig. 1, HNE and MDA levels were significantly elevated in the caudate nucleus (+67 and +75%, respectively) and, to a lesser extent, in the frontal cortex (+48 and +36%, respectively) of the MA users compared with those in the control subjects. The changes were also statistically significant using ANCOVA with post mortem time and/or age as covariates and when using analysis of variance. The slight (+14–15%) increases in HNE and MDA concentrations in cerebellar cortex of the MA users did not achieve statistical significance. Examination of the individual subject data revealed that the caudate striatal and frontal cortical values for the MA users were somewhat more scattered than the control subjects (see Fig. 1).
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Aldehyde Correlations with MA and Dopamine in the MA Users. Previously, we showed that levels of MA plus its metabolite amphetamine ("total MA levels") are homogenously distributed throughout the post mortem brain of chronic MA users (Kalasinsky et al., 2001). To establish whether aldehyde concentrations might have been influenced by the amount of MA recently taken, correlations (Spearman) were made between levels of aldehydes in the three brain regions examined and MA plus amphetamine concentrations in the occipital cortex. The correlations between brain levels of the aldehydes and drug levels were positive but only modest and not statistically significant (r = 0.37–0.47, n = 16), with that for MDA in the caudate nucleus just missing statistical significance (r = 0.47, p = 0.06). However, by subgrouping the MA users according to the brain drug level (Table 3), those with high brain drug levels (>20 nmol/g tissue) had significantly higher (by 41 and 53% in the caudate and by 69 and 73% in the frontal cortex) concentrations of the aldehydes and higher percentage increases (versus control levels) of the aldehydes in both the caudate and frontal cortex than those with lower drug levels (<16 nmol/g tissue). As shown in Fig. 1, the high drug level group had most (HNE and MDA in caudate and MDA in frontal cortex) or all (HNE in frontal cortex) of the individual subject aldehyde values above the upper limit of the control range.
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Although the high drug level group had a nonsignificant trend for lower dopamine levels in the caudate (Table 3), no significant correlation (Pearson) was observed between aldehyde and dopamine levels in the caudate (HNE, r = –0.18, p = 0.51; MDA, r = –0.15, p = 0.58). There was also no significant correlation (Pearson, r = 0.07 to –0.32, p > 0.33) between levels of the aldehydes and the duration of drug use in those cases (n = 11) for which some estimate of duration information was available.
Correlations with Brain Levels of the Antioxidants in the MA Users. Possible correlations (Pearson) in the MA users between levels of HNE or MDA and our previous reported (Mirecki et al., 2004) concentrations of several indices of brain antioxidant systems, namely reduced glutathione, Cu-Zn superoxide dismutase, and uric acid, were explored. Statistically significant correlations were limited to a positive correlation between levels of uric acid and HNE (r = 0.57, p < 0.05) and MDA (r = 0.51, p < 0.05) in the frontal cortex. A trend was also observed for a positive correlation between levels of uric acid and HNE (r = 0.46, p = 0.07) and MDA (r = 0.49, p = 0.05) in the caudate.
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Discussion |
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Limitations of the Post Mortem Brain Study. We attempted to address, as much as possible, a variety of confounding variables (e.g., age, post mortem time, uncertainty of drugs used) that are generic to autopsied human brain investigations of psychostimulant drug users. In this regard, the control and MA groups were matched with respect to age and post mortem time. Similar to the MA users, most of the control subjects died a "sudden" death. The limited or absence of significant correlations between the post mortem time and tissue levels of the aldehydes was consistent with earlier findings on MDA-like TBARS levels in a prospective animal study (up to 48 h post mortem; Dexter et al., 1989) and in a retrospective human brain study (10–70 h; Lyras et al., 1997). To ensure as much as possible that any differences in the MA group could be attributed to MA, forensic drug analyses were conducted in blood, brain, and, where available, hair of the drug users and controls to confirm use of MA and lack of use of other drugs that could be detected by these methods. However, we cannot exclude the possibility that the MA users might have taken other central nervous system-active drugs or had other characteristics that could have influenced levels of the outcome measures.
HNE and MDA in Normal Human Brain. A variety of procedures to measure levels of HNE and MDA in biological samples have been developed (for review, see Esterbauer and Zollner, 1989). The GC-MS method employed in the present study has the advantages of mass specificity, high sensitivity allowing for detection of HNE at the level of 50 fmol (Luo et al., 1995), mild derivatization conditions to minimize the artifactual production of lipid peroxidation aldehydic products during the experimental processes (see below), and simultaneous detection and quantification of both HNE and MDA in one sample. The use of stable, deuterated internal standards has addressed early concerns that the recovery of HNE might not be quantitative (Luo et al., 1995).
The concentration of MDA we observed in post mortem brain of normal subjects is similar to that in reports employing the improved TBARS assay coupled to HPLC separation (Hayn et al., 1996; Lyras et al., 1997; Odetti et al., 2000) and in studies using the colorimetric assay based on reactions of the aldehyde to N-methyl-2-phenyl-indole (Yoshida et al., 2000; Schuessel et al., 2004). The brain levels of HNE we obtained (
1 pmol/mg wet tissue) are within the physiological concentration range of HNE in biological tissues or fluids (1 µM; Esterbauer et al., 1991) and also agree with those reported using direct HPLC/UV detection of HNE (Odetti et al., 2000). However, post mortem human brain HNE concentrations reported by one group using an liquid chromatography-MS method (Williams et al., 2005b) and earlier by HPLC fluorescence detection (Markesbery and Lovell, 1998) are approximately 10-fold higher than those we obtained. This discrepancy could be explained by differences in the derivatization procedures because the above studies employed incubation at 60°C for 1 h in the absence of chelating reagents and antioxidants (Williams et al., 2005a; versus room temperature for 1 h in the presence of butylated hydroxy toluene and desferal in our study), which might promote in vitro lipid decomposition and production of aldehyde products including HNE.
HNE and MDA in MA Users. The simplest explanation for the HNE and MDA increases in the human MA users is that the psychostimulant induces oxidative stress in human brain, as in the case in animal models.
We predicted that aldehyde levels might be related to the recent "extent" of MA used by the drug users as indicated by brain drug levels and by the extent of (caudate) dopamine depletion most likely caused by MA and also by regional differences in dopamine levels in normal brain.
Brain levels of MA can provide some general index of recent drug use; however, interpretation of correlations of outcome measures with this estimate will be confounded to some extent by individual differences in drug metabolism, interval (usually uncertain) between last use of the drug and death, and in post mortem redistribution of MA between brain and other organs. Although only a nonsignificant trend for a positive association between brain levels of total MA and concentrations of the aldehydes could be observed, the subgroup of MA users having high brain drug levels had significantly higher concentrations of the aldehydes. To the extent that brain levels of MA are representative of amount of recent drug use, this suggests that part of the aldehyde increase could be explained by an acute (e.g., hours to days) exposure to MA as is the case in animal models (Acikgoz et al., 1998, 2000; Jayanthi et al., 1998; Yamamoto and Zhu, 1998; Kim et al., 1999; Kita et al., 2000; Wan et al., 2000; Gluck et al., 2001; Flora et al., 2002; Iwashita et al., 2004). Nevertheless, the possibility also has to be considered that chronic drug exposure (e.g., involving tolerance, sensitization) might also have modulated the effects of an acute exposure, as suggested by some animal data (Acikgoz et al., 1998, 2000).
Our working model, based on animal findings, was that the aldehyde increase would be inversely related to the extent of tissue dopamine depletion, which we suspect is an index of the severity of a pharmacological action of MA, and would be more marked in dopamine-rich versus -poor regions. Although we could not find an association in the MA users between caudate dopamine levels and HNE/MDA concentrations, we did find, as did those animal investigations in which multiple regions were examined (Kim et al., 1999; Gluck et al., 2001), that the extent of increase in the lipoperoxidation markers was most marked in the dopamine-rich (5000 ng/g tissue; Wilson et al., 1996) caudate and least (+14–15%, not significant) in the dopamine-poor (3 ng/g tissue; S.J. Kish, unpublished data) cerebellar cortex. Given that MA is homogeneously distributed throughout the post mortem brain (including cerebellar cortex) of the MA users (Kalasinsky et al., 2001), the animal and human post mortem data showing partial dopamine selectivity of changes in lipoperoxidation markers point toward the involvement of dopamine as a factor involved in promoting lipoperoxidation (e.g., MA-induced formation of dopamine-derived oxyradicals; Davidson et al., 2001). Although dopamine levels are very low and similar in frontal and cerebellar cortices (S. J. Kish, unpublished data) (Scatton et al., 1983), our finding that aldehyde levels were substantially elevated in frontal cortex but not in the cerebellar cortex could be explained by a more intense dopaminergic innervation of cerebral cortex (Melchitzky and Lewis, 2000; Swanson et al., 2006), although the question of cerebellar cortical innervation seems not to have been resolved in the human (Olsson et al., 1999; Melchitzky and Lewis, 2000). However, a case can also be made that part of the increase in HNE/MDA was not restricted to dopamine neurones. Indeed, it has been recently suggested that MA neurotoxicity might not be dopamine dependent (Gluck et al., 2001; Yuan et al., 2001).
HNE, MDA, and Brain Damage in MA Users? Although this topic is debated, findings in abstinent MA users suggest that MA might cause some structural damage to dopamine neurones but also that the damage is probably modest (for review, see Moszczynska et al., 2004; Johanson et al., 2006). In this regard, although formal neurological testing had not been conducted, examination of the MA case information did not disclose any report of obvious neurological illness. Because MDA and especially HNE have been used historically as gold standard markers of lipoperoxidation (Esterbauer et al., 1991), our data strongly suggest that oxidative damage to lipids in striatum and cerebral cortex of human MA users is, on average, increased over normal basal levels. The finding that one-half of the MA users, in particular those with high brain drug levels, had values for HNE (considered to be one of the most reactive aldehydes) falling above the upper limit of the control range in caudate and frontal cortex suggests that brain lipoperoxidative changes in some MA users can be "robust." The extent of increase in the lipoperoxidation markers we observed was also similar to that reported in experimental animal toxicity studies where MA was administered at doses that can cause persistent loss of dopamine nerve terminal markers, morphological signs of structural damage (cf. McCann and Ricaurte, 2004), and gliosis (O'Callaghan and Miller, 1994). Although the finding of increased levels of oxidatively damaged lipid products does not constitute proof of neurotoxic damage, it does suggest that the risk of toxicity due to oxidative stress is probably increased with recreational use of MA.
In conclusion, our post mortem data suggest that MA can increase pro-oxidant processes in both dopamine rich and poor areas of human brain and, in this respect, provide support for the relevance to the human of animal models of MA exposure in which similar findings have been reported.
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Footnotes |
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The assertions and opinions contained herein are the private views of the authors and are not to be construed as official or as reflecting views of the United States Department of Army or Department of Defense.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: MA, methamphetamine; HNE, 4-hydroxynonenal; HNE(d11), trans-4-hydroxy-nonenal-5,5,6,6,7,7,8,8,9,9,9-d11; MDA, malondialdehyde; TBARS, thiobarbituric acid reactive substances; PMI, post mortem interval; GC, gas chromatography; MS, mass spectrometry; TMS, trimethylsilyl; ANCOVA, analysis of covariance; HPLC, high-performance liquid chromatography; PFB, 2,3,4,5,6-pentafluoro-benzyl.
Address correspondence to: Dr. Stephen Kish, Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario M5T 1R8, Canada. E-mail: stephen_kish{at}camh.net
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