4-hydroxy-2-nonenal and Amphetamine-Related-Disorders

Animal studies suggest that the widely used psychostimulant drug methamphetamine (MA) can harm brain dopamine neurones, possibly by causing oxidative damage. However, evidence of oxidative damage in brain of human MA users is lacking. We tested the hypothesis that levels of two "gold standard" products generated from lipid peroxidation, 4-hydroxynonenal (one of the most reactive lipid peroxidation aldehyde products) and malondialdehyde, would be elevated in post mortem brain of 16 dopamine-deficient chronic MA users compared with those in 21 matched control subjects. Derivatized aldehyde concentrations were determined by gas chromatography-mass spectrometry. In the MA group, we found significantly increased levels of 4-hydroxynonenal and malondialdehyde in the dopamine-rich caudate nucleus (by 67 and 75%, respectively) and to a lesser extent in frontal cortex (48 and 36%, respectively) but not in the cerebellar cortex. Approximately half of the MA users had levels of 4-hydroxynonenal falling above the upper limit of the control range in caudate and frontal cortex. A subgroup of MA users with high brain drug levels had higher concentrations of the aldehydes. Our data suggest that MA exposure in human causes, as in experimental animals, above-normal formation of potentially toxic lipid peroxidation products in brain. This provides evidence for involvement of oxygen-based free radicals in the action of MA in both dopamine-rich (caudate) and -poor (cerebral cortex) areas of human brain.

Topics: Adult; Age Factors; Aldehydes; Amphetamine-Related Disorders; Brain; Brain Chemistry; Dopamine; Female; Gas Chromatography-Mass Spectrometry; Humans; Male; Malondialdehyde; Methamphetamine; Uric Acid

It is known that methamphetamine (MA) causes rhabdomyolysis, myoglobinuria, and acute renal failure. We conducted an immunohistochemical study on the kidney of 22 forensic autopsy cases in which MA had been detected. Myoglobin was positive in 17 cases. The concentration of the blood MA in the myoglobin-positive cases (8.39+/-3.43 micromol/dl) was higher than -negative cases (0.198+/-0.076 micromol/dl). And, the 70 kDa heat shock protein (HSP70), 8-hydroxy-2'-deoxyguanosine (8-OH-dG), 4-hydroxy-2-nonenal (4-HNE), and Cu/Zn superoxide dismutase (SOD) were also stained positively in five, ten, 11, nine cases of examined, respectively. In addition, 80% of HSP70-positive cases were myoglobin-positive. Myoglobin was also observed in 60% of 8-OH-dG-positive, in 82% of 4-HNE-positive, and in 78% of SOD-positive cases, respectively. Therefore, myoglobin rather than MA itself might induce oxidative damage. From these results, it was considered that MA abuse had caused the skeletal muscle damage before death. In forensic autopsy cases of drug abusers, the antemortem situation is not often known. The present research suggested that in addition to the measurement of the concentration of MA, immunohistochemical staining of myoglobin, HSP70, 8-OH-dG, 4-HNE, and SOD offers important information for the diagnosis of MA poisoning.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Aldehydes; Amphetamine-Related Disorders; Autopsy; Biomarkers; Cause of Death; Deoxyguanosine; Female; HSP70 Heat-Shock Proteins; Humans; Immunohistochemistry; Kidney; Male; Methamphetamine; Middle Aged; Myoglobin; Oxidative Stress; Superoxide Dismutase