Is brain gliosis a characteristic of chronic methamphetamine use in the human?
Animal data show that high doses of the stimulant drug methamphetamine can damage brain dopamine neurones; however, it is still uncertain whether methamphetamine, at any dose, is neurotoxic to human brain. Since gliosis is typically associated with brain damage and is observed in animal models of methamphetamine exposure, we measured protein levels (intact protein and fragments, if any) of markers of microgliosis (glucose transporter-5, human leukocyte antigens HLA-DRα [TAL.1B5] and HLA-DR/DQ/DPβ [CR3/43]) and astrogliosis (glial fibrillary acidic protein, vimentin, and heat shock protein-27) in homogenates of autopsied brain of chronic methamphetamine users (n=20) and matched controls (n=23). Intact protein levels of all markers were, as expected, elevated (+28%-1270%, P<0.05) in putamen of patients with the neurodegenerative disorder multiple system atrophy (as a positive control) as were concentrations of fragments of glial fibrillary acidic protein, vimentin and heat shock protein-27 (+170%-4700%, P<0.005). In contrast, intact protein concentrations of the markers were normal in dopamine-rich striatum (caudate, putamen) and in the frontal cortex of the drug users. However, striatal levels of cleaved vimentin and heat shock protein-27 were increased (by 98%-211%, P<0.05), with positive correlations (r=0.41-0.60) observed between concentrations of truncated heat shock protein-27 and extent of dopamine loss (P=0.006) and levels of lipid peroxidation products 4-hydroxynonenal (P=0.046) and malondialdehyde (P=0.11). Our failure to detect increased intact protein levels of commonly used markers of microgliosis and astrogliosis could be explained by exposure to methamphetamine insufficient to cause a toxic process associated with overt gliosis; however, about half of the subjects had died of drug intoxication suggesting that "high" drug doses might have been used. Alternatively, drug tolerance to toxic effects might have occurred in the subjects, who were all chronic methamphetamine users. Nevertheless, the finding of above-normal levels of striatal vimentin and heat shock protein-27 fragments (which constituted 10-28% of the intact protein), for which changes in the latter correlated with those of several markers possibly suggestive of damage, does suggest that some astrocytic "disturbance" had occurred, which might in principle be related to methamphetamine neurotoxicity or to a neuroplastic remodeling process. Taken together, our neurochemical findings do not provide strong evidence for either marked microgliosis or astrogliosis in at least a subgroup of human recreational methamphetamine users who used the drug chronically and shortly before death. However, a logistically more difficult quantitative histopathological study is needed to confirm whether glial changes occur or do not occur in brain of human methamphetamine (and amphetamine) users.
Human Brain Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Addiction Imaging Research Group, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. Electronic address: junchao.tong@camh.ca.
Junchao
J
Tong
ESR Institute of Environmental Science & Research, Auckland, New Zealand.
Paul
P
Fitzmaurice
Department of Neurology, Juntendo Tokyo Koto Geriatric Medical Center, and Faculty of Medicine, University & Postgraduate University of Juntendo, Tokyo, Japan.
Yoshiaki
Y
Furukawa
Office of the Polk County Medical Examiner, Des Moines, IA, USA.
Gregory A
GA
Schmunk
Clark County Office of the Medical Examiner, Vancouver, WA, USA.
Dennis J
DJ
Wickham
Division of Neuropathology, London Health Science Centre, University of Western Ontario, London, Ontario, Canada.
Lee-Cyn
LC
Ang
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Allan
A
Sherwin
Human Brain Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Tina
T
McCluskey
Addiction Imaging Research Group, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Isabelle
I
Boileau
Human Brain Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Stephen J
SJ
Kish
D000293:Adolescent; D000328:Adult; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D000697:Central Nervous System Stimulants; D005260:Female; D005911:Gliosis / Q000139:chemically induced* / Q000378:metabolism; D006801:Humans; D008297:Male; D008694:Methamphetamine; D055815:Young Adult
D000697:Central Nervous System Stimulants; D008694:Methamphetamine
Glial fibrillary acidic protein; Gliosis; Glucose transporter-5; Heat shock protein-27; Human leukocyte antigen; Methamphetamine; Multiple system atrophy; Postmortem human brain; Tolerance; Vimentin