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-DR alpha. [TAL1B5] and HLA-DR/DQ/DP beta [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. (C) 2014 Elsevier Inc. All rights reserved.