Is brain gliosis a characteristic of chronic methamphetamine use in the human?
Introduction
High doses of the psychostimulant drug methamphetamine (MA) can damage brain dopamine neurones in experimental animal studies (see Cadet et al., 2003, O'Callaghan et al., 2008, Yamamoto et al., 2010 for reviews), and it has been speculated that even “low” doses of amphetamine used clinically in psychiatry might cause brain damage (Ricaurte et al., 2005). Further, results of an epidemiological study revealed increased risk of development of Parkinson's disease in hospitalized patients with MA-use disorders (Callaghan et al., 2012). However, dopamine neurone loss has been difficult to prove in the human, primarily because of uncertainty whether reported low levels of brain dopamine nerve terminal markers (e.g., dopamine, dopamine transporter; for extensive review see (Kish, 2014)) in human MA users equal actual “physical” damage to the neurone.
Some attention therefore has been focused on whether brain of MA users displays signs of either microgliosis or astrogliosis, as these cellular changes, although not equaling brain damage, are typically observed following brain injury in general (Kreutzberg, 1996, Ridet et al., 1997), and in brain, primarily in the dopamine-rich striatum, of experimental animals exposed to high doses of MA (or amphetamine) (Escubedo et al., 1998, Hess et al., 1990, Krasnova et al., 2010, O'Callaghan and Miller, 1994, O'Callaghan et al., 2008, Thomas et al., 2004). Gliosis is a natural reactive process of glial cells (astrocytes and microglia) to brain injury, damage, infection, or disturbed homeostasis and is characterized in part by increased expression of glial-specific proteins and morphologically hypertrophied cell body and processes, and in some cases, also cell proliferation and migration. The functions of gliosis following brain injury and whether the response is helpful or detrimental continue to be debated (Sofroniew and Vinters, 2010, Streit, 2010, Zhang et al., 2010), but most likely include removal of cellular debris, wound repair, and possibly, some involvement in neuroregeneration.
In our postmortem (forensic) neuropathological examinations of brains of human MA users we did not observe any obvious signs of above-normal gliosis (Moszczynska et al., 2004); however, these findings are uncertain as no quantitative assessment could be performed on the material. The literature on this question is scanty and contradictory, limited to a brain imaging finding of massively increased binding of a putative marker of activated microglial cells (11C-PK11195) throughout the brain of abstinent MA users (Sekine et al., 2008) and a neuropathological investigation showing increased number of glucose transporter-5 (GLUT-5)-positive microglia in striatum of users who died of MA intoxication, but no evidence of reactive microgliosis (GLUT-5 or CR3/43) or astrocytosis [glial fibrillary acidic protein (GFAP) or S100B] (Kitamura et al., 2010).
The aim of our study was to establish, using measurement of protein levels of generally accepted markers of microglia and astroglia in postmortem brain homogenates, whether experimental animal findings showing brain gliosis following MA exposure might be relevant to chronic human (recreational) use of the drug. We hypothesized that concentrations of all gliosis markers would be above-normal in the dopamine-rich striatum, but less so, if at all, in dopamine-poor brain areas.
Section snippets
Brain materials
Postmortem brain from a total of 23 controls (21 males, 2 females) and 20 chronic users of MA (14 males, 6 females) was obtained from medical examiner offices in the USA and Canada using a standardized protocol. The study was approved by the Research Ethics Board of the Centre for Addiction and Mental Health at Toronto. Patient information, drug histories, and brain drug and dopamine levels are summarized in Table 1, with the information having been previously reported (Kalasinsky et al., 2001,
Neuropathological findings in brain of methamphetamine users
Quantitative histopathological examination of the formalin-fixed half brain was problematic because of incomplete fixation in many of the cases. Routine (qualitative only) neuropathological analysis of cerebral cortical and subcortical areas of the MA users did not reveal significant abnormalities including gliosis in any brain areas with the exception of prominent gliosis (by GFAP immunohistochemistry) and infarcts in putamen in case #M20 and mild gliosis in the substantia nigra in case #M13.
Discussion
The major finding of our study is that levels of protein markers of microgliosis and astrogliosis were, unexpectedly, normal in brain homogenates of chronic MA users, although concentrations of fragments of two markers (vimentin, Hsp27) were above normal.
Acknowledgments
This study was supported in part by the US NIDA/NIH DA07182, the New Zealand Institute of Environmental Science and Research, Ltd. and the Centre for Addiction and Mental Health Foundation.
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