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Acute Administration of 3,4‐Methylenedioxymethamphetamine Induces Profound Hyperthermia, Blood–Brain Barrier Disruption, Brain Edema Formation, and Cell Injury
Author(s) -
Sharma Hari Shanker,
Ali Syed F.
Publication year - 2008
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1432.052
Subject(s) - mdma , glial fibrillary acidic protein , evans blue , hyperthermia , blood–brain barrier , neurochemical , neurotoxicity , chemistry , hippocampus , pharmacology , endocrinology , neuroscience , medicine , central nervous system , toxicity , biology , immunohistochemistry
The psychostimulant 3,4‐,ethylenedioxymethamphetamine (MDMA, “ecstasy”) is known to induce hyperthermia and alterations in neurochemical metabolism in the CNS. However, the detailed cellular or molecular mechanisms behind MDMA‐induced neurotoxicity are still not well known. Since MDMA induces profound hyperthermia that could lead to intense cellular stress and cause disruption of the blood–brain barrier (BBB), this investigation examined the effects of acute MDMA on BBB dysfunction, brain edema, and cell injury in rats and mice. When MDMA (40 mg/kg, i.p.) was administered to rats or mice, these animals exhibited profound behavioral disturbances (hyperactivity and hyperlocomotion) and hyperthermia (>40 to 41°C) at 4 h. At this time, the leakage of Evans blue dye was evident, particularly in the cerebellum, hippocampus, cortex, thalamus, and hypothalamus. This effect was most pronounced in mice compared to rats. Marked increase in brain water along with Na + , K + , and Cl – content was also seen in the aforementioned brain regions. Presence of distorted neuronal and glial cells in brain regions associated with leakage of Evans blue is quite common in MDMA‐treated animals. Increased albumin immunoreactivity, indicating breakdown of the BBB, and upregulation of glial fibrillary acidic protein (GFAP), suggesting activation of astrocytes, were seen in most brain regions showing edematous changes. Upregulation of heat‐shock protein (HSP72) immunoreactivity in the nuclei and cell cytoplasm of the neurons located in the edematous brain regions are quite common. Taken together, these observations are the first to show that MDMA has the capacity to disrupt BBB permeability to proteins and to induce the formation of edema, probably by inducing hyperthermia and cellular stress, as evident with HSP overexpression leading to cell injury.