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Acute administration of 3,4-methylenedioxymethamphetamine induces profound hyperthermia, blood-brain barrier disruption, brain edema formation, and cell injury.
Ann N Y Acad Sci 2008; 1139:242-58AN

Abstract

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 degrees 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.

Authors+Show Affiliations

Laboratory of Neurochemistry, Division of Neurotoxicology, National Center of Toxicological Research, Food and Drug Administration, Jefferson, Arkansas, USA. Sharma@surgsci.uu.seNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18991870

Citation

Sharma, Hari Shanker, and Syed F. Ali. "Acute Administration of 3,4-methylenedioxymethamphetamine Induces Profound Hyperthermia, Blood-brain Barrier Disruption, Brain Edema Formation, and Cell Injury." Annals of the New York Academy of Sciences, vol. 1139, 2008, pp. 242-58.
Sharma HS, Ali SF. Acute administration of 3,4-methylenedioxymethamphetamine induces profound hyperthermia, blood-brain barrier disruption, brain edema formation, and cell injury. Ann N Y Acad Sci. 2008;1139:242-58.
Sharma, H. S., & Ali, S. F. (2008). Acute administration of 3,4-methylenedioxymethamphetamine induces profound hyperthermia, blood-brain barrier disruption, brain edema formation, and cell injury. Annals of the New York Academy of Sciences, 1139, pp. 242-58. doi:10.1196/annals.1432.052.
Sharma HS, Ali SF. Acute Administration of 3,4-methylenedioxymethamphetamine Induces Profound Hyperthermia, Blood-brain Barrier Disruption, Brain Edema Formation, and Cell Injury. Ann N Y Acad Sci. 2008;1139:242-58. PubMed PMID: 18991870.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Acute administration of 3,4-methylenedioxymethamphetamine induces profound hyperthermia, blood-brain barrier disruption, brain edema formation, and cell injury. AU - Sharma,Hari Shanker, AU - Ali,Syed F, PY - 2008/11/11/pubmed PY - 2008/12/17/medline PY - 2008/11/11/entrez SP - 242 EP - 58 JF - Annals of the New York Academy of Sciences JO - Ann. N. Y. Acad. Sci. VL - 1139 N2 - 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 degrees 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. SN - 1749-6632 UR - https://www.unboundmedicine.com/medline/citation/18991870/Acute_administration_of_34_methylenedioxymethamphetamine_induces_profound_hyperthermia_blood_brain_barrier_disruption_brain_edema_formation_and_cell_injury_ L2 - https://doi.org/10.1196/annals.1432.052 DB - PRIME DP - Unbound Medicine ER -