Enzymatic–nonenzymatic cellular antioxidant defense systems response and immunohistochemical detection of MDMA, VMAT2, HSP70, and apoptosis as biomarkers for MDMA (Ecstasy) neurotoxicity

Abstract

3,4-Methylenedioxymethamphetamine (MDMA)-induced neurotoxicity leads to the formation of quinone metabolities and hydroxyl radicals and then to the production of reactive oxygen species (ROS). We evaluated the effect of a single dose of MDMA (20 mg/kg, i.p.) on the enzymatic and nonenzymatic cellular antioxidant defense system in different areas of rat brain in the early hours (<6 hr) of the administration itself, and we identified the morphological expressions of neurotoxicity induced by MDMA on the vulnerable brain areas in the first 24 hr. The acute administration of MDMA produces a decrease of reduced and oxidized glutathione ratio, and antioxidant enzyme activities were significantly reduced after 3 hr and after 6 hr in frontal cortex. Ascorbic acid levels strongly increased in striatum, hippocampus, and frontal cortex after 3 and 6 hr. High levels of malonaldehyde with respect to control were measured in striatum after 3 and 6 hr and in hippocampus and frontal cortex after 6 hr. An immunohistochemical investigation on the frontal, thalamic, hypothalamic, and striatal areas was performed. A strong positive reaction to the antivesicular monoamine transporter 2 was observed in the frontal section, in the basal ganglia and thalamus. Cortical positivity, located in the most superficial layer was revealed only for heat shock protein 70 after 24 hr.

Acute and Chronic Effects of 3-4, Methylenedioxymethamphetamine on Pyramidal Cells of Hippocampus

“…The other finding was that the MDMA-induced toxicity in chronic-treated rats was more exaggerated than acute-treated rats. Consistent with our study, Riezzo et al showed that MDMA administration in rats caused cell death in the CA1 hippocampus (20). Furthermore, Kermanian et al reported an increase in dark cells in the hippocampus following MDMA administration (21).…”

“…Administration of MDMA causes rapid intracellular Ca 2+ influx, mitochondrial membrane depolarization and reactive oxygen species (ROS) production (22). It also causes oxidative stress, ROS generation (20) and glutathione (GSH) depletion (23) that lead to neurotoxic effects. It has been shown that GSH depletion causes spatial memory impairment (24).…”

Cytokines, Chaperones and Neuroinflammatory Responses in Heroin-Related Death: What Can We Learn from Different Patterns of Cellular Expression?

“…The international scientific panorama is actually rich with studies aimed to identify markers which can provide more and more accurate information about the time of onset of hypoxic-ischemic brain damage and inflammatory response in heroin-related death. However, data reported by the literature appear fragmentary and contradictory, often concerning experimental studies performed only on animals [29,30]. The histological study of the brain with traditional histochemical techniques can provide relevant data since it is well known that depending on mechanism, severity, and timing of the insult, the distribution and the histological pattern of lesions in the brain changes dramatically.…”

The timing of perinatal hypoxia/ischemia events in term neonates: a retrospective autopsy study. HSPs, ORP-150 and COX2 are reliable markers to classify acute, perinatal events

“…The histological study of the brain with traditional histochemical techniques can provide relevant data since it is well known that depending on mechanism, severity and timing of the insult, the distribution and the histological pattern of lesions in the brain changes dramatically [5,19]. By means of immunohistochemical techniques applied in studies both on animals and humans, it has been possible to identify in the brain tissue some markers of hypoxic-ischemic damage with reliable and reproducible results [20-23]. …”