High doses of methamphetamine that cause disruption of the blood-brain barrier in limbic regions produce extensive neuronal degeneration in mouse hippocampus

Abstract

Histological examination of brain after a single high (40 mg/kg) dose of D-methamphetamine (METH) was used to determine the relationships between blood-brain barrier (BBB) disruption, hyperthermia, intense seizure activity, and extensive degeneration that this exposure often produces. In very hyperthermic mice (body temperatures > 40.5 degrees C) exhibiting status epilepticus, increase in mouse IgG immunoreactivity (IgGIR) in the medial and ventral amygdala was observed within 90 min after METH exposure. In a few instances, where body temperature was in the 40.0 degrees C range, such IgGIR was also seen in animals that had exhibited status epilepticus. Variable increases in IgGIR, which correlated with neurodegeneration, also occurred within 12 h in the hippocampus, indicating BBB disruption in this region also. Degenerating neurons, Fluoro-Jade C (FJ-C) labeled, were first detected 4 h after METH in the amygdala and hippocampus. Extensive neurodegeneration occurred in the amygdaloid and hippocampal pyramidal cell regions in animals with marked IgGIR increase in these regions by 12 and 24 h after METH. A very rapid activation of brain microglia and/or infiltration of macrophages in regions of notable IgGIR increase with intense neurodegeneration were seen within 24 h. The phagocytosis rate of neurons in the hippocampus was so rapid that FJ-C labeling was virtually nonexistent 3 days after METH. METH did not produce IgGIR increase or neurodegeneration in the limbic regions in the absence of hyperthermia and seizures. Thus, high doses of METH can cause damage to the BBB when hyperthermia occurs, resulting in rapid and extensive hippocampal and amygdalar damage. The BBB disruption in the medial amygdala occurs first, and may well be contributing to the induction and severity of seizures, while BBB disruption in the hippocampus is likely a result of the seizures and hyperthermia. This hippocampal damage should be sufficient to compromise learning and memory.

A Visual Description of the Dissection of the Cerebral Surface Vasculature and Associated Meninges and the Choroid Plexus from Rat Brain

“…The tissue harvest is suitable for biochemical and physiological analysis, and the MAV has been shown to be sensitive to damage produced by amphetamine and hyperthermia 1,2 through gene expression analysis. These results are commensurate with what is also known about severe hyperthermia and exposure to amphetamines to the brain vasculature in general 18,19,20 . Human clinical data supports the belief that the subdural vasculature is sensitive to damage by amphetamine and methamphetamine 21,22 .…”

FosB Null Mutant Mice Show Enhanced Methamphetamine Neurotoxicity: Potential Involvement of FosB in Intracellular Feedback Signaling and Astroglial Function

“…Evaluation of BBB integrity using IgG immunoreactivity was performed essentially as described (Bowyer and Ali, 2006a;Bowyer et al, 2008). Briefly, the same staining protocol as the tyrosine hydroxylase immunostaining was applied, except that sections were directly incubated with a biotin-conjugated anti-mouse IgG secondary antibody (1 : 2000; Vector) after the blocking step.…”

“…We attempted to omit microglia-like IgG-positive cells from the counts, though some minor ambiguities may have been introduced. As a precaution, we therefore designated these as 'IgG immunoreactive bodies' according to a previous study (Bowyer and Ali, 2006a). The density of IgG immunoreactive bodies was averaged in each brain area of individual animals and subjected to statistical analysis.…”

“…As we found that neuronal death was colocalized with BBB dysfunction, astroglial dysfunction may mediate the enhanced METH toxicity in the forebrains of FosB(À/À) mice. Indeed, several studies have reported the relevance of BBB dysfunction with neuronal death (Bowyer and Ali, 2006a;Kiyatkin et al, 2007). In the case of the excitotoxic injury model made by hippocampal kinate injection, however, neuronal death and BBB breakdown are separate, independent processes: BBB dysfunction occurs too late to initiate neurodegeneration, and BBB breakdown occurs without neuronal death (Chen et al, 1999).…”

Methamphetamine-induced neuronal necrosis: the role of electrographic seizure discharges

“…It is recognized that epileptic seizures can occur following METH administration (Bowyer and Ali, 2006;Cadet et al, 2007), but this has relied on behavioral observations alone. In this study we show that seizure-like behavior is not a reliable indication of electrographic seizure activity, that recording EEG activity should be done to determine if seizure discharges are present, and that widespread METH-induced neuronal necrosis only occurs in mice with repetitive electrographic seizure discharges (RESDs).…”