Protective Role for the Disulfide Isomerase PDIA3 in Methamphetamine Neurotoxicity

Methamphetamine abuse continues to be a worldwide problem, damaging the individual user as well as society. Only minimal information exists on molecular changes in the brain that result from methamphetamine administered in patterns typical of human abusers. In order to investigate such changes, we examined the effect of methamphetamine on the transcriptional profile in brains of monkeys. Gene expression profiling of caudate and hippocampus identified protein disulfide isomerase family member A3 (PDIA3) to be significantly up-regulated in the animals treated with methamphetamine as compared to saline treated control monkeys. Methamphetamine treatment of mice also increased striatal PDIA3 expression. Treatment of primary striatal neurons with methamphetamine revealed an up-regulation of PDIA3, showing a direct effect of methamphetamine on neurons to increase PDIA3. In vitro studies using a neuroblastoma cell line demonstrated that PDIA3 expression protects against methamphetamine-induced cell toxicity and methamphetamine-induced intracellular reactive oxygen species production, revealing a neuroprotective role for PDIA3. The current study implicates PDIA3 to be an important cellular neuroprotective mechanism against a toxic drug, and as a potential target for therapeutic investigations

PDIA3 is increased by METH in rodents <i>in vivo</i>.

<p>Time course of gene expression, determined by qRTPCR, in striatum from mice treated with 10 mg/kg METH at the indicated time points. (A) PDIA3 (B) HSPA5 (as a positive control). *p<0.05 as determined by a one-way ANOVA followed by a post hoc Tukey's test.</p

METH induction of PDIA3 <i>in vitro</i> in rodent neurons.

<p>Primary rat striatal neurons (8 DIV) stained for levels and distribution of PDIA3 after 250 µM METH treatment for 24 h along with MAP2 staining for neuronal structure and DAPI for cell nucleus. Control cells show basal levels of PDIA3 while cells treated with METH show an increase and redistribution of PDIA3 along the neuronal processes indicated by arrowheads. Scale bar = 10 µm.</p

PDIA3 is increased in by METH in monkeys <i>in vivo</i>.

<p>Levels of PDIA3 mRNA expression from qRTPCR in brain regions from the two groups of animals, differing only by METH treatment. (A) caudate and (B) hippocampus. **p<0.01, unpaired Student's t-test.</p

List of genes up-regulated in both the caudate and hippocampus from SIV infected, METH and PBS administered monkeys.

<p>The gene symbol, gene name, p-value (unpaired Student's t-test) and fold change between the groups is indicated. Genes with p<0.01 and a fold change of >2 in both regions are shown.</p