Abstract
Methamphetamine (MA) is one of the commonly used illicit drugs and the central nervous system toxicity of MA is well documented. The mechanisms contributing to this toxicity have not been fully elucidated. In this study, we investigated the effect of MA on the expression levels of the proinflammatory cytokines/chemokines, IL-6 and IL-8 in an astrocytic cell line. The IL-6 and IL-8 RNA levels were found to increase by 4.6 ± 0.2 fold and 3.5 ± 0.2 fold, respectively, after exposure to MA for three days. Exposure of astrocytes to MA for 24 hours also caused increased expression of IL-6 and IL-8 at the level of both RNA and protein. The potential involvement of the nuclear factor-Kappa B (NF-κB) pathway was explored as one of the possible mechanism(s) responsible for the increased induction of IL-6 and IL-8 by MA. The MA-mediated increases in IL-6 and IL-8 were significantly abrogated by SC514. We also found that exposure of astrocytes to MA results in activation of NF-κB through the phosphorylation of IκB-α, followed by translocation of active NF-κB from the cytoplasm to the nucleus. In addition, treatment of cells with a specific inhibitor of metabotropic glutamate receptor-5 (mGluR5) revealed that MA-mediated expression levels of IL-6 and IL-8 were abrogated by this treatment by 42.6 ± 5.8% and 65.5 ± 3.5%, respectively. Also, LY294002, an inhibitor of the Akt/PI3K pathway, abrogated the MA-mediated induction of IL-6 and IL-8 by 77.9 ± 6.6% and 81.4 ± 2.6%, respectively. Thus, our study demonstrates the involvement of an NF-κB-mediated signaling mechanism in the induction of IL-6 and IL-8 by MA. Furthermore, we showed that blockade of mGluR5 can protect astrocytes from MA-mediated increases of proinflammatory cytokines/chemokines suggesting mGluR5 as a potential therapeutic target in treating MA-mediated neurotoxicity.
Highlights
Methamphetamine (MA) is a psychostimulant in the amphetamine class of drugs and is one of the most commonly abused agents by illicit-drug users
Methamphetamine increases the expression of proinflammatory cytokines/chemokines in astrocytes The neurotoxic effects of MA have been attributed to its potential for inducing oxidative stress through dopamine (DA) receptor and dopamine transporter (DT) dependent mechanisms reviewed in [33,34,35]
These results clearly indicate that MA can increase the expression of proinflammatory cytokines/chemokines such as IL-6 and IL-8
Summary
Methamphetamine (MA) is a psychostimulant in the amphetamine class of drugs and is one of the most commonly abused agents by illicit-drug users. The interaction of MA with DA receptors and transporters has been shown to be associated with oxidative stress, which is among the several different mechanisms believed to be responsible for the central nervous system (CNS) toxicity associated with MA [3,4,5]. It is generally accepted that MA induces oxidative stress, which can increase proinflammatory cytokines by increasing the activities of transcription factors such as nuclear factor-Kappa B (NF-B), activator protein-1 (AP-1) and the cAMP-response element-binding protein (CREB) [17,18]. The role of dopamine receptors and transporters in MA-mediated oxidative stress and neuroinflammation has been extensively investigated [19,20]. The role of astrocytes has been relatively unexplored in terms of the regulation of inflammatory cytokines and the mechanisms underlying MAmediated expression of proinflammatory cytokines
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