Involvement of metabotropic glutamate receptor 5, AKT/PI3K Signaling and NF-κB pathway in methamphetamine-mediated increase in IL-6 and IL-8 expression in astrocytes

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.

Melatonin promotes blood-brain barrier integrity in methamphetamine-induced inflammation in primary rat brain microvascular endothelial cells

“…The nuclear factor-ĸB (NF-κB) signaling is the major pathway that regulates the inflammatory cytokine expression and has been widely studied in inflammatory responses (Kawai and Akira, 2007). Previous studies have reported several stimuli such as lipopolysaccharide (LPS) and METH-induced inflammation in both neuronal cells and glial cells by the overactivation of NF-κB signaling (Flora et al, 2003;Shah et al, 2012;Wires et al, 2012;Perpoonpattana et al, 2013;Coelho-Santos et al, 2015;Jumnongprakhon et al, 2015). Therefore, the inhibition of these negative effects may be beneficial in protecting BBB impairment.…”

WITHDRAWN: Melatonin improves methamphetamine-induced blood brain barrier impairment through NADPH oxidase-2 in primary rat brain microvascular endothelium cells

“…Previous studies have reported several stimuli such as lipopolysaccharide (LPS) and METHinduced inflammation in both neuronal cells and glial cells by the overactivation of NF-κB signaling (Flora et al, 2003;Shah et al, 2012;Wires et al, 2012;Permpoonpattana et al, 2013;Coelho-Santos et al, 2015;Jumnongprakhon et al, 2015). Therefore, the inhibition of these negative effects may be beneficial in protecting BBB impairment.…”

The Cytokine Model of Schizophrenia: Emerging Therapeutic Strategies

“…The authors further showed that repeated administration of IL-6 sensitizes rats to the locomotor-stimulating effects of amphetamine, further suggesting a close interaction between IL-6 and the mesolimbic dopaminergic system (50). Furthermore, in an astrocytic cell line, both acute and chronic exposure to methamphetamine increased IL-6 mRNA and protein levels (51). …”