title: 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.
authors.affiliation: Division of Pharmacology, UMKC-School of Pharmacy, Kansas City, MO 64108, USA.
authors.forename: Ankit
authors.initials: A
authors.lastname: Shah
authors.forename: Peter S
authors.initials: PS
authors.lastname: Silverstein
authors.forename: Dhirendra P
authors.initials: DP
authors.lastname: Singh
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
mesh_terms: D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D008694:Methamphetamine / Q000494:pharmacology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016207:Cytokines; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; C578935:GRM5 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D008694:Methamphetamine; D051058:Oncogene Protein v-akt