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
© Shah et al; licensee BioMed Central Ltd. 2012
Received: 7 January 2012
Accepted: 15 March 2012
Published: 15 March 2012
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.
Keywordsgp120 IL-8 Astrocytes NF-kB siRNA
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 effects of MA are primarily attributed to its action on dopamine (DA) receptors and transporters [1, 2]. Furthermore, 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 [3–5]. In addition to oxidative stress, MA has been shown to increase mitochondrial dysfunction, excitotoxicity , blood brain barrier (BBB) damage [6–8] and monocyte infiltration into the CNS  along with increased levels of inflammatory markers such as IL-6 and TNF-α .
The proinflammatory cytokines/chemokines IL-6 and IL-8 are among the inflammatory responses associated with various neurological disorders including Parkinson's disease , Alzheimer's disease , and amyotrophic lateral sclerosis (ALS) . A single high dose of MA has been shown to induce IL-6 and TNF-α in the striatum and hippocampus of mice [14, 15] and IL-1β in the hypothalamus of rats . However, the specific molecular mechanism(s) involved in the increased expression of these proinflammatory cytokines is still unknown. 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-κB), activator protein-1 (AP-1) and the cAMP-response element-binding protein (CREB) [17, 18]. Furthermore, the role of dopamine receptors and transporters in MA-mediated oxidative stress and neuroinflammation has been extensively investigated [19, 20]. A more direct cytotoxic role of MA has been demonstrated to be mediated by the c-Jun N-terminal kinases/mitogen-activated protein kinase (JNK-MAPK) pathway followed by the activation of caspases and the induction of apoptosis . However, the role of astrocytes has been relatively unexplored in terms of the regulation of inflammatory cytokines and the mechanisms underlying MA-mediated expression of proinflammatory cytokines.
Low levels of cytokines and chemokines are constitutively expressed by microglia in the CNS and these can be induced to higher levels by inflammatory mediators [22, 23]. However, astrocytes constitute the major cell type present in the brain. Astrocytes are also involved in regulation of numerous pro- and anti-inflammatory cytokines . Oxidative stress in astrocytes is found to be mediated via Akt/PI3K, Nrf2 and NF-κB pathways . Increased inflammatory markers released from astrocytes is associated with a variety of CNS complications such as Alzheimer's disease , multiple sclerosis, glaucoma  and Parkinson's disease . Furthermore, astrocyte activation has been shown to be critical in the regulation of the rewarding effects induced by drugs of abuse . Thus, it is important to consider the role of astrocytes in neuroinflammatory signaling induced by MA. Our present study was undertaken to address whether MA induced proinflammatory cytokines in astrocytes and to determine the mechanisms responsible for MA-mediated expression of these cytokines.
Materials and methods
Cell culture and reagents
All the experiments were performed using SVGA, a clone of SVG astrocytes . The cells were cultured at 37°C in a humidified chamber with 5% CO2 in Dulbecco's Modified Eagle's Medium supplemented with 10% FBS, 1% L-glutamine, 1% sodium bicarbonate, 1% non-essential amino acids and 0.1% gentamicin. The cells were allowed to adhere overnight before any treatment. All the experiments lasted for three days and were performed in T-75 flasks. For MA treatments the cells were treated once a day with the drug.
MA and MPEP (an mGluR5 antagonist) were obtained from Sigma (Sigma-Aldrich, St. Louis, MO, US). SC514 and LY294002 were obtained from Cayman chemicals (Cayman Chemicals, Ann Arbor, MI, US). The antagonist treatment was given 1 hour prior to the treatments with MA every day. Specific antibodies against Phospho-IκB-α (Ser32) (14D4), β Tubulin (D-10), Actin (C-2), IκB-α, Lamin B (C-20) and NF-κB p50 (H-119) were obtained from Santa Cruz Biotechnology (Santa Cruz, CA, US).
Real time RT PCR
SVGA astrocytes were harvested and lysed using RIPA buffer (Boston BioProducts, Ashland, MA, US) upon termination of the treatments to obtain whole cell lysates. Nuclear and cytoplasmic extracts of the cells were prepared using a NE-PER Nuclear Extraction kit (Thermo Fisher, Rockford, IL, US) according to the manufacturer's protocol. The proteins were separated and visualized using western blot analysis as mentioned previously .
Cell viability assay
SVGA astrocytes were enzymatically isolated in the culture medium and stained with 0.4% W/V trypan blue. The total cell count was obtained using a hemocytometer chamber by excluding the dead cells which were stained with the dye.
SVGA cells (4 × 105) were cultured on glass cover slips in a 12-well plate and treated with 500 μM of MA. The culture media was supplemented with 1 mg/ml GolgiStop™ (BD Biosciences, San Jose, CA, US) 6 hours prior to termination of the incubation in order to prevent the release of the cytokines. After 24 hours of incubation with MA the cells were fixed with 1:1 ice-cold methanol for 20 minutes at -20°C. The cells were rinsed three times with cold PBS and permeabilized with PBS containing 0.1% Triton X-100 (PBST). The cells were washed three times with PBS followed by blocking with 1% BSA in 0.1% PBST for 30 minutes at room temperature. All the antibodies were diluted in blocking buffer. After blocking, the cells were incubated with either rabbit anti-IL-6 (1:500) or rabbit anti-IL-8 (1:500) and mouse MAb anti-GFAP (GH5) (1:1500) at 4°C overnight in a humidified chamber. After three washes for 5 minutes each with PBS, the cells were incubated in the dark for 1 hour at room temperature with blocking buffer containing either anti-mouse antibody conjugated with Alexa Fluor 555 (1:1000), or anti-rabbit antibody conjugated with Alexa Fluor 488. Finally, the cells were washed three times with PBS for 5 minutes each and mounted on a slide with 10 μl of Vectashield mounting medium with DAPI (Vector Laboratories, Burlingame, CA, US). The fluorescence was observed using a fluorescent Nikon Eclipse E800 confocal microscope (Nikon Instruments, Melville, NY, US). The images were captured using a 60× zoom lens.
All the data are expressed as mean ± SE of three independent experiments with each experiment done in triplicate. The statistical significance was calculated using Student's t-test and a significant value of P < 0.05 was considered to be statistically significant.
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 [33–35]. We wished to determine whether MA could increase the expression of proinflammatory cytokines/chemokines such as IL-6 and IL-8 in astrocytes. SVGA astrocytes were treated with 250 μM, 500 μM and 1000 μM of MA for 24 hours. The doses of MA were physiologically relevant based on the levels of MA found in post-mortem brain samples from MA abusers (0.8 to 1 mM) . The mRNA expression levels of IL-6 and IL-8 showed a dose-dependent increase. The MA-induced expression of IL-6 and IL-8 was found to be 1.7 ± 0.1, 2.7 ± 0.1, and 4.2 ± 0.2 fold and 1.4 ± 0.1, 3.5 ± 0.2 and 5.6 ± 0.2 fold, respectively for 250 μM, 500 μM and 1000 μM of MA, respectively (Figure 1A, B). Furthermore, we also wanted to determine the effect of chronic exposure of MA on astrocytes. We treated the astrocytes with 500 μM MA for three days, once a day, as the dose is relevant to the levels found physiologically in MA abusers . The chronic treatment with MA resulted in increased expression of IL-6 and IL-8 by 4.6 ± 0.2 fold and 3.5 ± 0.2 fold, respectively (Figure 1C, D). These results clearly indicate that MA can increase the expression of proinflammatory cytokines/chemokines such as IL-6 and IL-8.
Methamphetamine increases intracellular levels of IL-6 and IL-8
Methamphetamine-mediated induction of proinflammatory cytokines/chemokines is mediated via NF-κB pathway
In order to further confirm these results we measured the phosphorylated form of IκB-α in the whole cell lysates of the astrocytes treated with 500 μM of MA over a period of 0 to 120 minutes. Consistent with the previous results, MA treatment was found to increase the phosphorylation of IκB-α, as evidenced by the increased levels of p-IκB-α in MA-treated astrocytes at 10 minutes (Figure 3C).
We also evaluated the effect of SC514, a specific inhibitor of inhibitory Kappa B kinase (IKK) on the expression levels of IL-6 and IL-8 in MA-treated astrocytes. The cells were treated with 10 μM SC514 (IC50 = 14.5 μM) one hour prior to each MA treatment over the three-day course of the experiment. The concentration of the antagonist was determined based on the IC50 value of the SC-514 and the viability of the cells, which was found to be approximately 90% at the concentration that was used (data not shown). The mRNA expression levels of IL-6 and IL-8 were measured using real time RT-PCR and the percent inhibition of MA-mediated expression levels of IL-6 and IL-8 were found to be 56.7 ± 5.1% and 78.4 ± 7.8%, respectively (Figure 3D, E). Together, all these results strongly suggest that induction of IL-6 and IL-8 by MA involves the activation and translocation of NF-κB.
Role of mGluR5 and Akt/PI3K in MA-mediated expression of proinflammatory cytokines/chemokines
In order to determine the downstream signaling cascade leading to the NF-κB pathway, we investigated the potential role of the Akt/PI3K pathway. The metabotropic glutamate receptor pathway requires the activation of the Akt/PI3K signaling cascade for its activity [44–46]. Therefore, we treated the astrocytes with 10 μM of LY294002, a specific inhibitor of Akt/PI3K, for 1 hour prior to MA treatment for each of three days. The dose of LY294002 was determined based on the cell viability as observed by trypan blue staining (data not shown). As per our hypothesis, LY294002 did abrogate the MA-mediated expression levels of IL-6 and IL-8 by 77.9 ± 6.6% and 81.4 ± 2.6%, respectively (Figure 4C, D). Thus, these results provide strong evidence for the involvement of the Akt/PI3K signaling mechanism in the induction of IL-6 and IL-8 by MA.
In the CNS, astrocytes are the most abundant cells and they are associated with several functions including metabolic support of neurons and modulation of neurotransmission. In the present study, we investigated the role of astrocytes in neuroinflammation produced by MA. We found that MA treatment of astrocytes can result in increased levels of IL-6 and IL-8 in a dose dependent manner. Furthermore, we demonstrated that the increases in IL-6 and IL-8 expression observed at the level of RNA were consistent with our observation of increased expression of IL-6 and IL-8 proteins. A single dose of MA in mice has been found to be associated with neurotoxicity mediated by increased expression of proinflammatory cytokines such as TNF-α, IL-1β and IL-6 [10, 15]. In this study, we investigated the effect of multiple doses of MA on the expression of proinflammatory cytokines in astrocytes. Our results demonstrate that MA can produce neuroinflammation in prolonged treatments. Furthermore, the expression of these cytokines is more pronounced with increasing doses of MA, indicative of increased neurotoxicity at higher doses of MA.
We next investigated the signaling mechanisms responsible for the MA-mediated increases in expression of IL-6 and IL-8. MA-mediated oxidative stress and mitochondrial dysfunction are found to play a major role in its neuroinflammatory effects [6, 47, 48]. The induction of a neuroinflammatory response due to MA has been shown to be associated with increased activities of certain transcription factors, including STAT1, STAT3, AP1, CREB and NF-κB [17, 49]. Since NF-κB has also been found to be associated with multiple neurological disorders and neuroinflammatory complications, we investigated whether NF-κB plays any role in the increased cytokine expression induced by MA. Our studies clearly showed multiple lines of evidence that support our hypothesis that the MA-mediated increase of proinflammatory cytokines/chemokines is dependent on the NF-κB pathway. To our knowledge, this is the first demonstration that MA-induced increases in proinflammatory cytokines/chemokines are mediated through the NF-κB pathway. Thus, the NF-κB pathway appears to be involved in mediating the induction of proinflammatory cytokines/chemokines by MA, as well as in mediating the response to oxidative stress induced by MA. The role of the dopamine receptor and transporters has been extensively studied to address the neuroinflammatory roles of MA in the CNS [33–35]. Recently, however, the effect on the excitatory neurotransmitter via glutamate receptors has also been shown to be responsible for MA-mediated cognitive impairments . Furthermore, inhibition of the metabotropic glutamate receptors, mGluR5 in particular, has been shown to reduce the self-administration of MA in rats . MA-mediated extracellular glutamate is found to augment the excitotoxicity in the striatums of rats . Furthermore, our results in the present study clearly demonstrate that mGluR5 plays a role in the MA-mediated induction of IL-6 and IL-8. Thus, our study suggests a possible link between the oxidative stress and mGluR5 activity since both phenomena are due to MA treatment. Furthermore, recent studies in spinal cord injury and neonatal excitotoxic lesions have suggested the potential utilization of mGluR5 as a therapeutic target [52, 53]. Our findings also suggest mGluR5 as a therapeutic target for abrogation of MA-mediated expression of neuroinflammatory cytokines/chemokines. Furthermore, we sought to investigate a link between the effects of MA on mGluR5 and NF-κB activation. Since the classical Huntington's disease pathway involves activation of the Akt/PI3K pathway, which is mediated via the mGluR5 receptor , we hypothesized a role for Akt/PI3K in the signaling cascade induced by MA. Our results support this hypothesis, because the antagonist for Akt/PI3K abrogated MA-mediated expression of IL-6 and IL-8.
We thank Dr. Avindra Nath for providing the SVGA cell line. The work reported in the manuscript was supported by grants from the National Institute on Drug Abuse (DA025528 and DA025011).
- Fumagalli F, Gainetdinov RR, Valenzano KJ, Caron MG: Role of dopamine transporter in methamphetamine-induced neurotoxicity: evidence from mice lacking the transporter. J Neurosci. 1998, 18: 4861-4869.PubMedGoogle Scholar
- Xu W, Zhu JP, Angulo JA: Induction of striatal pre- and postsynaptic damage by methamphetamine requires the dopamine receptors. Synapse. 2005, 58: 110-121. 10.1002/syn.20185.PubMed CentralView ArticlePubMedGoogle Scholar
- Jayanthi S, Ladenheim B, Cadet JL: Methamphetamine-induced changes in antioxidant enzymes and lipid peroxidation in copper/zinc-superoxide dismutase transgenic mice. Ann N Y Acad Sci. 1998, 844: 92-102. 10.1111/j.1749-6632.1998.tb08224.x.View ArticlePubMedGoogle Scholar
- LaVoie MJ, Hastings TG: Dopamine quinone formation and protein modification associated with the striatal neurotoxicity of methamphetamine: evidence against a role for extracellular dopamine. J Neurosci. 1999, 19: 1484-1491.PubMedGoogle Scholar
- Ramirez SH, Potula R, Fan S, Eidem T, Papugani A, Reichenbach N, Dykstra H, Weksler BB, Romero IA, Couraud PO, Persidsky Y: Methamphetamine disrupts blood-brain barrier function by induction of oxidative stress in brain endothelial cells. J Cereb Blood Flow Metab. 2009, 29: 1933-1945. 10.1038/jcbfm.2009.112.PubMed CentralView ArticlePubMedGoogle Scholar
- Yamamoto BK, Raudensky J: The role of oxidative stress, metabolic compromise, and inflammation in neuronal injury produced by amphetamine-related drugs of abuse. J Neuroimmune Pharmacol. 2008, 3: 203-217. 10.1007/s11481-008-9121-7.PubMed CentralView ArticlePubMedGoogle Scholar
- Persidsky Y, Ramirez SH, Haorah J, Kanmogne GD: Blood-brain barrier: structural components and function under physiologic and pathologic conditions. J Neuroimmune Pharmacol. 2006, 1: 223-236. 10.1007/s11481-006-9025-3.View ArticlePubMedGoogle Scholar
- Silva AP, Martins T, Baptista S, Goncalves J, Agasse F, Malva JO: Brain injury associated with widely abused amphetamines: neuroinflammation, neurogenesis and blood-brain barrier. Curr Drug Abuse Rev. 2010, 3: 239-254.View ArticlePubMedGoogle Scholar
- Bowyer JF, Ali S: High doses of methamphetamine that cause disruption of the blood-brain barrier in limbic regions produce extensive neuronal degeneration in mouse hippocampus. Synapse. 2006, 60: 521-532. 10.1002/syn.20324.View ArticlePubMedGoogle Scholar
- Goncalves J, Martins T, Ferreira R, Milhazes N, Borges F, Ribeiro CF, Malva JO, Macedo TR, Silva AP: Methamphetamine-induced early increase of IL-6 and TNF-alpha mRNA expression in the mouse brain. Ann N Y Acad Sci. 2008, 1139: 103-111. 10.1196/annals.1432.043.View ArticlePubMedGoogle Scholar
- Nagatsu T, Mogi M, Ichinose H, Togari A: Changes in cytokines and neurotrophins in Parkinson's disease. J Neural Transm Suppl. 2000, 60: 277-290.PubMedGoogle Scholar
- McGeer EG, McGeer PL: The importance of inflammatory mechanisms in Alzheimer disease. Exp Gerontol. 1998, 33: 371-378. 10.1016/S0531-5565(98)00013-8.View ArticlePubMedGoogle Scholar
- Kuhle J, Lindberg RL, Regeniter A, Mehling M, Steck AJ, Kappos L, Czaplinski A: Increased levels of inflammatory chemokines in amyotrophic lateral sclerosis. Eur J Neurol. 2009, 16: 771-774. 10.1111/j.1468-1331.2009.02560.x.View ArticlePubMedGoogle Scholar
- Sriram K, Miller DB, O'Callaghan JP: Minocycline attenuates microglial activation but fails to mitigate striatal dopaminergic neurotoxicity: role of tumor necrosis factor-alpha. J Neurochem. 2006, 96: 706-718. 10.1111/j.1471-4159.2005.03566.x.View ArticlePubMedGoogle Scholar
- Goncalves J, Baptista S, Martins T, Milhazes N, Borges F, Ribeiro CF, Malva JO, Silva AP: Methamphetamine-induced neuroinflammation and neuronal dysfunction in the mice hippocampus: preventive effect of indomethacin. Eur J Neurosci. 2010, 31: 315-326. 10.1111/j.1460-9568.2009.07059.x.View ArticlePubMedGoogle Scholar
- Yamaguchi T, Kuraishi Y, Minami M, Nakai S, Hirai Y, Satoh M: Methamphetamine-induced expression of interleukin-1 beta mRNA in the rat hypothalamus. Neurosci Lett. 1991, 128: 90-92. 10.1016/0304-3940(91)90766-M.View ArticlePubMedGoogle Scholar
- Lee YW, Son KW, Flora G, Hennig B, Nath A, Toborek M: Methamphetamine activates DNA binding of specific redox-responsive transcription factors in mouse brain. J Neurosci Res. 2002, 70: 82-89. 10.1002/jnr.10370.View ArticlePubMedGoogle Scholar
- Lee YW, Hennig B, Yao J, Toborek M: Methamphetamine induces AP-1 and NF-kappaB binding and transactivation in human brain endothelial cells. J Neurosci Res. 2001, 66: 583-591. 10.1002/jnr.1248.View ArticlePubMedGoogle Scholar
- Pu C, Vorhees CV: Protective effects of MK-801 on methamphetamine-induced depletion of dopaminergic and serotonergic terminals and striatal astrocytic response: an immunohistochemical study. Synapse. 1995, 19: 97-104. 10.1002/syn.890190205.View ArticlePubMedGoogle Scholar
- Guillot TS, Shepherd KR, Richardson JR, Wang MZ, Li Y, Emson PC, Miller GW: Reduced vesicular storage of dopamine exacerbates methamphetamine-induced neurodegeneration and astrogliosis. J Neurochem. 2008, 106: 2205-2217. 10.1111/j.1471-4159.2008.05568.x.PubMed CentralView ArticlePubMedGoogle Scholar
- Wang SF, Yen JC, Yin PH, Chi CW, Lee HC: Involvement of oxidative stress-activated JNK signaling in the methamphetamine-induced cell death of human SH-SY5Y cells. Toxicology. 2008, 246: 234-241. 10.1016/j.tox.2008.01.020.View ArticlePubMedGoogle Scholar
- Farber K, Kettenmann H: Physiology of microglial cells. Brain Res Brain Res Rev. 2005, 48: 133-143.View ArticlePubMedGoogle Scholar
- Mennicken F, Maki R, de Souza EB, Quirion R: Chemokines and chemokine receptors in the CNS: a possible role in neuroinflammation and patterning. Trends Pharmacol Sci. 1999, 20: 73-78. 10.1016/S0165-6147(99)01308-5.View ArticlePubMedGoogle Scholar
- Miljkovic D, Timotijevic G, Stojkovic MM: Astrocytes in the tempest of multiple sclerosis. FEBS Lett. 2011, 585: 3781-3788. 10.1016/j.febslet.2011.03.047.View ArticlePubMedGoogle Scholar
- Lee E, Yin Z, Sidoryk-Wegrzynowicz M, Jiang H, Aschner M: 15-Deoxy-Delta12,14-prostaglandin J(2) modulates manganese-induced activation of the NF-kappaB, Nrf2, and PI3K pathways in astrocytes. Free Radic Biol Med. 2012, 52: 1067-1074. 10.1016/j.freeradbiomed.2011.12.016.PubMed CentralView ArticlePubMedGoogle Scholar
- Zhao J, O'Connor T, Vassar R: The contribution of activated astrocytes to Abeta production: implications for Alzheimer's disease pathogenesis. J Neuroinflammation. 2011, 8: 150-10.1186/1742-2094-8-150.PubMed CentralView ArticlePubMedGoogle Scholar
- Morgan JE: Optic nerve head structure in glaucoma: astrocytes as mediators of axonal damage. Eye (Lond). 2000, 14: 437-444. 10.1038/eye.2000.128.View ArticleGoogle Scholar
- Kato H, Araki T, Imai Y, Takahashi A, Itoyama Y: Protection of dopaminergic neurons with a novel astrocyte modulating agent (R)-(-)-2-propyloctanoic acid (ONO-2506) in an MPTP-mouse model of Parkinson's disease. J Neurol Sci. 2003, 208: 9-15. 10.1016/S0022-510X(02)00411-2.View ArticlePubMedGoogle Scholar
- Narita M, Miyatake M, Shibasaki M, Shindo K, Nakamura A, Kuzumaki N, Nagumo Y, Suzuki T: Direct evidence of astrocytic modulation in the development of rewarding effects induced by drugs of abuse. Neuropsychopharmacology. 2006, 31: 2476-2488. 10.1038/sj.npp.1301007.View ArticlePubMedGoogle Scholar
- Major EO, Miller AE, Mourrain P, Traub RG, de Widt E, Sever J: Establishment of a line of human fetal glial cells that supports JC virus multiplication. Proc Natl Acad Sci USA. 1985, 82: 1257-1261. 10.1073/pnas.82.4.1257.PubMed CentralView ArticlePubMedGoogle Scholar
- Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001, 25: 402-408. 10.1006/meth.2001.1262.View ArticlePubMedGoogle Scholar
- Shah A, Verma AS, Patel KH, Noel R, Rivera-Amill V, Silverstein PS, Chaudhary S, Bhat HK, Stamatatos L, Singh DP, Buch S, Kumar A: HIV-1 gp120 induces expression of IL-6 through a nuclear factor-kappa B-dependent mechanism: suppression by gp120 specific small interfering RNA. PLoS One. 2011, 6: e21261-10.1371/journal.pone.0021261.PubMed CentralView ArticlePubMedGoogle Scholar
- Kita T, Miyazaki I, Asanuma M, Takeshima M, Wagner GC: Dopamine-induced behavioral changes and oxidative stress in methamphetamine-induced neurotoxicity. Int Rev Neurobiol. 2009, 88: 43-64.View ArticlePubMedGoogle Scholar
- Silverstein PS, Shah A, Gupte R, Liu X, Piepho RW, Kumar S, Kumar A: Methamphetamine toxicity and its implications during HIV-1 infection. J Neurovirol. 2011, 17: 401-415. 10.1007/s13365-011-0043-4.PubMed CentralView ArticlePubMedGoogle Scholar
- Cadet JL, Krasnova IN: Molecular bases of methamphetamine-induced neurodegeneration. Int Rev Neurobiol. 2009, 88: 101-119.View ArticlePubMedGoogle Scholar
- Talloczy Z, Martinez J, Joset D, Ray Y, Gacser A, Toussi S, Mizushima N, Nosanchuk JD, Goldstein H, Loike J, Sulzer D, Santambrogio L: Methamphetamine inhibits antigen processing, presentation, and phagocytosis. PLoS Pathog. 2008, 4: e28-10.1371/journal.ppat.0040028.PubMed CentralView ArticlePubMedGoogle Scholar
- Beg AA, Baltimore D: An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science. 1996, 274: 782-784. 10.1126/science.274.5288.782.View ArticlePubMedGoogle Scholar
- Kaltschmidt B, Baeuerle PA, Kaltschmidt C: Potential involvement of the transcription factor NF-kappa B in neurological disorders. Mol Aspects Med. 1993, 14: 171-190. 10.1016/0098-2997(93)90004-W.View ArticlePubMedGoogle Scholar
- Kunsch C, Rosen CA: NF-kappa B subunit-specific regulation of the interleukin-8 promoter. Mol Cell Biol. 1993, 13: 6137-6146.PubMed CentralView ArticlePubMedGoogle Scholar
- Sparacio SM, Zhang Y, Vilcek J, Benveniste EN: Cytokine regulation of interleukin-6 gene expression in astrocytes involves activation of an NF-kappa B-like nuclear protein. J Neuroimmunol. 1992, 39: 231-242. 10.1016/0165-5728(92)90257-L.View ArticlePubMedGoogle Scholar
- Battaglia G, Fornai F, Busceti CL, Aloisi G, Cerrito F, De Blasi A, Melchiorri D, Nicoletti F: Selective blockade of mGlu5 metabotropic glutamate receptors is protective against methamphetamine neurotoxicity. J Neurosci. 2002, 22: 2135-2141.PubMedGoogle Scholar
- Golembiowska K, Konieczny J, Wolfarth S, Ossowska K: Neuroprotective action of MPEP, a selective mGluR5 antagonist, in methamphetamine-induced dopaminergic neurotoxicity is associated with a decrease in dopamine outflow and inhibition of hyperthermia in rats. Neuropharmacology. 2003, 45: 484-492. 10.1016/S0028-3908(03)00209-0.View ArticlePubMedGoogle Scholar
- Reichel CM, Schwendt M, McGinty JF, Olive MF, See RE: Loss of object recognition memory produced by extended access to methamphetamine self-administration is reversed by positive allosteric modulation of metabotropic glutamate receptor 5. Neuropsychopharmacology. 2011, 36: 782-792. 10.1038/npp.2010.212.PubMed CentralView ArticlePubMedGoogle Scholar
- Hou L, Klann E: Activation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. J Neurosci. 2004, 24: 6352-6361. 10.1523/JNEUROSCI.0995-04.2004.View ArticlePubMedGoogle Scholar
- Ribeiro FM, Paquet M, Cregan SP, Ferguson SS: Group I metabotropic glutamate receptor signalling and its implication in neurological disease. CNS Neurol Disord Drug Targets. 2010, 9: 574-595.View ArticlePubMedGoogle Scholar
- Ribeiro FM, Paquet M, Ferreira LT, Cregan T, Swan P, Cregan SP, Ferguson SS: Metabotropic glutamate receptor-mediated cell signaling pathways are altered in a mouse model of Huntington's disease. J Neurosci. 2010, 30: 316-324. 10.1523/JNEUROSCI.4974-09.2010.View ArticlePubMedGoogle Scholar
- Tata DA, Yamamoto BK: Interactions between methamphetamine and environmental stress: role of oxidative stress, glutamate and mitochondrial dysfunction. Addiction. 2007, 102 (Suppl 1): 49-60.View ArticlePubMedGoogle Scholar
- Potula R, Hawkins BJ, Cenna JM, Fan S, Dykstra H, Ramirez SH, Morsey B, Brodie MR, Persidsky Y: Methamphetamine causes mitrochondrial oxidative damage in human T lymphocytes leading to functional impairment. J Immunol. 2010, 185: 2867-2876. 10.4049/jimmunol.0903691.PubMed CentralView ArticlePubMedGoogle Scholar
- Hebert MA, O'Callaghan JP: Protein phosphorylation cascades associated with methamphetamine-induced glial activation. Ann N Y Acad Sci. 2000, 914: 238-262.View ArticlePubMedGoogle Scholar
- Osborne MP, Olive MF: A role for mGluR5 receptors in intravenous methamphetamine self-administration. Ann N Y Acad Sci. 2008, 1139: 206-211. 10.1196/annals.1432.034.View ArticlePubMedGoogle Scholar
- Tata DA, Yamamoto BK: Chronic stress enhances methamphetamine-induced extracellular glutamate and excitotoxicity in the rat striatum. Synapse. 2008, 62: 325-336. 10.1002/syn.20497.PubMed CentralView ArticlePubMedGoogle Scholar
- Drouin-Ouellet J, Brownell AL, Saint-Pierre M, Fasano C, Emond V, Trudeau LE, Levesque D, Cicchetti F: Neuroinflammation is associated with changes in glial mGluR5 expression and the development of neonatal excitotoxic lesions. Glia. 2011, 59: 188-199. 10.1002/glia.21086.View ArticlePubMedGoogle Scholar
- Pajoohesh-Ganji A, Byrnes KR: Novel neuroinflammatory targets in the chronically injured spinal cord. Neurotherapeutics. 2011, 8: 195-205. 10.1007/s13311-011-0036-2.PubMed CentralView ArticlePubMedGoogle Scholar
- Ribeiro FM, Pires RG, Ferguson SS: Huntington's disease and Group I metabotropic glutamate receptors. Mol Neurobiol. 2011, 43: 1-11. 10.1007/s12035-010-8153-1.View ArticlePubMedGoogle Scholar
- Chen T, Zhang L, Qu Y, Huo K, Jiang X, Fei Z: The selective mGluR5 agonist CHPG protects against traumatic brain injury. Int J Mol Med. 2012, 29: 630-636.PubMed CentralPubMedGoogle Scholar
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