The online version of this article (doi:10.1186/s12974-017-0825-6) contains supplementary material, which is available to authorized users.
Astrocyte activation is one of the earliest findings in the brain of methamphetamine (Meth) abusers. Our goal in this study was to identify the characteristics of the astrocytic acute response to the drug, which may be critical in pathogenic outcomes secondary to the use.
We developed an integrated analysis of gene expression data to study the acute gene changes caused by the direct exposure to Meth treatment of astrocytes in vitro, and to better understand how astrocytes respond, what are the early molecular markers associated with this response. We examined the literature in search of similar changes in gene signatures that are found in central nervous system disorders.
We identified overexpressed gene networks represented by genes of an inflammatory and immune nature and that are implicated in neuroactive ligand-receptor interactions. The overexpressed networks are linked to molecules that were highly upregulated in astrocytes by all doses of methamphetamine tested and that could play a role in the central nervous system. The strongest overexpressed signatures were the upregulation of MAP2K5, GPR65, and CXCL5, and the gene networks individually associated with these molecules. Pathway analysis revealed that these networks are involved both in neuroprotection and in neuropathology. We have validated several targets associated to these genes.
Gene signatures for the astrocytic response to Meth were identified among the upregulated gene pool, using an in vitro system. The identified markers may participate in dysfunctions of the central nervous system but could also provide acute protection to the drug exposure. Further in vivo studies are necessary to establish the role of these gene networks in drug abuse pathogenesis.
Additional file 1: Visualization of gene changes and networks for identifying over-expression patterns and for initializing the analysis of astrocytic gene network behaviors upon Meth exposure. Genes were connected based on pathway, physical and genetic interactions, shared protein domains, or co-expression, using GeneMania and JActiveModules in Cytoscape platform. Highest score nodes were grouped by circular layout. (PNG 6917 kb)12974_2017_825_MOESM1_ESM.png
Bowyer JF, Davies DL, Schmued L, Broening HW, Newport GD, Slikker Jr W, Holson RR. Further studies of the role of hyperthermia in methamphetamine neurotoxicity. J Pharmacol Exp Ther. 1994;268:1571–80. PubMed
Strojnik T, Kavalar R, Zajc I, Diamandis EP, Oikonomopoulou K, Lah TT. Prognostic impact of CD68 and kallikrein 6 in human glioma. Anticancer Res. 2009;29:3269–79. PubMed
Berezovsky AD, Poisson LM, Cherba D, Webb CP, Transou AD, Lemke NW, Hong X, Hasselbach LA, Irtenkauf SM, Mikkelsen T, DeCarvalho AC. Sox2 promotes malignancy in glioblastoma by regulating plasticity and astrocytic differentiation. Neoplasia. 2014;16:193–206. 206 e119-125. CrossRefPubMedPubMedCentral
Rosko AE, McColl KS, Zhong F, Ryder CB, Chang MJ, Sattar A, Caimi PF, Hill BT, Al-Harbi S, Almasan A, Distelhorst CW. Acidosis sensing receptor GPR65 correlates with anti-apoptotic Bcl-2 family member expression in CLL cells: potential implications for the CLL microenvironment. J Leuk (Los Angel). 2014;2:5.
Feldmann J, Prieur AM, Quartier P, Berquin P, Certain S, Cortis E, Teillac-Hamel D, Fischer A, De Saint BG. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet. 2002;71:198–203. CrossRefPubMedPubMedCentral
Yagami T, Koma H, Yamamoto Y. Pathophysiological roles of cyclooxygenases and prostaglandins in the central nervous system. Mol Neurobiol. 2015.
Ichimura K, Bolin MB, Goike HM, Schmidt EE, Moshref A, Collins VP. Deregulation of the p14ARF/MDM2/p53 pathway is a prerequisite for human astrocytic gliomas with G1-S transition control gene abnormalities. Cancer Res. 2000;60:417–24. PubMed
Ihara Y, Kihara Y, Hamano F, Yanagida K, Morishita Y, Kunita A, Yamori T, Fukayama M, Aburatani H, Shimizu T, Ishii S. The G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) facilitates tumor development by serving as an extracellular pH sensor. Proc Natl Acad Sci U S A. 2010;107:17309–14. CrossRefPubMedPubMedCentral
Kashiwagi M, Hara K, Liu Z, Kageura M, Matsusue A, Sugimura T, Kubo S. Diagnostic approach to drug-screening tests for fatal diabetic ketoacidosis: forensic autopsy of a methamphetamine abuser. Leg Med (Tokyo). 2010;12:192–4. CrossRef
Zaremba J, Skrobanski P, Losy J. The level of chemokine CXCL5 in the cerebrospinal fluid is increased during the first 24 hours of ischaemic stroke and correlates with the size of early brain damage. Folia Morphol (Warsz). 2006;65:1–5.
Marcondes MC, Burdo TH, Sopper S, Huitron-Resendiz S, Lanigan C, Watry D, Flynn C, Zandonatti M, Fox HS. Enrichment and persistence of virus-specific CTL in the brain of simian immunodeficiency virus-infected monkeys is associated with a unique cytokine environment. J Immunol. 2007;178:5812–9. CrossRefPubMed
Baker DJ, Blackburn DJ, Keatinge M, Sokhi D, Viskaitis P, Heath PR, Ferraiuolo L, Kirby J, Shaw PJ. Lysosomal and phagocytic activity is increased in astrocytes during disease progression in the SOD1 (G93A) mouse model of amyotrophic lateral sclerosis. Front Cell Neurosci. 2015;9:410. PubMedPubMedCentral
Bortell NM B, Basova L, Fox HS, Marcondes MC. Phenotypic changes in the brain of SIV-infected macaques exposed to methamphetamine parallel macrophage activation patterns induced by the common gamma-chain cytokine system. Front Microbiol. 2015;6:900. CrossRef
Pan F, Yang TL, Chen XD, Chen Y, Gao G, Liu YZ, Pei YF, Sha BY, Jiang Y, Xu C, et al. Impact of female cigarette smoking on circulating B cells in vivo: the suppressed ICOSLG, TCF3, and VCAM1 gene functional network may inhibit normal cell function. Immunogenetics. 2010;62:237–51. CrossRefPubMedPubMedCentral
- Astrocyte-specific overexpressed gene signatures in response to methamphetamine exposure in vitro
Howard S. Fox
Maria Cecilia G. Marcondes
- BioMed Central