title: Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes.
abstract: Methamphetamine (MA) is a potent psychostimulant with a high addictive capacity, which induces many deleterious effects on the brain. Chronic MA abuse leads to cognitive dysfunction and motor impairment. MA affects many cells in the brain, but the effects on astrocytes of repeated MA exposure is not well understood. In this report, we used Gene chip array to analyze the changes in the gene expression profile of primary human astrocytes treated with MA for 3 days. Range of genes were found to be differentially regulated, with a large number of genes significantly downregulated, including NEK2, TTK, TOP2A, and CCNE2. Gene ontology and pathway analysis showed a highly significant clustering of genes involved in cell cycle progression and DNA replication. Further pathway analysis showed that the genes downregulated by multiple MA treatment were critical for G2/M phase progression and G1/S transition. Cell cycle analysis of SVG astrocytes showed a significant reduction in the percentage of cell in the G2/M phase with a concomitant increase in G1 percentage. This was consistent with the gene array and validation data, which showed that repeated MA treatment downregulated the genes associated with cell cycle regulation. This is a novel finding, which explains the effect of MA treatment on astrocytes and has clear implication in neuroinflammation among the drug abusers.
authors.affiliation: Division of Pharmacology and Toxicology, University of Missouri-Kansas City School of Pharmacy, Kansas City, Missouri, United States of America.
authors.forename: Austin R
authors.initials: AR
authors.lastname: Jackson
authors.affiliation: Division of Pharmacology and Toxicology, University of Missouri-Kansas City School of Pharmacy, Kansas City, Missouri, United States of America.
authors.forename: Ankit
authors.initials: A
authors.lastname: Shah
authors.affiliation: Division of Pharmacology and Toxicology, University of Missouri-Kansas City School of Pharmacy, Kansas City, Missouri, United States of America.
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008694:Methamphetamine / Q000494:pharmacology*; D058977:Molecular Sequence Annotation; D005810:Multigene Family; D000072379:NIMA-Related Kinases; D020411:Oligonucleotide Array Sequence Analysis; D000075223:Poly-ADP-Ribose Binding Proteins; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013566:Sympathomimetics / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; C503688:CCNE2 protein, human; D018797:Cell Cycle Proteins; D016213:Cyclins; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D013566:Sympathomimetics; D008694:Methamphetamine; D011505:Protein-Tyrosine Kinases; C089441:NEK2 protein, human; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human