title: Transcriptional profiling of mefloquine-induced disruption of calcium homeostasis in neurons in vitro.
abstract: Mefloquine is associated with adverse neurological effects that are mediated via unknown mechanisms. Recent in vitro studies have shown that mefloquine disrupts neuronal calcium homeostasis via liberation of the endoplasmic reticulum (ER) store and induction of calcium influx across the plasma membrane. In the present study, global changes in gene expression induced in neurons in response to mefloquine-induced disruption of calcium homeostasis and appropriate control agents were investigated in vitro using Affymetrix arrays. The mefloquine transcriptome was found to be enriched for important regulatory sequences of the unfolded protein response and the drug was also found to induce key ER stress proteins, albeit in a manner dissimilar to, and at higher equivalent concentrations than, known ER-tropic agents like thapsigargin. Mefloquine also down-regulated several important functional categories of genes, including transcripts encoding G proteins and ion channels. These effects may be related to intrusion of extracellular calcium since they were also observed after glutamate, but not thapsigargin, hydrogen peroxide, or low-dose mefloquine treatment. Mefloquine could be successfully differentiated from other treatments on the basis of principle component analysis of its "calcium-relevant" transcriptome. These data may aid interpretation of expression of results from future in vivo studies.
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA. geoffrey.dow@na.amedd.army.mil
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Dow
authors.forename: Diana
authors.initials: D
authors.lastname: Caridha
authors.forename: Michelle
authors.initials: M
authors.lastname: Goldberg
authors.forename: Lesley
authors.initials: L
authors.lastname: Wolf
authors.forename: Michael L
authors.initials: ML
authors.lastname: Koenig
authors.forename: Debra L
authors.initials: DL
authors.lastname: Yourick
authors.forename: Zhining
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000009:adverse effects* / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism; D020869:Gene Expression Profiling; D006706:Homeostasis; D007473:Ion Channels / Q000187:drug effects; D015767:Mefloquine / Q000009:adverse effects* / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D011489:Protein Denaturation; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D007473:Ion Channels; D019204:GTP-Binding Proteins; D002118:Calcium; D015767:Mefloquine