title: 5-HT2A serotonin receptor agonist DOI alleviates cytotoxicity in neuroblastoma cells: role of the ERK pathway.
abstract: Disturbances of serotonergic signaling, including the serotonin 2A (5-HT2A) receptor, have been implicated in neuropsychiatric and neurodegenerative disorders. The aim of the present study was to characterize the effect of a 5-HT2A receptor agonist on cytotoxicity in a neuronal cell line and address the involved mechanism. HTR2A mRNA and protein expression in human neuroblastoma SK-N-SH cells was confirmed. Cells were subjected to serum deprivation and cell viability was monitored continuously with xCELLigence. In a dose-response study the 5-HT2A agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) (25 nM to 5 μM) protected against serum deprivation cytotoxicity. The selective 5-HT2A receptor antagonist MDL 11,939, the general protein tyrosine kinase inhibitor genistein, and the extracellular signal-regulated kinase (ERK) pathway MEK inhibitor U0126, all attenuated DOI's protective effect. An antibody array suggested that 1 μM DOI affected phosphorylation of several tyrosine kinases. Western blot further confirmed that DOI transiently increased ERK phosphorylation, indicating its activation. Finally, protective concentrations of DOI increased cellular mitochondrial mass, an effect prevented by pretreatment with U0126. In conclusion, our results suggest that DOI protects SK-N-SH cells against serum deprivation through ERK pathway activation. They imply 5-HT2A receptor modulation as a potential target for neuroprotection.
authors: Hospital of Child and Adolescent Psychiatry, University of Zurich, Neumuensterallee 9, 8032 Zurich, Switzerland. Zoya.Marinova@kjpdzh.ch
authors: Zoya
authors: Z
authors: Marinova
authors: Susanne
authors: S
authors: Walitza
authors: Edna
authors: E
authors: Grünblatt
mesh_terms: D000662:Amphetamines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016895:Culture Media, Serum-Free / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D009447:Neuroblastoma / Q000473:pathology; D009930:Organic Chemicals; D010880:Piperidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D036223:Receptor, EphB3 / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000662:Amphetamines; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; C507919:MitoTracker Red 580; D009930:Organic Chemicals; D010880:Piperidines; D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C066169:alpha-phenyl-1-(2-phenylethyl)-4-piperidinemethanol; D036223:Receptor, EphB3; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine