title: The mechanisms responsible for neuroprotective capacity of arylpiperazine dopaminergic ligands against cell death induced by sodium nitroprusside.
abstract: A group of sixteen arylpiperazines had been previously synthesized and evaluated for atypical antipsychotic activity. Here we examined these compounds for their neuroprotective capacity. The affinity and agonist/antagonist action of the arylpiperazines at dopamine hD(2S) receptors were determined in vitro on membranes from stably transfected CHO-hD(2S) cell line. The assays for cell viability and antioxidative capacity (total glutathione and total superoxide dismutase activity), amount of nitric oxide and superoxide radicals, as well as influence on prosurvival pathways (Akt and ERK), were performed on the human neuroblastoma cell line SH-SY5Y. Cell death was induced by oxidative or nitrosative stress, or by growing cells in the medium deprived of serum. Only four of the arylpiperazines exhibited notable neuroprotection against cell death induced by sodium nitroprusside. Two of these arylpiperazines induced elevations of pAkt, while two other compounds reduced the levels of pErk, whereas these actions are considered to support the cell survival. The benzimidazole heteroaryl-group, that mimics catechol moiety of the dopamine molecule, might be the prerequisite structure for the neuroprotective action of these ligands. It is postulated that neuroprotection was acquired also by elevation of endogenous glutathione or total superoxide dismutase activity.
authors.affiliation: Department of Biochemistry, Institute for Biological Research, University of Belgrade, 142 Despot Stefana Blvd., 11060 Belgrade, Serbia. djurdjica@ibiss.bg.ac.rs
authors.forename: Đurđica
authors.initials: Đ
authors.lastname: Ignjatović
authors.forename: Danijela
authors.initials: D
authors.lastname: Vojnović Milutinović
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Nikolić-Kokić
authors.forename: Marija
authors.initials: M
authors.lastname: Slavić
authors.forename: Deana
authors.initials: D
authors.lastname: Andrić
authors.forename: Mirko
authors.initials: M
authors.lastname: Tomić
authors.forename: Slađana
authors.initials: S
authors.lastname: Kostić-Rajačić
mesh_terms: D000818:Animals; D016466:CHO Cells; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D018491:Dopamine Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D008024:Ligands; D009419:Nerve Tissue Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000633:toxicity; D009599:Nitroprusside / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020033:Protein Isoforms / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D010879:Piperazines; D020033:Protein Isoforms; D017448:Receptors, Dopamine D2; D011994:Recombinant Proteins; D009599:Nitroprusside