title: Neuroprotective effects of mGluR II and III activators against staurosporine- and doxorubicin-induced cellular injury in SH-SY5Y cells: New evidence for a mechanism involving inhibition of AIF translocation.
abstract: There are several experimental data sets demonstrating the neuroprotective effects of activation of group II and III metabotropic glutamate receptors (mGluR II/III), however, their effect on neuronal apoptotic processes has yet to be fully recognized. Thus, the comparison of the neuroprotective potency of the mGluR II agonist LY354740, mGluR III agonist ACPT-I, mGluR4 PAM VU0361737, mGluR8 PAM AZ12216052 and allosteric mGluR7 agonist AMN082 against staurosporine (St-) and doxorubicin (Dox)-induced cell death has been performed in undifferentiated (UN-) and retinoic acid differentiated (RA-) human neuroblastoma SH-SY5Y cells. The highest neuroprotection in UN-SH-SY5Y cells was noted for AZ12216052 (0.01-1 µM) and VU0361737 (1-10 µM), with both agents partially attenuating the St- and Dox-evoked cell death. LY354740 (0.01-10 µM) and ACPT-I (10 µM) were protective only against the St-evoked cell damage, whereas AMN082 (0.001-0.01 µM) attenuated only the Dox-induced cell death. In RA-SH-SY5Y, a moderate neuroprotective response of mGluR II/III activators was observed for LY354740 (10 µM) and AZ12216052 (0.01 and 10 µM), which afforded protection only against the St-induced cell damage. The protection mediated by mGluR II/III activators against the St- and Dox-evoked cell death in UN-SH-SY5Y cells was not related to attenuation of caspase-3 activity, however, a decrease in the number of TUNEL-positive nuclei was found. Moreover, mGluR II/III activators attenuated the cytosolic level of the apoptosis inducing factor (AIF), which was increased after St and Dox exposure. Our data point to differential neuroprotective efficacy of various mGluR II/III activators in attenuating St- and Dox-evoked cell damage in SH-SY5Y cells, and dependence of the effects on the cellular differentiation state, as well on the type of the pro-apoptotic agent that is employed. Moreover, the neuroprotection mediated by mGluR II/III activators is accompanied by inhibition of caspase-3-independent DNA fragmentation evoked by AIF translocation.
authors: Department of Experimental Neuroendocrinology, Polish Academy of Sciences, Smetna 12 Street, Krakow PL 31-343, Poland. Electronic address: jantas@if-pan.krakow.pl.
authors: D
authors: D
authors: Jantas
authors: Department of Experimental Neuroendocrinology, Polish Academy of Sciences, Smetna 12 Street, Krakow PL 31-343, Poland.
authors: A
authors: A
authors: Greda
authors: Department of Experimental Neuroendocrinology, Polish Academy of Sciences, Smetna 12 Street, Krakow PL 31-343, Poland.
authors: M
authors: M
authors: Leskiewicz
authors: Department of Experimental Neuroendocrinology, Polish Academy of Sciences, Smetna 12 Street, Krakow PL 31-343, Poland.
authors: B
authors: B
authors: Grygier
authors: Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, Krakow PL 31-343, Poland.
authors: A
authors: A
authors: Pilc
authors: Department of Experimental Neuroendocrinology, Polish Academy of Sciences, Smetna 12 Street, Krakow PL 31-343, Poland.
authors: W
authors: W
authors: Lason
mesh_terms: D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*; D019311:Staurosporine / Q000633:toxicity*
chemical_list: D051033:Apoptosis Inducing Factor; D001643:Bridged Bicyclo Compounds; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D004317:Doxorubicin; D019311:Staurosporine; C104753:eglumetad
keywords: ACPT-I; AIF; AMN082; AZ12216052; LY354740; VU0361737