Neuroprotective effects of metabotropic glutamate receptor group II and III activators against MPP(+)-induced cell death in human neuroblastoma SH-SY5Y cells: the impact of cell differentiation state.
Recent studies have documented that metabotropic glutamate receptors from group II and III (mGluR II/III) are a potential target in the symptomatic treatment of Parkinson's disease (PD), however, the neuroprotective effects of particular mGluR II/III subtypes in relation to PD pathology are recognized only partially. In the present study, we investigated the effect of various mGluR II/III activators in the in vitro model of PD using human neuroblastoma SH-SY5Y cell line and mitochondrial neurotoxin MPP(+). We demonstrated that all tested mGluR ligands: mGluR II agonist - LY354740, mGluR III agonist - ACPT-I, mGluR4 PAM - VU0361737, mGluR8 agonist - (S)-3,4-DCPG, mGluR8 PAM - AZ12216052 and mGluR7 allosteric agonist - AMN082 were protective against MPP(+)-evoked cell damage in undifferentiated (UN-) SH-SY5Y cells with the highest neuroprotection mediated by mGluR8-specific agents. However, in retinoic acid- differentiated (RA-) SH-SY5Y cells we found protection mediated only by mGluR8 activators. We also demonstrated the cell proliferation stimulating effect for mGluR4 and mGluR8 PAMs. Next, we showed that the protection mediated by mGluR II/III activators in UN-SH-SY5Y was not accompanied by the modulation of caspase-3 activity, however, a decrease in the number of apoptotic nuclei was found. Finally, we showed that the inhibitor of necroptosis, necrostatin-1 blocked the mGluR III-mediated protection. Altogether our comparative in vitro data add a further proof to neuroprotective effects of mGluR agonists or PAMs and point to mGluR8 as a promising target for neuroprotective interventions in PD. The results also suggest the participation of necroptosis-related molecular pathways in neuroprotective effects of mGluR III activation.
Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, PL 31-343 Krakow, Poland. Electronic address: jantas@if-pan.krakow.pl.
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Jantas
Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, PL 31-343 Krakow, Poland.
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Greda
Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, PL 31-343 Krakow, Poland.
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Golda
Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, PL 31-343 Krakow, Poland.
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Korostynski
Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, PL 31-343 Krakow, Poland.
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Grygier
Department of Brain Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, PL 31-343 Krakow, Poland.
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Roman
Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, PL 31-343 Krakow, Poland.
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Pilc
Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, PL 31-343 Krakow, Poland.
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Lason
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D009447:Neuroblastoma; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D018696:Neuroprotective Agents; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; C102719:metabotropic glutamate receptor 7; C111435:metabotropic glutamate receptor 8; D015655:1-Methyl-4-phenylpyridinium
(S)-3,4-DCPG; ACPT-I; AMN082; AZ12216052; LY354740; Necrostatin-1; VU0361737; [(3)H]MPP(+) uptake; mGluR II/III expression