title: The mGluR5 positive allosteric modulator CDPPB inhibits SO₂-induced protein radical formation and mitochondrial dysfunction through activation of Akt in mouse hippocampal HT22 cells.
abstract: Sulfur dioxide (SO2) is a common gas pollutant that is detrimental to many organs. Previous studies have shown that SO2 exposure is involved in neurotoxicity and increased risk of many brain disorders; however, our understanding of the mechanisms underlying SO2-induced cytotoxicity on neuronal cells remains elusive. The group I metabotropic glutamate receptor 5 (mGluR5) can modulate addiction, pain, and neuronal cell death. In the present study, we showed that SO2 derivatives exposure induced protein radical formation, mitochondrial dysfunction, and apoptotic cell death in neuronal HT22 cells. Pretreatment with 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) (CDPPB), a positive allosteric modulator of mGluR5, significantly attenuated SO2-induced neurotoxicity, which was fully prevented by the mGluR5 antagonist MPEP. CDPPB reduced the protein radical formation and inducible nitric oxide synthase (iNOS)-derived generation of nitric oxide, and inhibited mitochondrial dysfunction in both HT22 cells and isolated mitochondria after SO2 treatment. Moreover, CDPPB increased the activation of Akt in the presence and absence of SO2 treatment. Blocking Akt activation using the selective inhibitor LY294002 partially reversed the CDPPB-induced protection against SO2-induced neurotoxicity. This study provides mechanistic experimental support for oxidative stress and mitochondrial dysfunction after SO2 exposure in neuronal cells, and also introduces a novel therapeutic approach for SO2-induced neurotoxicity.
authors.affiliation: Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
authors.forename: Dong-Feng
authors.initials: DF
authors.lastname: Guan
authors.forename: Peng-Yu
authors.initials: PY
authors.lastname: Ren
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.forename: Yue-Lin
authors.initials: YL
authors.lastname: Zhang
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D005609:Free Radicals / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000066829:Neuroprotection / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D013458:Sulfur Dioxide / Q000494:pharmacology*
chemical_list: C494553:3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; D001549:Benzamides; D005609:Free Radicals; D011720:Pyrazoles; D064529:Receptor, Metabotropic Glutamate 5; D013458:Sulfur Dioxide; D052247:Nitric Oxide Synthase Type II; D051057:Proto-Oncogene Proteins c-akt