title: The effects of metabotropic glutamate receptor 7 allosteric agonist N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride on developmental sevoflurane neurotoxicity: role of extracellular signal-regulated kinase 1 and 2 mitogen-activated protein kinase signaling pathway.
abstract: The present study was designed to evaluate the possible neuroprotective effects of metabotropic glutamate receptor (mGluR7) allosteric agonist N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) on developmental sevoflurane neurotoxicity. To achieve the objective, hippocampal cultures (7 DIV, 7 day in vitro) were treated with different doses of L-(+)-2-amino-4-phosphonobutyric acid (L-AP4, an agonist of group III mGluRs), (RS)-α-Methylserine-O-phosphate (MSOP, an antagonist of group III mGluRs), AMN082 or cis-2-[[(3,5-dichlorophenyl)amino]carbonyl]cyclohexanecarboxylic acid (VU0155041, an agonist of mGluR4) before exposed to sevoflurane. Cell apoptosis were determined by flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL)-staining. For in vivo study, rat pups (7 PND, 7 postnatal day) were injected with AMN082, L-AP4 or saline before sevoflurane exposure. Extracellular signal-regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, caspase-3, Bcl-2, and Bax were detected by Western blot. The locomotor activity and cognitive functions were evaluated by open-field test and Morris water maze (MWM), respectively. We found that L-AP4 prevented sevoflurane-induced cell apoptosis, but MSOP promoted. Specially, application of AMN082 contributed to the relief of sevoflurane-induced apoptosis in vitro, whereas VU0155041 did not. In addition, sevoflurane treatment led to a decrease of Bcl-2 and an increase of caspase-3 and Bax, which were mitigated by AMNO82 in vivo. Moreover, we showed that sevoflurane treatment resulted in a remarkable suppression of phospho-ERK1/2, which was restored by AMN082. Application of U0126 (an inhibitor of MEK) abolished the neuroprotective effects of AMN082 on sevoflurane neurotoxicity both in vitro and in vivo. In addition, sevoflurane exposure also led to an increase of phospho-JNK, but SP600125 (an inhibitor of JNK) did not attenuate sevoflurane-induced apoptosis. The total and phosphorylated p38 remained unchanged in sevoflurane-treated rat pups. Finally, AMN082 improved the learning and memory defects caused by postnatal sevoflurane exposure without alternations in emotion or locomotor activity. These preliminary data indicate that AMN082 may protect immature brain against sevoflurane neurotoxicity, and the ERK1/2 MAP kinase signaling is likely to be involved. Further studies are needed to fully assess the neuroprotective role of mGluR7 agonist AMN082 in developmental anesthetic neurotoxicity.
authors.affiliation: Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Ruijin Er Road 197, 200025 Shanghai, China.
authors.forename: W-Y
authors.initials: WY
authors.lastname: Wang
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Luo
authors.forename: L-J
authors.initials: LJ
authors.lastname: Jia
authors.forename: J-N
authors.initials: JN
authors.lastname: Zhao
authors.forename: H-H
authors.initials: HH
authors.lastname: Zhang
authors.forename: Z-W
authors.initials: ZW
authors.lastname: Ma
authors.forename: Q-S
authors.initials: QS
authors.lastname: Xue
authors.forename: B-W
authors.initials: BW
authors.lastname: Yu
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D018685:Anesthetics, Inhalation / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D001559:Benzhydryl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology / Q000627:therapeutic use; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology*; D008738:Methyl Ethers / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000502:physiology; D000077149:Sevoflurane
chemical_list: D018685:Anesthetics, Inhalation; D001559:Benzhydryl Compounds; D018690:Excitatory Amino Acid Agonists; D008738:Methyl Ethers; C507346:N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride; D018696:Neuroprotective Agents; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7; D000077149:Sevoflurane; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3