Longistyline C acts antidepressant in vivo and neuroprotection in vitro against glutamate-induced cytotoxicity by regulating NMDAR/NR2B-ERK pathway in PC12 cells

• Published in: PloS one 2017-09, Vol.12 (9), p.e0183702
• Main Authors: Liu, Yamin, Zhao, Ning, Li, Chenchen, Chang, Qi, Liu, Xinmin, Liao, Yonghong, Pan, Ruile
• Format: Article
• Language: English
• Subjects: Amino acids; Animals; Annexin V; Antidepressants; Antidepressive Agents - pharmacology; Apoptosis; Behavior, Animal; Biocompatibility; Biology and Life Sciences; Ca2+/calmodulin-dependent protein kinase II; Cajanus cajan; Calcium; Calcium - metabolism; Calcium binding proteins; Calcium-binding protein; Calmodulin; Caspase 12 - metabolism; Caspase 9 - metabolism; Cell Survival; Cyclic AMP response element-binding protein; Cytotoxicity; Drug screening; Drugs; Endoplasmic reticulum; Exercise Test; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Glutamate; Glutamates - adverse effects; Glutamic acid receptors; Heat-Shock Proteins - metabolism; Herbal medicine; Hypotheses; Immunoglobulins; In vitro methods and tests; In vivo methods and tests; Injuries; Kinases; L-Lactate dehydrogenase; L-Lactate Dehydrogenase - metabolism; Laboratory animals; Lactate dehydrogenase; Lactic acid; Male; MAP Kinase Signaling System - drug effects; Medicine and Health Sciences; Mental depression; Metabolic pathways; Mice; Mice, Inbred ICR; N-Methyl-D-aspartic acid receptors; Neuroprotection; Neurosciences; Overexpression; PC12 Cells; Pheochromocytoma cells; Proteins; Rankings; Rats; Reactive Oxygen Species - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Research and analysis methods; Rodents; Signal Transduction; Stilbene; Stilbenes - pharmacology; Swimming; Toxicity; Transcription Factor CHOP - metabolism; X-Box Binding Protein 1 - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0183702

Depressive disorder is a common psychiatric disease which ranks among the leading cause of disability worldwide. The antidepressants presently used had low cure rate and caused a variety of side-effects. The screening of antidepressant drugs is usually used classic behavioural tests and neuroprotective strategy. Longistyline C, a natural stilbene isolated from the leaves of Cajanuscajan (L.) Millsp, was firstly investigated the antidepressant effect using animal behavioural tests, and studied the neuroprotection and its possible signaling pathways on glutamate-induced injury in PC12 cells. The results of animal test demonstrated that longistyline C had the antidepressant activity, which the effect is similar to the positive control. In current study, we investigated the effect of longistyline C on glutamate-induced injury in PC12 cells and explored its possible signaling pathways. The results demonstrated that pretreatment with longistyline C at the concentrations of 2-8 μmol/L for 24 h had a significant reduction of the cytotoxicity induced by glutamate (15 mmol/L) in PC12 cells using MTT, lactate dehydrogenase (LDH) release assay and Annexin V-PI double staining. Subsequently, we found that pretreatment with longistyline C (8 μmol/L) could drastically down-regulate the over-expression of NMDAR/NR2B and Ca2+/calmodulin-dependent protein kinase II (CaMKII), up-regulate the expressions of p-ERK and p-CREB and alleviate ER stress. In conclusison, longistyline C is most possibly through regulating NMDAR/NR2B-ERK1/2 related pathway and restoring endoplasmic reticulum function to exert neuroprotective effect against glutamate-induced injury in PC12 cells.