Aluminum has been associated with neurodegenerative diseases.ALA(α-linolenic acid),an essential dietary component for human health,possesses prominent biological activities.Herein,we aim to explore the neuroprotectiv...Aluminum has been associated with neurodegenerative diseases.ALA(α-linolenic acid),an essential dietary component for human health,possesses prominent biological activities.Herein,we aim to explore the neuroprotective effects of ALA on aluminum toxicity and reveal the underlying mechanism.Results show that aluminum chloride(denoted as Al)enabled cell viability decline and apoptosis with oxidative stress and mitochondrial damage in differentiated rat pheochromocytoma cells(PC12)for 24 h incubation.Compared with Al(10 mmol/L)treatment alone,ALA(50μmol/L)pretreatment for 24 h significantly enhanced cell viability by 28.40%,and hindered cell apoptosis by 12.35%,together with recovering redox state balance and alleviating mitochondrial damage.It was measured that ALA treatment upregulated Bcl-2 expression and down-regulated Bax level,accompanied with an expression decline of caspase-3 and caspase-9.Meanwhile,ALA pretreatment was proved to increase protein kinase A(PKA)expression and to promote phosphorylation of cAMP response element-binding protein(p-CREB),resulting in elevation on the level of brain-derived neurotrophic factor(BDNF).The above results showed that ALA attenuated Al toxicity in PC12 cells by mediating the PKA-CREBBDNF signaling pathway.展开更多
Nicotinicα4β2 receptor antagonists have drawn increasing attention in the development of new antidepressants.In this study,we aimed to investigate the protective effect of VMY-2-95,the new selective antagonist ofα4...Nicotinicα4β2 receptor antagonists have drawn increasing attention in the development of new antidepressants.In this study,we aimed to investigate the protective effect of VMY-2-95,the new selective antagonist ofα4β2 nicotinic acetylcholine receptor(nAChR)on corticosterone(CORT)injured mice and cellular models.Fluoxetine was applied as a positive control,and the effects of VMY-2-95 were investigated with three different doses or concentrations(1,3,10 mg/kg in mice,and 0.003,0.03,0.1μmol/L in cells).As a result,VMY-2-95 showed significant antidepressant-like effects in the CORT injured mice by improving neuromorphic function,promoting hippocampal nerve proliferation,and regulating the contents of monoamine transmitters.Meanwhile,VMY-2-95 exhibited protective effects on cell viability,cell oxidant,cell apoptosis,and mitochondrial energy metabolism on corticosterone-impaired SH-SY5 Y cells.Also,the PKA-CREB-BDNF signaling pathway was up-regulated by VMY-2-95 both in vitro and in vivo,and pathway blockers were also combined with VMY-2-95 to verify the effects furtherly.Therefore,we preliminarily proved that VMY-2-95 had protective effects in depressed mice and SH-SY5 Y cells against injuries induced by corticosterone.This work indicated that the application of VMY-2-95 is a potential pharmacological solution for depression.This study also supported the development ofα4β2 nAChR antagonists towards neuropsychiatric dysfunctions.展开更多
基金supported by the National Natural Science Foundation of China (31972041, 32101955)the China Agriculture Research System of MOF and MARA (CARS-12)+1 种基金the Agricultural Science and Technology Innovation Project of Chinese Academy of Agricultural Sciences (CAASASTIP-2016-OCRI)the Key Scientific Research Projects of Hubei Province (2020BCA086)
文摘Aluminum has been associated with neurodegenerative diseases.ALA(α-linolenic acid),an essential dietary component for human health,possesses prominent biological activities.Herein,we aim to explore the neuroprotective effects of ALA on aluminum toxicity and reveal the underlying mechanism.Results show that aluminum chloride(denoted as Al)enabled cell viability decline and apoptosis with oxidative stress and mitochondrial damage in differentiated rat pheochromocytoma cells(PC12)for 24 h incubation.Compared with Al(10 mmol/L)treatment alone,ALA(50μmol/L)pretreatment for 24 h significantly enhanced cell viability by 28.40%,and hindered cell apoptosis by 12.35%,together with recovering redox state balance and alleviating mitochondrial damage.It was measured that ALA treatment upregulated Bcl-2 expression and down-regulated Bax level,accompanied with an expression decline of caspase-3 and caspase-9.Meanwhile,ALA pretreatment was proved to increase protein kinase A(PKA)expression and to promote phosphorylation of cAMP response element-binding protein(p-CREB),resulting in elevation on the level of brain-derived neurotrophic factor(BDNF).The above results showed that ALA attenuated Al toxicity in PC12 cells by mediating the PKA-CREBBDNF signaling pathway.
基金supported by the National Natural Science Foundation of China(No.81603100)the Drug Innovation Major Project(2018ZX09711001-003-005,2018ZX09711001-012,China)+1 种基金CAMS Innovation Fund for Medical Sciences(2017-I2M1-010,China)Peking Union Medical College Graduate Innovation Fund Project(2017-1007-11,China)
文摘Nicotinicα4β2 receptor antagonists have drawn increasing attention in the development of new antidepressants.In this study,we aimed to investigate the protective effect of VMY-2-95,the new selective antagonist ofα4β2 nicotinic acetylcholine receptor(nAChR)on corticosterone(CORT)injured mice and cellular models.Fluoxetine was applied as a positive control,and the effects of VMY-2-95 were investigated with three different doses or concentrations(1,3,10 mg/kg in mice,and 0.003,0.03,0.1μmol/L in cells).As a result,VMY-2-95 showed significant antidepressant-like effects in the CORT injured mice by improving neuromorphic function,promoting hippocampal nerve proliferation,and regulating the contents of monoamine transmitters.Meanwhile,VMY-2-95 exhibited protective effects on cell viability,cell oxidant,cell apoptosis,and mitochondrial energy metabolism on corticosterone-impaired SH-SY5 Y cells.Also,the PKA-CREB-BDNF signaling pathway was up-regulated by VMY-2-95 both in vitro and in vivo,and pathway blockers were also combined with VMY-2-95 to verify the effects furtherly.Therefore,we preliminarily proved that VMY-2-95 had protective effects in depressed mice and SH-SY5 Y cells against injuries induced by corticosterone.This work indicated that the application of VMY-2-95 is a potential pharmacological solution for depression.This study also supported the development ofα4β2 nAChR antagonists towards neuropsychiatric dysfunctions.
