Depression is a devastating mental disorder and major depressive disorder(MDD) that afflicts 16% of the global population at some point in their lives.Currently available classical antide.pressants(SSRIs,SNRIs,TCAs an...Depression is a devastating mental disorder and major depressive disorder(MDD) that afflicts 16% of the global population at some point in their lives.Currently available classical antide.pressants(SSRIs,SNRIs,TCAs and MOIs),require a minimum of 2–4 weeks of continuous treat.ment to elicit therapeutic relief in depressed patients and are associated with high rates of non-respon.siveness,and limited duration of efficacy.Therefore,faster-acting antidepressant therapies are need.ed,particularly for patients at risk for suicide for current therapies for depression.Although the molecu.lar mechanisms underlying the pathogenesis of depression are still largely unclear,previous studies have suggested that modulators of mammalian target of rapamycin complex 1(mTORC1) signaling may have beneficial neuroprotective and antidepressant effects.Here,we review recent advances in understanding mTORC1 signaling in depression and potential therapeutic strategies resulting from modulation of the mTORC1 signaling network.We also highlight recent studies considered to support mTORC1 signaling modulation as a rapid-acting antidepressant therapy(e.g.ketamine,scopolamine,GLYX-13,(2R,6 R)-HNK,Ro-256891 etc.) and discuss future research directions.Studies on prospec.tive next-generation rapid-acting antidepressant therapies should focus on developing more selective glutamate receptors(e.g.α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors(AMPARs)agonists or activators) that activate the mTORC1 signaling pathway free of ketamine's adverse effects.展开更多
20C,a bibenzyl compound isolated from Gastrodia elata,possesses antioxidative properties in PC12 cells,but its in-depth molecular mechanisms against rotenone-induced neurotoxicity remains unknown.Recent studies indica...20C,a bibenzyl compound isolated from Gastrodia elata,possesses antioxidative properties in PC12 cells,but its in-depth molecular mechanisms against rotenone-induced neurotoxicity remains unknown.Recent studies indicate that without intact DJ-1,nuclear factor erythroid 2-related factor(Nrf2)protein becomes unstable,and the activity of Nrf2-mediated downstream antioxidant enzymes are thereby suppressed.Therefore,increasing the nuclear translocation of Nrf2 by DJ-1 may present a helpful means for the prevention and treatment of chronic diseases related to oxidative stress.Our results showed that 20C clearly protected PC12 and SH-SY5Y cells against rotenone-induced oxidative injury in a concentration-dependent manner.Furthermore,20C markedly up-regulated the levels of DJ-1,which in turn activated phosphoinositide-3-kinase(PI3K)/Akt signaling and inhibited glycogen synthase kinase 3β(GSK3β)activation,eventually promoting Nrf2 nuclear translocation and inducing the expression of Nrf2-mediated downstream antioxidative enzymes such as HO-1.The antioxidative effects of 20C could be partially blocked by ShR NA-mediated knockdown of DJ-1 and inhibition of the PI3K/Akt pathways with Akt1/2 kinase inhibitor in PC12 and SH-SY5Y cells,respectively.Conclusively,our findings confirm that DJ-1 is necessary for 20C-mediated protection against rotenone-induced oxidative damage,at least in part,by activating PI3K/Akt signaling,and subsequently enhancing the nuclear accumulation of Nrf2.The findings from our investigation suggest that 20C should be developed as a novel candidate for preventing or alleviating the consequences of PD in the future.展开更多
OBJECTIVE(1) To estimate the value of the subacute MPTP mouse model in aspects of behavioral performance,biochemical changes and pathological abnormalities.(2) To find effective positive drugs.METHODS Male C57 BL/6 mi...OBJECTIVE(1) To estimate the value of the subacute MPTP mouse model in aspects of behavioral performance,biochemical changes and pathological abnormalities.(2) To find effective positive drugs.METHODS Male C57 BL/6 mice were injected with MPTP(30 mg·kg^(-1)·d^(-1),ip) for 5 consecutive days.Three days before MPTP injection,the mice were orally administered selegiline(3 mg·kg^(-1)·d^(-1)),pramipexole(3 mg·kg^(-1)·d^(-1)),or medopar(100 mg·kg^(-1)·d^(-1)) for 18 d.Behavioral performance was assessed in the open field test,pole test and rotarod test.Neurotransmitters in the striatum were detected using HPLC.Protein levels were measured by Western blot.Pathological characteristics were examined by immunohistochemistry.Ultrastructure changes were observed by electron microscopy.RESULTS The subacute MPTP treatment did not induce evident motor defects despite severe injuries in the dopaminergic system.Additionally,MPTP significantly increased the α-synuclein levels and the number of astrocytes in the striatum,and destroyed the blood-brain barrier(BBB) in the substantianigra pars compacta.Both selegiline and pramipexole were able to protect the mice against MPTP injuries.CONCLUSION The subacute MPTP mouse model does not show visible motor defects;it is not enough to evaluate the validity of a candidate just based on behavioral examination,much attention should also be paid to the alterations in neurotransmitters,astrocytes,α-synuclein and the BBB.In addition,selegiline or pramipexole is a better choice than medopar as an effective positive control for the subacute MPTP model.展开更多
OBJECTIVE To evaluate these activities of Rg1 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)/probenecid(MPTP/p)-induced PD mouse model for the first time and to elucidate the underlying mechanisms.METHODS M...OBJECTIVE To evaluate these activities of Rg1 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)/probenecid(MPTP/p)-induced PD mouse model for the first time and to elucidate the underlying mechanisms.METHODS Male C57BL/6 mice were randomly assigned to six groups.One hour prior to MPTP/p injection,GroupⅢ-Ⅵmice received 10 mg·kg^(-1),20 mg·kg^(-1),or 40 mg·kg^(-1) Rg1 or 3 mg·kg^(-1) selegiline,respectively,orally from D(-3) to D49.GroupⅠ-Ⅱmice received solvent water.Subsequently,GroupⅡ-Ⅵmice received by injection MPTP-HCl(25 mg·kg^(-1) bw dissolved in0.9%saline,sc)on a 40-d schedule at intervals of 4 d between consecutive doses in combination with an adjuvant drug,probenecid(250 mg·kg^(-1) bw in 0.03 mL of DMSO,ip);GroupⅠmice were injected with saline and probenecid.Behavioral performance was assessed in the open field test,pole test and rotarod test.Neurotransmitters in the striatum were detected using HPLC.Protein levels were measured by Western blot.Pathological characteristics were examined by immunohistochemistry.Ultrastructure changes were observed by electron microscopy.RESULTS Oral treatment with Rg1 significantly attenuated the high MPTP-induced mortality,behavior defects,loss of dopamine neurons and abnormal ultrastructure changes in the SNpc.Other assays indicated that the protective effect of Rg1 may be mediated by its anti-neuroinflammatory properties.Rg1 regulated MPTP-induced reactive astrocytes and microglia and decreased the release of cytokines such as tumor necrosis factor-α(TNF-α)and interleukin-1b(IL^(-1)b)in the SNpc.Rg1 also al eviated the unusual MPTP induced increase in oligomeric,phosphorylated and disease-related a-synuclein in the SNpc.CONCLUSION Rg1 protects dopaminergic neurons,most likely by reducing aberrant a-synuclein-mediated neuroinflammation,and holds promise for Parkinson disease therapeutics.展开更多
Neuroinflammation is a key contributor to the pathogenic cascades induced by hypoxic-ischemic(HI)insult in the neonatal brain.AD-16 is a novel anti-inflammatory compound,recently found to exert potent inhibition of th...Neuroinflammation is a key contributor to the pathogenic cascades induced by hypoxic-ischemic(HI)insult in the neonatal brain.AD-16 is a novel anti-inflammatory compound,recently found to exert potent inhibition of the lipopolysaccharide-induced production of pro-inflammatory and neurotoxic mediators.In this study,we evaluated the effect of AD-16 on primary astrocytes and neurons under oxygen-glucose deprivation(OGD)in vitro and in mice with neonatal HI brain injury in vivo.We demonstrated that AD-16 protected against OGD-induced astrocytic and neuronal cell injury.Single dose post-treatment with AD-16(1 mg/kg)improved the neurobehavioral outcome and reduced the infarct volume with a therapeutic window of up to 6 h.Chronic administration reduced the mortality rate and preserved whole-brain morphology following neonatal HI.The in vitro and in vivo effects suggest that AD-16 offers promising therapeutic efficacy in attenuating the progression of HI brain injury and protecting against the associated mortality and morbidity.展开更多
基金supported by Beijing Natural Science Foundation(7182114)Project of NDRC and State Administration of Traditional Chinese Medicine(60011000)Hunan Provincial Key Laboratory for Standardization of Important Chinese Herbal Pieces(4981-0901020)
文摘Depression is a devastating mental disorder and major depressive disorder(MDD) that afflicts 16% of the global population at some point in their lives.Currently available classical antide.pressants(SSRIs,SNRIs,TCAs and MOIs),require a minimum of 2–4 weeks of continuous treat.ment to elicit therapeutic relief in depressed patients and are associated with high rates of non-respon.siveness,and limited duration of efficacy.Therefore,faster-acting antidepressant therapies are need.ed,particularly for patients at risk for suicide for current therapies for depression.Although the molecu.lar mechanisms underlying the pathogenesis of depression are still largely unclear,previous studies have suggested that modulators of mammalian target of rapamycin complex 1(mTORC1) signaling may have beneficial neuroprotective and antidepressant effects.Here,we review recent advances in understanding mTORC1 signaling in depression and potential therapeutic strategies resulting from modulation of the mTORC1 signaling network.We also highlight recent studies considered to support mTORC1 signaling modulation as a rapid-acting antidepressant therapy(e.g.ketamine,scopolamine,GLYX-13,(2R,6 R)-HNK,Ro-256891 etc.) and discuss future research directions.Studies on prospec.tive next-generation rapid-acting antidepressant therapies should focus on developing more selective glutamate receptors(e.g.α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors(AMPARs)agonists or activators) that activate the mTORC1 signaling pathway free of ketamine's adverse effects.
基金supported by National Natural Science Foundation of China(U1402221,81573640,81603316)Beijing Natural Science Foundation(7161011)+3 种基金CAMS Innovation Fund for Medical Sciences(CIFMS)(2016-I2M-1-004)Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study(BZ0150)Key Research and Development Project of Hunan Province(2015SK2029-1)Scientific Research Foundation of the Higher Education Institutions of Hunan Province(15K091)
文摘20C,a bibenzyl compound isolated from Gastrodia elata,possesses antioxidative properties in PC12 cells,but its in-depth molecular mechanisms against rotenone-induced neurotoxicity remains unknown.Recent studies indicate that without intact DJ-1,nuclear factor erythroid 2-related factor(Nrf2)protein becomes unstable,and the activity of Nrf2-mediated downstream antioxidant enzymes are thereby suppressed.Therefore,increasing the nuclear translocation of Nrf2 by DJ-1 may present a helpful means for the prevention and treatment of chronic diseases related to oxidative stress.Our results showed that 20C clearly protected PC12 and SH-SY5Y cells against rotenone-induced oxidative injury in a concentration-dependent manner.Furthermore,20C markedly up-regulated the levels of DJ-1,which in turn activated phosphoinositide-3-kinase(PI3K)/Akt signaling and inhibited glycogen synthase kinase 3β(GSK3β)activation,eventually promoting Nrf2 nuclear translocation and inducing the expression of Nrf2-mediated downstream antioxidative enzymes such as HO-1.The antioxidative effects of 20C could be partially blocked by ShR NA-mediated knockdown of DJ-1 and inhibition of the PI3K/Akt pathways with Akt1/2 kinase inhibitor in PC12 and SH-SY5Y cells,respectively.Conclusively,our findings confirm that DJ-1 is necessary for 20C-mediated protection against rotenone-induced oxidative damage,at least in part,by activating PI3K/Akt signaling,and subsequently enhancing the nuclear accumulation of Nrf2.The findings from our investigation suggest that 20C should be developed as a novel candidate for preventing or alleviating the consequences of PD in the future.
基金supported by National Natural Science Foundation of China(81373997,U1402221,81573640 and 81603316)Beijing Natural Science Foundation(7161011)+3 种基金Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study(BZ0150)CAMS Innovation Fund for Medical Sciences(CIFMS)(2016-I2M-1-004)Key Research and Development Project of Hunan Province(2015SK2029-1)Scientific Research Foundation of the Higher Education Institutions of Hunan Province(15K091)
文摘OBJECTIVE(1) To estimate the value of the subacute MPTP mouse model in aspects of behavioral performance,biochemical changes and pathological abnormalities.(2) To find effective positive drugs.METHODS Male C57 BL/6 mice were injected with MPTP(30 mg·kg^(-1)·d^(-1),ip) for 5 consecutive days.Three days before MPTP injection,the mice were orally administered selegiline(3 mg·kg^(-1)·d^(-1)),pramipexole(3 mg·kg^(-1)·d^(-1)),or medopar(100 mg·kg^(-1)·d^(-1)) for 18 d.Behavioral performance was assessed in the open field test,pole test and rotarod test.Neurotransmitters in the striatum were detected using HPLC.Protein levels were measured by Western blot.Pathological characteristics were examined by immunohistochemistry.Ultrastructure changes were observed by electron microscopy.RESULTS The subacute MPTP treatment did not induce evident motor defects despite severe injuries in the dopaminergic system.Additionally,MPTP significantly increased the α-synuclein levels and the number of astrocytes in the striatum,and destroyed the blood-brain barrier(BBB) in the substantianigra pars compacta.Both selegiline and pramipexole were able to protect the mice against MPTP injuries.CONCLUSION The subacute MPTP mouse model does not show visible motor defects;it is not enough to evaluate the validity of a candidate just based on behavioral examination,much attention should also be paid to the alterations in neurotransmitters,astrocytes,α-synuclein and the BBB.In addition,selegiline or pramipexole is a better choice than medopar as an effective positive control for the subacute MPTP model.
基金supported by National Natural Science Foundation of China(81274122,81373997,U1402221,81573640,81273629)Beijing Natural Science Foundation(7131013)+1 种基金Specialized Research Fund for the Doctoral Program of Higher Education of China(20121106130001)Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study(BZ0150)
文摘OBJECTIVE To evaluate these activities of Rg1 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)/probenecid(MPTP/p)-induced PD mouse model for the first time and to elucidate the underlying mechanisms.METHODS Male C57BL/6 mice were randomly assigned to six groups.One hour prior to MPTP/p injection,GroupⅢ-Ⅵmice received 10 mg·kg^(-1),20 mg·kg^(-1),or 40 mg·kg^(-1) Rg1 or 3 mg·kg^(-1) selegiline,respectively,orally from D(-3) to D49.GroupⅠ-Ⅱmice received solvent water.Subsequently,GroupⅡ-Ⅵmice received by injection MPTP-HCl(25 mg·kg^(-1) bw dissolved in0.9%saline,sc)on a 40-d schedule at intervals of 4 d between consecutive doses in combination with an adjuvant drug,probenecid(250 mg·kg^(-1) bw in 0.03 mL of DMSO,ip);GroupⅠmice were injected with saline and probenecid.Behavioral performance was assessed in the open field test,pole test and rotarod test.Neurotransmitters in the striatum were detected using HPLC.Protein levels were measured by Western blot.Pathological characteristics were examined by immunohistochemistry.Ultrastructure changes were observed by electron microscopy.RESULTS Oral treatment with Rg1 significantly attenuated the high MPTP-induced mortality,behavior defects,loss of dopamine neurons and abnormal ultrastructure changes in the SNpc.Other assays indicated that the protective effect of Rg1 may be mediated by its anti-neuroinflammatory properties.Rg1 regulated MPTP-induced reactive astrocytes and microglia and decreased the release of cytokines such as tumor necrosis factor-α(TNF-α)and interleukin-1b(IL^(-1)b)in the SNpc.Rg1 also al eviated the unusual MPTP induced increase in oligomeric,phosphorylated and disease-related a-synuclein in the SNpc.CONCLUSION Rg1 protects dopaminergic neurons,most likely by reducing aberrant a-synuclein-mediated neuroinflammation,and holds promise for Parkinson disease therapeutics.
基金Funding: National Natural Science Foundation of China (Grant No. 81530099, Grant No.81473375), China Postdoctoral Science Foundation (Grant No. 2013M540066), Research Project Supported by Shanxi Scholarship Council of China (Grant No. 2013-134). Fund Program for the Scientific Activities of Selected Returned Overseas Professionals in Shanxi Province, Program for the Innovative Talents of Higher Learning Institutions of Shanxi.
基金This work was supported by the Canadian Institutes of Health Research(CIHR PJT-153155)ZPF and a Natural Sciences and Engineering Research Council of Canada Discovery Grant(NSERC RGPIN-2016-04574)to HSS.
文摘Neuroinflammation is a key contributor to the pathogenic cascades induced by hypoxic-ischemic(HI)insult in the neonatal brain.AD-16 is a novel anti-inflammatory compound,recently found to exert potent inhibition of the lipopolysaccharide-induced production of pro-inflammatory and neurotoxic mediators.In this study,we evaluated the effect of AD-16 on primary astrocytes and neurons under oxygen-glucose deprivation(OGD)in vitro and in mice with neonatal HI brain injury in vivo.We demonstrated that AD-16 protected against OGD-induced astrocytic and neuronal cell injury.Single dose post-treatment with AD-16(1 mg/kg)improved the neurobehavioral outcome and reduced the infarct volume with a therapeutic window of up to 6 h.Chronic administration reduced the mortality rate and preserved whole-brain morphology following neonatal HI.The in vitro and in vivo effects suggest that AD-16 offers promising therapeutic efficacy in attenuating the progression of HI brain injury and protecting against the associated mortality and morbidity.