Use of glucagon-like peptide-1 receptor agonist or dipeptidyl peptidase 4 inhibitor has been shown to lower the incidence of Parkinson's disease in patients with diabetes mellitus.Therefore,using these two treatme...Use of glucagon-like peptide-1 receptor agonist or dipeptidyl peptidase 4 inhibitor has been shown to lower the incidence of Parkinson's disease in patients with diabetes mellitus.Therefore,using these two treatments may help treat Parkinson's disease.To further investigate the mechanisms of action of these two compounds,we established a model of Parkinson's disease by treating mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and then subcutaneously injected them with the glucagon-like peptide-1 receptor agonist exendin-4 or the dipeptidyl peptidase 4 inhibitor linagliptin.We found that both exendin-4 and linagliptin reversed motor dysfunction,glial activation,and dopaminergic neuronal death in this model.In addition,both exendin-4 and linagliptin induced microglial polarization to the anti-inflammatory M2 phenotype and reduced pro-inflammatory cytokine secretion.Moreover,in vitro experiments showed that treatment with exendin-4 and linagliptin inhibited activation of the nucleotide-binding oligomerization domain-and leucine-rich-repeat-and pyrin-domaincontaining 3/caspase-1/interleukin-1βpathway and subsequent pyroptosis by decreasing the production of reactive oxygen species.These findings suggest that exendin-4 and linagliptin exert neuroprotective effects by attenuating neuroinflammation through regulation of microglial polarization and the nucleotidebinding oligomerization domain-and leucine-rich-repeat-and pyrin-domain-containing 3/caspase-1/interleukin-1βpathway in a mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.Therefore,these two drugs may serve as novel anti-inflammatory treatments for Parkinson's disease.展开更多
Tp53, a stress response gene, is involved in diverse cell death pathways and its activation is implicated in the pathogenesis of Parkinson＇s disease. However, whether the neuronal Tp53 protein plays a direct role in ...Tp53, a stress response gene, is involved in diverse cell death pathways and its activation is implicated in the pathogenesis of Parkinson＇s disease. However, whether the neuronal Tp53 protein plays a direct role in regulating dopaminergic （DA） neuronal cell death or neuronal terminal damage in different neurotoxicant models is unknown. In our recent studies, in contrast to the global inhibition of Tp53 function by phar- macological inhibitors and in traditional Tp53 knock-out mice, we examined the effects of DA-specific Tp53 gene deletion after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and methamphetamine exposure. Our data suggests that the Tp53 gene might be involved in both neuronal apoptosis and neuronal termi- nal damage caused by different neurotoxicants. Additional results from other studies also suggest that as a master regulator of many pathways that regulate apoptosis and synaptic terminal damage, it is possible that Tp53 may function as a signaling hub to integrate different signaling pathways to mediate distinctive target pathways. Tp53 protein as a signaling hub might be able to evaluate the microenvironment of neurons, assess the forms and severities of injury incurred, and determine whether apoptotic cell death or neuro- nal terminal degeneration occurs. Identification of the precise mechanisms activated in distinct neuronal damage caused by different forms and severities of injuries might allow for development of specific Tp53 inhibitors or ways to modulate distinct downstream target pathways involved.展开更多
1-Methy-4-phenyl-1,2,3,6-tetrahydropyridine（MPTP）is a neurotoxin that selectively damages dopaminergic neurons in the substantia nigra pars compacta and induces Parkinson＇s like symptoms in rodents.Quercetin（QC）i...1-Methy-4-phenyl-1,2,3,6-tetrahydropyridine（MPTP）is a neurotoxin that selectively damages dopaminergic neurons in the substantia nigra pars compacta and induces Parkinson＇s like symptoms in rodents.Quercetin（QC）is a natural polyphenolic bioflavonoid with potent antioxidant and anti-inflammatory properties but lacks of clinical attraction due to low oral bioavailability.Piperine is a well established bioavailability enhancer used pre-clinically to improve the bioavailability of antioxidants（e.g.,Quercetin）.Therefore,the present study was designed to evaluate the neuroprotective potential of QC together with piperine against MPTP-induced neurotoxicity in rats.MPTP（100μg/μL/rat,bilaterally）was injected intranigrally on days 1,4 and 7 using a digital stereotaxic apparatus.QC（25 and 50 mg/kg,intragastrically）and QC（25 mg/kg,intragastrically）in combination with piperine（2.5 mg/kg,intragastrically）were administered daily for 14 days starting from day 8 after the 3^（rd） injection of MPTP.On day 22,animals were sacrificed and the striatum was isolated for oxidative stress parameter（thiobarbituric acid reactive substances,nitrite and glutathione）,neuroinflammatory cytokine（interleukin-1β,interleukin-6,and tumor necrosis factor-α）and neurotransmitter（dopamine,norepinephrine,serotonin,gamma-aminobutyric acid,glutamate,3,4-dihydroxyphenylacetic acid,homovanillic acid,and 5-hydroxyindoleacetic acid）evaluations.Bilateral infusion of MPTP into substantia nigra pars compacta led to significant motor deficits as evidenced by impairments in locomotor activity and rotarod performance in open field test and grip strength and narrow beam walk performance.Both QC（25 and 50 mg/kg）and QC（25 mg/kg）in combination with piperine（2.5 mg/kg）,in particular the combination therapy,significantly improved MPTP-induced behavioral abnormalities in rats,reversed the abnormal alterations of neurotransmitters in the striatum,and alleviated oxidative stress and inflammatory response in the st展开更多
OBJECTIVE:To investigate the regulatory mechanism of the c-Jun N-terminal protein kinase(JNK)signaling pathway in substantia nigra(SN) dopaminergic neurons inflammation and apoptosis, and the neuroprotective effect of...OBJECTIVE:To investigate the regulatory mechanism of the c-Jun N-terminal protein kinase(JNK)signaling pathway in substantia nigra(SN) dopaminergic neurons inflammation and apoptosis, and the neuroprotective effect of Zishenpingchan granules in mice with Parkinson's disease(PD) induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP).METHODS:PD model mice were established by intraperitoneally injecting MPTP.Sixty mice were divided into a model group, Traditional Chinese Medicine(TCM) group and control group.The mice of the TCM group were administered Zishenpingchan granules 7 days before PD induction.Seven days after PD induction, we examined locomotor activity,and performed the rotarod test and swimming test,to evaluate limb movement function.Furthermore,we used immunohistochemistry and western blotting to examine the expression of tyrosine hydroxylase(TH), cyclooxygenase-2(Cox-2), caspase-3 and p-JNK.The terminal deoxynucleotidyl transferase mediated d UTP nick end labeling(TUNEL) method was used to examine neuron apoptosis in the SN.RESULTS:Compared with the control group, the mean score of locomotor activity, rotarod test and swimming test was significantly lower in the model group(P < 0.05); the TH-positive neuron expression was significantly decreased in the SN pars compacta(SNpc); the protein expression levels of Cox-2,caspase-3 and p-JNK was obviously increased; and the number of TUNEL-positive neurons in the SN was increased(P < 0.01).Compared with the model group, the mean score of neurobehavioral tests in the TCM group was obviously higher, the loss of TH-positive neurons ignificantly decreased, the protein expression levels of Cox-2, caspase-3 and p-JNK obviously decreased, and the number of TUNEL-positive neurons in the SN clearly decreased(P < 0.01).CONCLUSION:The JNK pathway plays an important role in the regulation of inflammation and apoptosis in nigral cells in PD mice.TCM can suppress the over-activation of the JNK pathway in the SN, and alleviate the inflammatory response in nigral cells 展开更多
The positive effect of levodopa in the treatment of Parkinson’s disease,although it is limited in time and has severe side effects,has encouraged the scientific community to look for new drugs that can stop the neuro...The positive effect of levodopa in the treatment of Parkinson’s disease,although it is limited in time and has severe side effects,has encouraged the scientific community to look for new drugs that can stop the neurodegenerative process or even regenerate the neuromelanin-containing dopaminergic nigrostriatal neurons.Successful preclinical studies with coenzyme Q10,mitoquinone,isradipine,nilotinib,TCH346,neurturin,zonisamide,deferiprone,prasinezumab,and cinpanemab prompted clinical trials.However,these failed and after more than 50 years levodopa continues to be the key drug in the treatment of the disease,despite its severe side effects after 4–6 years of chronic treatment.The lack of translated successful results obtained in preclinical investigations based on the use of neurotoxins that do not exist in the human body as new drugs for Parkinson’s disease treatment is a big problem.In our opinion,the cause of these failures lies in the experimental animal models involving neurotoxins that do not exist in the human body,such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine,that induce a very fast,massive and expansive neurodegenerative process,which contrasts with the extremely slow one of neuromelanin-containing dopaminergic neurons.The exceedingly slow progress of the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson’s patients is due to(i)a degenerative model in which the neurotoxic effect of an endogenous neurotoxin affects a single neuron,(ii)a neurotoxic event that is not expansive and(iii)the fact that the neurotoxin that triggers the neurodegenerative process is produced inside the neuromelanin-containing dopaminergic neurons.The endogenous neurotoxin that fits this degenerative model involving one single neuron at a time is aminochrome,since it(i)is generated within neuromelanin-containing dopaminergic neurons,(ii)does not cause an expansive neurotoxic effect and(iii)triggers all the mechanisms involved in the neurodegenerative process of the nigr展开更多
基金supported by the National Natural Science Foundation of China,Nos.81771271(to JF),31800898(to WL),81430025(to JYL),and U1801681(to JYL)Key Research and Development Program of Liaoning Province,No.2020JH2/10300047(to JF)+1 种基金the Key Field Research Development Program of Guangdong Province,No.2018B030337001(to JYL)the Outstanding Scientific Fund of Shengjing Hospital,No.M0475(to JF)。
文摘Use of glucagon-like peptide-1 receptor agonist or dipeptidyl peptidase 4 inhibitor has been shown to lower the incidence of Parkinson's disease in patients with diabetes mellitus.Therefore,using these two treatments may help treat Parkinson's disease.To further investigate the mechanisms of action of these two compounds,we established a model of Parkinson's disease by treating mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and then subcutaneously injected them with the glucagon-like peptide-1 receptor agonist exendin-4 or the dipeptidyl peptidase 4 inhibitor linagliptin.We found that both exendin-4 and linagliptin reversed motor dysfunction,glial activation,and dopaminergic neuronal death in this model.In addition,both exendin-4 and linagliptin induced microglial polarization to the anti-inflammatory M2 phenotype and reduced pro-inflammatory cytokine secretion.Moreover,in vitro experiments showed that treatment with exendin-4 and linagliptin inhibited activation of the nucleotide-binding oligomerization domain-and leucine-rich-repeat-and pyrin-domaincontaining 3/caspase-1/interleukin-1βpathway and subsequent pyroptosis by decreasing the production of reactive oxygen species.These findings suggest that exendin-4 and linagliptin exert neuroprotective effects by attenuating neuroinflammation through regulation of microglial polarization and the nucleotidebinding oligomerization domain-and leucine-rich-repeat-and pyrin-domain-containing 3/caspase-1/interleukin-1βpathway in a mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.Therefore,these two drugs may serve as novel anti-inflammatory treatments for Parkinson's disease.
文摘Tp53, a stress response gene, is involved in diverse cell death pathways and its activation is implicated in the pathogenesis of Parkinson＇s disease. However, whether the neuronal Tp53 protein plays a direct role in regulating dopaminergic （DA） neuronal cell death or neuronal terminal damage in different neurotoxicant models is unknown. In our recent studies, in contrast to the global inhibition of Tp53 function by phar- macological inhibitors and in traditional Tp53 knock-out mice, we examined the effects of DA-specific Tp53 gene deletion after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and methamphetamine exposure. Our data suggests that the Tp53 gene might be involved in both neuronal apoptosis and neuronal termi- nal damage caused by different neurotoxicants. Additional results from other studies also suggest that as a master regulator of many pathways that regulate apoptosis and synaptic terminal damage, it is possible that Tp53 may function as a signaling hub to integrate different signaling pathways to mediate distinctive target pathways. Tp53 protein as a signaling hub might be able to evaluate the microenvironment of neurons, assess the forms and severities of injury incurred, and determine whether apoptotic cell death or neuro- nal terminal degeneration occurs. Identification of the precise mechanisms activated in distinct neuronal damage caused by different forms and severities of injuries might allow for development of specific Tp53 inhibitors or ways to modulate distinct downstream target pathways involved.
基金Science and Engineering Board(SERB),Department of Science and Technology,Government of India,New Delhi for providing financial assistance under Fast Track Scheme(DST-SERB-FTYS)(SB/FT/LS-139/2012) to Dr.PK
文摘1-Methy-4-phenyl-1,2,3,6-tetrahydropyridine（MPTP）is a neurotoxin that selectively damages dopaminergic neurons in the substantia nigra pars compacta and induces Parkinson＇s like symptoms in rodents.Quercetin（QC）is a natural polyphenolic bioflavonoid with potent antioxidant and anti-inflammatory properties but lacks of clinical attraction due to low oral bioavailability.Piperine is a well established bioavailability enhancer used pre-clinically to improve the bioavailability of antioxidants（e.g.,Quercetin）.Therefore,the present study was designed to evaluate the neuroprotective potential of QC together with piperine against MPTP-induced neurotoxicity in rats.MPTP（100μg/μL/rat,bilaterally）was injected intranigrally on days 1,4 and 7 using a digital stereotaxic apparatus.QC（25 and 50 mg/kg,intragastrically）and QC（25 mg/kg,intragastrically）in combination with piperine（2.5 mg/kg,intragastrically）were administered daily for 14 days starting from day 8 after the 3^（rd） injection of MPTP.On day 22,animals were sacrificed and the striatum was isolated for oxidative stress parameter（thiobarbituric acid reactive substances,nitrite and glutathione）,neuroinflammatory cytokine（interleukin-1β,interleukin-6,and tumor necrosis factor-α）and neurotransmitter（dopamine,norepinephrine,serotonin,gamma-aminobutyric acid,glutamate,3,4-dihydroxyphenylacetic acid,homovanillic acid,and 5-hydroxyindoleacetic acid）evaluations.Bilateral infusion of MPTP into substantia nigra pars compacta led to significant motor deficits as evidenced by impairments in locomotor activity and rotarod performance in open field test and grip strength and narrow beam walk performance.Both QC（25 and 50 mg/kg）and QC（25 mg/kg）in combination with piperine（2.5 mg/kg）,in particular the combination therapy,significantly improved MPTP-induced behavioral abnormalities in rats,reversed the abnormal alterations of neurotransmitters in the striatum,and alleviated oxidative stress and inflammatory response in the st
基金Supported by the Natural Science Foundation of China(Effect of Dopamine D1/D2 Receptor-MAPK/ERK Signal Transduction in PD Levodopa-induced Dyskinesias with Shudi Pingchan Tang,No.81302926)the National Natural Science Foundation of China(Study on Inhibiting the Abnormal Aggregation and Misfolding of α-synuclein and Prevention of Parkinson's Disease with Shudipingchan Prescription,No.81673726)the National Clinical Research Base of Traditional Chinese Medicine Practitioners Program(Study on Inhibiting the Abnormal Aggregation and Misfolding of α-synuclein and Prevention of Parkinson's Disease with Acteoside,No.LYTD-34)
文摘OBJECTIVE:To investigate the regulatory mechanism of the c-Jun N-terminal protein kinase(JNK)signaling pathway in substantia nigra(SN) dopaminergic neurons inflammation and apoptosis, and the neuroprotective effect of Zishenpingchan granules in mice with Parkinson's disease(PD) induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP).METHODS:PD model mice were established by intraperitoneally injecting MPTP.Sixty mice were divided into a model group, Traditional Chinese Medicine(TCM) group and control group.The mice of the TCM group were administered Zishenpingchan granules 7 days before PD induction.Seven days after PD induction, we examined locomotor activity,and performed the rotarod test and swimming test,to evaluate limb movement function.Furthermore,we used immunohistochemistry and western blotting to examine the expression of tyrosine hydroxylase(TH), cyclooxygenase-2(Cox-2), caspase-3 and p-JNK.The terminal deoxynucleotidyl transferase mediated d UTP nick end labeling(TUNEL) method was used to examine neuron apoptosis in the SN.RESULTS:Compared with the control group, the mean score of locomotor activity, rotarod test and swimming test was significantly lower in the model group(P < 0.05); the TH-positive neuron expression was significantly decreased in the SN pars compacta(SNpc); the protein expression levels of Cox-2,caspase-3 and p-JNK was obviously increased; and the number of TUNEL-positive neurons in the SN was increased(P < 0.01).Compared with the model group, the mean score of neurobehavioral tests in the TCM group was obviously higher, the loss of TH-positive neurons ignificantly decreased, the protein expression levels of Cox-2, caspase-3 and p-JNK obviously decreased, and the number of TUNEL-positive neurons in the SN clearly decreased(P < 0.01).CONCLUSION:The JNK pathway plays an important role in the regulation of inflammation and apoptosis in nigral cells in PD mice.TCM can suppress the over-activation of the JNK pathway in the SN, and alleviate the inflammatory response in nigral cells
文摘The positive effect of levodopa in the treatment of Parkinson’s disease,although it is limited in time and has severe side effects,has encouraged the scientific community to look for new drugs that can stop the neurodegenerative process or even regenerate the neuromelanin-containing dopaminergic nigrostriatal neurons.Successful preclinical studies with coenzyme Q10,mitoquinone,isradipine,nilotinib,TCH346,neurturin,zonisamide,deferiprone,prasinezumab,and cinpanemab prompted clinical trials.However,these failed and after more than 50 years levodopa continues to be the key drug in the treatment of the disease,despite its severe side effects after 4–6 years of chronic treatment.The lack of translated successful results obtained in preclinical investigations based on the use of neurotoxins that do not exist in the human body as new drugs for Parkinson’s disease treatment is a big problem.In our opinion,the cause of these failures lies in the experimental animal models involving neurotoxins that do not exist in the human body,such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine,that induce a very fast,massive and expansive neurodegenerative process,which contrasts with the extremely slow one of neuromelanin-containing dopaminergic neurons.The exceedingly slow progress of the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson’s patients is due to(i)a degenerative model in which the neurotoxic effect of an endogenous neurotoxin affects a single neuron,(ii)a neurotoxic event that is not expansive and(iii)the fact that the neurotoxin that triggers the neurodegenerative process is produced inside the neuromelanin-containing dopaminergic neurons.The endogenous neurotoxin that fits this degenerative model involving one single neuron at a time is aminochrome,since it(i)is generated within neuromelanin-containing dopaminergic neurons,(ii)does not cause an expansive neurotoxic effect and(iii)triggers all the mechanisms involved in the neurodegenerative process of the nigr
