Physical activity and exercise have several beneficial roles in enhancing both physiological and psychological well-being of an individual.In addition to aiding the regulation of aerobic and anaerobic metabolism,exerc...Physical activity and exercise have several beneficial roles in enhancing both physiological and psychological well-being of an individual.In addition to aiding the regulation of aerobic and anaerobic metabolism,exercise can stimulate the synthesis of exerkine hormones in the circulatory system.Among several exerkines that have been investigated for their therapeutic potential,Brain-derived neurotrophic factor(BDNF)is considered the most promising candidate,especially in the management of neurodegenerative diseases.Owing to the ability of physical activity to enhance BDNF synthesis,several experimental studies conducted so far have validated this hypothesis and produced satisfactory results at the pre-clinical level.This review highlights some of the recent animal model studies that have evaluated the efficiency of exercise in enhancing BDNF synthesis and promoting neuroprotective effects.Further,this review focuses on understanding the therapeutic benefits of exercise-induced exerkine synthesis as a non-pharmacological strategy in Parkinson’s disease(PD).Regarding physical activity and exerkine induction,the neuromuscular electrical stimulation(NMES)strategy could be considered as an alternate treatment modality for patients affected with PD.展开更多
Parkinson＇s disease （PD） is a chronic, progressive neurodegenerative central nervous system disease which occurs in the substantia nigra-corpus striatum system. The main pathological feature of PD is selective dopa...Parkinson＇s disease （PD） is a chronic, progressive neurodegenerative central nervous system disease which occurs in the substantia nigra-corpus striatum system. The main pathological feature of PD is selective dopaminergic neuronal loss with distinctive Lewy bodies in populations of surviving dopaminergic neurons. In the clinical and neuropathological diagnosis of PD, brain-derived neurotrophic factor mRNA expression in the substantia nigra pars compacta is reduced by 70%, and surviving dopaminergic neurons in the PD substantia nigra pars compacta express less brain-derived neurotrophic factor （BDNF） mRNA （20%） than their normal counterparts. In recent years, knowledge surrounding the relationship between neurotrophic factors and PD has increased, and detailed pathogenesis of the role of neurotrophic factors in PD becomes more important.展开更多
Parkinson＇s disease is a progressive neurological disease characterized by the degeneration of dopaminergic neurons in the substantia nigra.A highly similar pattern of neurodegeneration can be induced by 1-methyl-4-p...Parkinson＇s disease is a progressive neurological disease characterized by the degeneration of dopaminergic neurons in the substantia nigra.A highly similar pattern of neurodegeneration can be induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine（MPTP） or 1-methyl-4-phenylpyridinium ion（MPP＋）,which cause the death of dopaminergic neurons.Administration of MPTP or MPP＋ results in Parkinson＇s disease-like symptoms in rodents.However,it remains unclear whether intracerebroventricular MPP＋ administration affects neurogenesis in the substantia nigra and subgranular zone or whether brain-derived neurotrophic factor alters the effects of MPP＋.In this study,MPP＋（100 nmol） was intracerebroventricularly injected into mice to model Parkinson＇s disease.At 7 days after administration,the number of bromodeoxyuridine（Brd U）-positive cells in the subgranular zone of the hippocampal dentate gyrus increased,indicating enhanced neurogenesis.In contrast,a reduction in Brd U-positive cells was detected in the substantia nigra.Administration of brain-derived neurotrophic factor（100 ng） 1 day after MPP＋ administration attenuated the effect of MPP＋ in the subgranular zone and the substantia nigra.These findings reveal the complex interaction between neurotrophic factors and neurotoxins in the Parkinsonian model that result in distinct effects on the catecholaminergic system and on neurogenesis in different brain regions.展开更多
Acupuncture for the treatment of Parkinson＇s disease has a precise clinical outcome. This study investigated the effect of electroacupuncture at Fengfu （GV16） and Taichong （LR3） acupoints in rat models of Parkin...Acupuncture for the treatment of Parkinson＇s disease has a precise clinical outcome. This study investigated the effect of electroacupuncture at Fengfu （GV16） and Taichong （LR3） acupoints in rat models of Parkinson＇s disease induced by subcutaneous injection of rotenone into rat neck and back. Reverse transcription-PCR demonstrated that brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor mRNA expression was significantly increased in the substantia nigra of rat models of Parkinson＇s disease, and that abnormal behavior of rats was significantly improved following electroacupuncture treatment. These results indicated that electroacupuncture treatment upregulated brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor mRNA expression in the substantia nigra of rat models of Parkinson＇s disease. Thus, electroacupuncture may be useful in the treatment of Parkinson＇s disease.展开更多
Pitx3 is strongly associated with the phenotype, differentiation, and survival of dopaminergic neurons. The relationship between Pitx3 and glial cell line-derived neurotrophic factor（GDNF） in dopaminergic neurons re...Pitx3 is strongly associated with the phenotype, differentiation, and survival of dopaminergic neurons. The relationship between Pitx3 and glial cell line-derived neurotrophic factor（GDNF） in dopaminergic neurons remains poorly understood. The present investigation sought to construct and screen a lentivirus expression plasmid carrying a rat Pitx3 short hairpin（sh）RNA and to assess the impact of Pitx3 gene knockdown on GDNF transcriptional activity in MES23.5 dopaminergic neurons. Three pairs of interference sequences were designed and separately ligated into GV102 expression vectors. These recombinant plasmids were transfected into MES23.5 cells and western blot assays were performed to detect Pitx3 protein expression. Finally, the most effective Pitx3 sh RNA and a dual-luciferase reporter gene plasmid carrying the GDNF promoter region（GDNF-luciferase） were cotransfected into MES23.5 cells. Sequencing showed that the synthesized sequences were identical to the three Pitx3 interference sequences. Inverted fluorescence microscopy revealed that the lentivirus expression plasmids carrying Pitx3-sh RNA had 40-50% transfection efficiency. Western blot assay confirmed that the corresponding Pitx3 of the third knockdown sequence had the lowest expression level. Dual-luciferase reporter gene results showed that the GDNF transcriptional activity in dopaminergic cells cotransfected with both plasmids was decreased compared with those transfected with GDNF-luciferase alone. Together, the results showed that the designed Pitx3-sh RNA interference sequence decreased Pitx3 protein expression, which decreased GDNF transcriptional activity.展开更多
Parkinson’s disease is the most common movement disorder,affecting about 1%of the population over the age of 60 years.Parkinson’s disease is characterized clinically by resting tremor,bradykinesia,rigidity and postu...Parkinson’s disease is the most common movement disorder,affecting about 1%of the population over the age of 60 years.Parkinson’s disease is characterized clinically by resting tremor,bradykinesia,rigidity and postural instability,as a result of the progressive loss of nigrostriatal dopaminergic neurons.In addition to this neuronal cell loss,Parkinson’s disease is characterized by the accumulation of intracellular protein aggregates,Lewy bodies and Lewy neurites,composed primarily of the proteinα-synuclein.Although it was first described almost 200 years ago,there are no disease-modifying drugs to treat patients with Parkinson’s disease.In addition to conventional therapies,non-pharmacological treatment strategies are under investigation in patients and animal models of neurodegenerative disorders.Among such strategies,environmental enrichment,comprising physical exercise,cognitive stimulus,and social interactions,has been assessed in preclinical models of Parkinson’s disease.Environmental enrichment can cause structural and functional changes in the brain and promote neurogenesis and dendritic growth by modifying gene expression,enhancing the expression of neurotrophic factors and modulating neurotransmission.In this review article,we focus on the current knowledge about the molecular mechanisms underlying environmental enrichment neuroprotection in Parkinson’s disease,highlighting its influence on the dopaminergic,cholinergic,glutamatergic and GABAergic systems,as well as the involvement of neurotrophic factors.We describe experimental pre-clinical data showing how environmental enrichment can act as a modulator in a neurochemical and behavioral context in different animal models of Parkinson’s disease,highlighting the potential of environmental enrichment as an additional strategy in the management and prevention of this complex disease.展开更多
Aging is a physiological event dependent on multiple pathways that are linked to lifespan and processes leading to cognitive decline.This process represents the major risk factor for aging-related diseases such as Alz...Aging is a physiological event dependent on multiple pathways that are linked to lifespan and processes leading to cognitive decline.This process represents the major risk factor for aging-related diseases such as Alzheimer’s disease,Parkinson’s disease,and ischemic stroke.The incidence of all these pathologies increases exponentially with age.Research on aging biology has currently focused on elucidating molecular mechanisms leading to the development of those pathologies.Cognitive deficit and neurodegeneration,common features of aging-related pathologies,are related to the alteration of the activity and levels of neurotrophic factors,such as brain-derived neurotrophic factor,nerve growth factor,and glial cell-derived neurotrophic factor.For this reason,treatments that modulate neurotrophin levels have acquired a great deal of interest in preventing neurodegeneration and promoting neural regeneration in several neurological diseases.Those treatments include both the direct administration of neurotrophic factors and the induced expression with viral vectors,neurotrophins’binding with biomaterials or other molecules to increase their bioavailability but also cell-based therapies.Considering neurotrophins’crucial role in aging pathologies,here we discuss the involvement of several neurotrophic factors in the most common brain aging-related diseases and the most recent therapeutic approaches that provide direct and sustained neurotrophic support.展开更多
Dysfunctional autophagy often occurs during the development of neurodegenerative diseases,such as Parkinson’s disease,Huntington’s disease,and Alzheimer’s disease.The purinergic P2X4 receptor is an ATP-gated ion ch...Dysfunctional autophagy often occurs during the development of neurodegenerative diseases,such as Parkinson’s disease,Huntington’s disease,and Alzheimer’s disease.The purinergic P2X4 receptor is an ATP-gated ion channel that is widely expressed in the microglia,astrocytes,and neurons of the central and peripheral nervous systems.P2X4R is involved in the regulation of cellular excitability,synaptic transmission,and neuroinflammation.However,the role played by P2X4R in Parkinson’s disease remains poorly understood.Rat models of Parkinson’s disease were established by injecting 6-hydroxydopamine into the substantia nigra pars compacta.P2X4R-targeted small interfering RNA(siRNA)was injected into the same area 1 week before injury induction to inhibit the expression of the P2X4 receptor.The results showed that the inhibition of P2X4 receptor expression in Parkinson’s disease model rats reduced the rotation behavior induced by apomorphine treatment,increased the latency on the rotarod test,and upregulated the expression of tyrosine hydroxylase,brain-derived neurotrophic factor,LC3-II/LC3-I,Beclin-1,and phosphorylated tropomyosin receptor kinase B(TrkB)in brain tissue,while simultaneously reducing p62 levels.These findings suggest that P2X4 receptor activation might inhibit neuronal autophagy through the regulation of the brain-derived neurotrophic factor/TrkB signaling pathway,leading to dopaminergic neuron damage in the substantia nigra and the further inhibition of P2X4 receptor-mediated autophagy.These results indicate that P2X4 receptor might serve as a potential novel target for the treatment of Parkinson’s disease.This study was approved by the Animal Ethics Committee of Affiliated Hospital of Qingdao University(approval No.QYFYWZLL26119)on April 12,2016.展开更多
Parkinson’s disease (PD) is a slowly progressive, age-related, second most common neurodegenerative disorder after Alzheimer’s disease of unknown etiology. Dopamine replacement therapies were introduced five decades...Parkinson’s disease (PD) is a slowly progressive, age-related, second most common neurodegenerative disorder after Alzheimer’s disease of unknown etiology. Dopamine replacement therapies were introduced five decades ago and still remain the mainstay of treatment for Parkinson’s disease. However, with long-term treatment with L-dopa, more than 50% of patients were found to develop motor response complications approximately after 4 - 5 years of initiation of continuous treatment, in 80% of patients treated for 10 years, and in nearly 100% patients with young-onset disease. The complications of long–term treatment with levodopa include-motor fluctuations, dyskinesias, and nonmotor fluctuations are such as mood disturbance, cognitive dysfunction, dysautonomia and pain. Till date, there are various therapeutic approaches having been developed for the treatment of advanced PD comprising Pharmacotherapy, neurotrophic factors, surgical procedures such as DBS, cell-based therapies and gene therapies. The pharmacological and surgical therapies are only aiming to improve the symptoms of PD, but none are proven to have a significant effect on the underlying disease process with respect to either slowing disease progression or restoring the affected dopaminergic neurons. Although there is no cure for PD, Gene based therapy has significant prospective advantages over the conventional treatment modalities for PD, as it could theoretically be used to preserve or restore dopaminergic neurons affected by PD through the action of neurotrophic factors or alternatively increase the availability of enzymes required for dopamine synthesis. All commonly employed PD therapies focus on the amelioration of symptoms and do not cure disease. In this review only we summarize the newer therapeutic strategies for the treatment of PD such as anti-inflammatories, neurotrophic factors, neurosurgical procedures (DBS), cell based therapies and gene therapies.展开更多
文摘Physical activity and exercise have several beneficial roles in enhancing both physiological and psychological well-being of an individual.In addition to aiding the regulation of aerobic and anaerobic metabolism,exercise can stimulate the synthesis of exerkine hormones in the circulatory system.Among several exerkines that have been investigated for their therapeutic potential,Brain-derived neurotrophic factor(BDNF)is considered the most promising candidate,especially in the management of neurodegenerative diseases.Owing to the ability of physical activity to enhance BDNF synthesis,several experimental studies conducted so far have validated this hypothesis and produced satisfactory results at the pre-clinical level.This review highlights some of the recent animal model studies that have evaluated the efficiency of exercise in enhancing BDNF synthesis and promoting neuroprotective effects.Further,this review focuses on understanding the therapeutic benefits of exercise-induced exerkine synthesis as a non-pharmacological strategy in Parkinson’s disease(PD).Regarding physical activity and exerkine induction,the neuromuscular electrical stimulation(NMES)strategy could be considered as an alternate treatment modality for patients affected with PD.
文摘Parkinson＇s disease （PD） is a chronic, progressive neurodegenerative central nervous system disease which occurs in the substantia nigra-corpus striatum system. The main pathological feature of PD is selective dopaminergic neuronal loss with distinctive Lewy bodies in populations of surviving dopaminergic neurons. In the clinical and neuropathological diagnosis of PD, brain-derived neurotrophic factor mRNA expression in the substantia nigra pars compacta is reduced by 70%, and surviving dopaminergic neurons in the PD substantia nigra pars compacta express less brain-derived neurotrophic factor （BDNF） mRNA （20%） than their normal counterparts. In recent years, knowledge surrounding the relationship between neurotrophic factors and PD has increased, and detailed pathogenesis of the role of neurotrophic factors in PD becomes more important.
基金supported by the National Natural Science Foundation of China,No.31320103906(to TB)
文摘Parkinson＇s disease is a progressive neurological disease characterized by the degeneration of dopaminergic neurons in the substantia nigra.A highly similar pattern of neurodegeneration can be induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine（MPTP） or 1-methyl-4-phenylpyridinium ion（MPP＋）,which cause the death of dopaminergic neurons.Administration of MPTP or MPP＋ results in Parkinson＇s disease-like symptoms in rodents.However,it remains unclear whether intracerebroventricular MPP＋ administration affects neurogenesis in the substantia nigra and subgranular zone or whether brain-derived neurotrophic factor alters the effects of MPP＋.In this study,MPP＋（100 nmol） was intracerebroventricularly injected into mice to model Parkinson＇s disease.At 7 days after administration,the number of bromodeoxyuridine（Brd U）-positive cells in the subgranular zone of the hippocampal dentate gyrus increased,indicating enhanced neurogenesis.In contrast,a reduction in Brd U-positive cells was detected in the substantia nigra.Administration of brain-derived neurotrophic factor（100 ng） 1 day after MPP＋ administration attenuated the effect of MPP＋ in the subgranular zone and the substantia nigra.These findings reveal the complex interaction between neurotrophic factors and neurotoxins in the Parkinsonian model that result in distinct effects on the catecholaminergic system and on neurogenesis in different brain regions.
基金supported by the National Natural Science Foundation of China,No.30973787,30973809the Open Research Fund of Zhejiang First-foremost Key Subject-Acupuncture & Moxibustion,No.ZTK2010A10+1 种基金the Natural Science Foundation of Hubei Province,No.2009CDA068the Integrated Traditional and Western Medicine project by the Health Department of Hubei Province,No.2010Z-Z01
文摘Acupuncture for the treatment of Parkinson＇s disease has a precise clinical outcome. This study investigated the effect of electroacupuncture at Fengfu （GV16） and Taichong （LR3） acupoints in rat models of Parkinson＇s disease induced by subcutaneous injection of rotenone into rat neck and back. Reverse transcription-PCR demonstrated that brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor mRNA expression was significantly increased in the substantia nigra of rat models of Parkinson＇s disease, and that abnormal behavior of rats was significantly improved following electroacupuncture treatment. These results indicated that electroacupuncture treatment upregulated brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor mRNA expression in the substantia nigra of rat models of Parkinson＇s disease. Thus, electroacupuncture may be useful in the treatment of Parkinson＇s disease.
基金supported by the National Natural Science Foundation of China,No.81372698
文摘Pitx3 is strongly associated with the phenotype, differentiation, and survival of dopaminergic neurons. The relationship between Pitx3 and glial cell line-derived neurotrophic factor（GDNF） in dopaminergic neurons remains poorly understood. The present investigation sought to construct and screen a lentivirus expression plasmid carrying a rat Pitx3 short hairpin（sh）RNA and to assess the impact of Pitx3 gene knockdown on GDNF transcriptional activity in MES23.5 dopaminergic neurons. Three pairs of interference sequences were designed and separately ligated into GV102 expression vectors. These recombinant plasmids were transfected into MES23.5 cells and western blot assays were performed to detect Pitx3 protein expression. Finally, the most effective Pitx3 sh RNA and a dual-luciferase reporter gene plasmid carrying the GDNF promoter region（GDNF-luciferase） were cotransfected into MES23.5 cells. Sequencing showed that the synthesized sequences were identical to the three Pitx3 interference sequences. Inverted fluorescence microscopy revealed that the lentivirus expression plasmids carrying Pitx3-sh RNA had 40-50% transfection efficiency. Western blot assay confirmed that the corresponding Pitx3 of the third knockdown sequence had the lowest expression level. Dual-luciferase reporter gene results showed that the GDNF transcriptional activity in dopaminergic cells cotransfected with both plasmids was decreased compared with those transfected with GDNF-luciferase alone. Together, the results showed that the designed Pitx3-sh RNA interference sequence decreased Pitx3 protein expression, which decreased GDNF transcriptional activity.
文摘Parkinson’s disease is the most common movement disorder,affecting about 1%of the population over the age of 60 years.Parkinson’s disease is characterized clinically by resting tremor,bradykinesia,rigidity and postural instability,as a result of the progressive loss of nigrostriatal dopaminergic neurons.In addition to this neuronal cell loss,Parkinson’s disease is characterized by the accumulation of intracellular protein aggregates,Lewy bodies and Lewy neurites,composed primarily of the proteinα-synuclein.Although it was first described almost 200 years ago,there are no disease-modifying drugs to treat patients with Parkinson’s disease.In addition to conventional therapies,non-pharmacological treatment strategies are under investigation in patients and animal models of neurodegenerative disorders.Among such strategies,environmental enrichment,comprising physical exercise,cognitive stimulus,and social interactions,has been assessed in preclinical models of Parkinson’s disease.Environmental enrichment can cause structural and functional changes in the brain and promote neurogenesis and dendritic growth by modifying gene expression,enhancing the expression of neurotrophic factors and modulating neurotransmission.In this review article,we focus on the current knowledge about the molecular mechanisms underlying environmental enrichment neuroprotection in Parkinson’s disease,highlighting its influence on the dopaminergic,cholinergic,glutamatergic and GABAergic systems,as well as the involvement of neurotrophic factors.We describe experimental pre-clinical data showing how environmental enrichment can act as a modulator in a neurochemical and behavioral context in different animal models of Parkinson’s disease,highlighting the potential of environmental enrichment as an additional strategy in the management and prevention of this complex disease.
文摘Aging is a physiological event dependent on multiple pathways that are linked to lifespan and processes leading to cognitive decline.This process represents the major risk factor for aging-related diseases such as Alzheimer’s disease,Parkinson’s disease,and ischemic stroke.The incidence of all these pathologies increases exponentially with age.Research on aging biology has currently focused on elucidating molecular mechanisms leading to the development of those pathologies.Cognitive deficit and neurodegeneration,common features of aging-related pathologies,are related to the alteration of the activity and levels of neurotrophic factors,such as brain-derived neurotrophic factor,nerve growth factor,and glial cell-derived neurotrophic factor.For this reason,treatments that modulate neurotrophin levels have acquired a great deal of interest in preventing neurodegeneration and promoting neural regeneration in several neurological diseases.Those treatments include both the direct administration of neurotrophic factors and the induced expression with viral vectors,neurotrophins’binding with biomaterials or other molecules to increase their bioavailability but also cell-based therapies.Considering neurotrophins’crucial role in aging pathologies,here we discuss the involvement of several neurotrophic factors in the most common brain aging-related diseases and the most recent therapeutic approaches that provide direct and sustained neurotrophic support.
基金This work was supported by the National Natural Science Foundation of China,Nos.81571225 and 81971192(both to AMX).
文摘Dysfunctional autophagy often occurs during the development of neurodegenerative diseases,such as Parkinson’s disease,Huntington’s disease,and Alzheimer’s disease.The purinergic P2X4 receptor is an ATP-gated ion channel that is widely expressed in the microglia,astrocytes,and neurons of the central and peripheral nervous systems.P2X4R is involved in the regulation of cellular excitability,synaptic transmission,and neuroinflammation.However,the role played by P2X4R in Parkinson’s disease remains poorly understood.Rat models of Parkinson’s disease were established by injecting 6-hydroxydopamine into the substantia nigra pars compacta.P2X4R-targeted small interfering RNA(siRNA)was injected into the same area 1 week before injury induction to inhibit the expression of the P2X4 receptor.The results showed that the inhibition of P2X4 receptor expression in Parkinson’s disease model rats reduced the rotation behavior induced by apomorphine treatment,increased the latency on the rotarod test,and upregulated the expression of tyrosine hydroxylase,brain-derived neurotrophic factor,LC3-II/LC3-I,Beclin-1,and phosphorylated tropomyosin receptor kinase B(TrkB)in brain tissue,while simultaneously reducing p62 levels.These findings suggest that P2X4 receptor activation might inhibit neuronal autophagy through the regulation of the brain-derived neurotrophic factor/TrkB signaling pathway,leading to dopaminergic neuron damage in the substantia nigra and the further inhibition of P2X4 receptor-mediated autophagy.These results indicate that P2X4 receptor might serve as a potential novel target for the treatment of Parkinson’s disease.This study was approved by the Animal Ethics Committee of Affiliated Hospital of Qingdao University(approval No.QYFYWZLL26119)on April 12,2016.
文摘Parkinson’s disease (PD) is a slowly progressive, age-related, second most common neurodegenerative disorder after Alzheimer’s disease of unknown etiology. Dopamine replacement therapies were introduced five decades ago and still remain the mainstay of treatment for Parkinson’s disease. However, with long-term treatment with L-dopa, more than 50% of patients were found to develop motor response complications approximately after 4 - 5 years of initiation of continuous treatment, in 80% of patients treated for 10 years, and in nearly 100% patients with young-onset disease. The complications of long–term treatment with levodopa include-motor fluctuations, dyskinesias, and nonmotor fluctuations are such as mood disturbance, cognitive dysfunction, dysautonomia and pain. Till date, there are various therapeutic approaches having been developed for the treatment of advanced PD comprising Pharmacotherapy, neurotrophic factors, surgical procedures such as DBS, cell-based therapies and gene therapies. The pharmacological and surgical therapies are only aiming to improve the symptoms of PD, but none are proven to have a significant effect on the underlying disease process with respect to either slowing disease progression or restoring the affected dopaminergic neurons. Although there is no cure for PD, Gene based therapy has significant prospective advantages over the conventional treatment modalities for PD, as it could theoretically be used to preserve or restore dopaminergic neurons affected by PD through the action of neurotrophic factors or alternatively increase the availability of enzymes required for dopamine synthesis. All commonly employed PD therapies focus on the amelioration of symptoms and do not cure disease. In this review only we summarize the newer therapeutic strategies for the treatment of PD such as anti-inflammatories, neurotrophic factors, neurosurgical procedures (DBS), cell based therapies and gene therapies.
