Parkinson’s disease is chara cterized by the loss of dopaminergic neurons in the substantia nigra pars com pacta,and although restoring striatal dopamine levels may improve symptoms,no treatment can cure or reve rse ...Parkinson’s disease is chara cterized by the loss of dopaminergic neurons in the substantia nigra pars com pacta,and although restoring striatal dopamine levels may improve symptoms,no treatment can cure or reve rse the disease itself.Stem cell therapy has a regenerative effect and is being actively studied as a candidate for the treatment of Parkinson’s disease.Mesenchymal stem cells are considered a promising option due to fewer ethical concerns,a lower risk of immune rejection,and a lower risk of teratogenicity.We performed a meta-analysis to evaluate the therapeutic effects of mesenchymal stem cells and their derivatives on motor function,memory,and preservation of dopamine rgic neurons in a Parkinson’s disease animal model.We searched bibliographic databases(PubMed/MEDLINE,Embase,CENTRAL,Scopus,and Web of Science)to identify articles and included only pee r-reviewed in vivo interve ntional animal studies published in any language through J une 28,2023.The study utilized the random-effect model to estimate the 95%confidence intervals(CI)of the standard mean differences(SMD)between the treatment and control groups.We use the systematic review center for laboratory animal expe rimentation’s risk of bias tool and the collaborative approach to meta-analysis and review of animal studies checklist for study quality assessment.A total of 33studies with data from 840 Parkinson’s disease model animals were included in the meta-analysis.Treatment with mesenchymal stem cells significantly improved motor function as assessed by the amphetamine-induced rotational test.Among the stem cell types,the bone marrow MSCs with neurotrophic factor group showed la rgest effect size(SMD[95%CI]=-6.21[-9.50 to-2.93],P=0.0001,I^(2)=0.0%).The stem cell treatment group had significantly more tyrosine hydroxylase positive dopamine rgic neurons in the striatum([95%CI]=1.04[0.59 to 1.49],P=0.0001,I^(2)=65.1%)and substantia nigra(SMD[95%CI]=1.38[0.89 to 1.87],P=0.0001,I^(2)=75.3%),indicating a protective effect on dopaminergic neurons.Subgroup analysis of the amphetamine-induced rotation test showed a significant reduction only in the intracranial-striatum route(SMD[95%CI]=-2.59[-3.25 to-1.94],P=0.0001,I^(2)=74.4%).The memory test showed significant improvement only in the intravenous route(SMD[95%CI]=4.80[1.84 to 7.76],P=0.027,I^(2)=79.6%).Mesenchymal stem cells have been shown to positively impact motor function and memory function and protect dopaminergic neurons in preclinical models of Parkinson’s disease.Further research is required to determine the optimal stem cell types,modifications,transplanted cell numbe rs,and delivery methods for these protocols.展开更多
BACKGROUND: Inflammatory injury induced by microglial activation plays an important role in the occurrence and development of Parkinson's disease (PD). However, few studies have examined the relationship between m...BACKGROUND: Inflammatory injury induced by microglial activation plays an important role in the occurrence and development of Parkinson's disease (PD). However, few studies have examined the relationship between microglia and substantia nigra damage or dopaminergic neuron loss in animals with rotenone-induced PD.OBJECTIVE: To explore the relationship between activated microglia and loss of the substantia nigra, and the changes in concentration and dose of rotenone in the brain of rats with rotenone-induced PD.DESIGN, TIME AND SETTING: The neuropathological experiment was performed at the School of Traditional Chinese Medicine, Capital Medical University, China, from July 2007 to July 2008. MATERIALS: Rotenone was purchased from Sigma, USA. METHODS: The Parkinson's model was induced by injection of a rotenone oily-emulsion (2 mg/kg daily) subcutaneously into the back of 58 male adult Wistar rats for 3-6 weeks. Another three rats served as normal controls.MAIN OUTCOME MEASURES: Neurobehavioral changes were observed and recorded following rotenone treatment. Tyrosine hydroxylase and complement receptor OX42 were separately analyzed by immunohistochemical staining within 4 weeks following stopping rotenone treatment. Rotenone content was measured using high performance liquid chromatography in the cerebellum of rats that scored 2.4-6.RESULTS: Rotenone induced a loss of dopaminergic neurons in the substantia nigra as well as microglial activation, with increased behavior scores. Dopaminergic loss was still ongoing even when rotenone was stopped. Dopaminergic neuronal degeneration in the substantia nigra was initially 6%, but was 85% at 2 weeks after scoring, and degeneration depended on activated microglia. Rotenone was detected in the cerebellum at concentrations between 78.9 μg/L and 309.6 μg/L. CONCLUSION: Nigrostriatal dopaminergic degeneration paralleled the microglial activation. Rotenone absorbed into the brain in its original form initiated pathological injury in the substantia niara of PD rats.展开更多
Extensive iron deposition has been observed in the midbrain substantia nigra (SN) of Parkinson's disease (PD) patients, but the mechanisms of iron deposition in the SN remain poorly understood. The present study ...Extensive iron deposition has been observed in the midbrain substantia nigra (SN) of Parkinson's disease (PD) patients, but the mechanisms of iron deposition in the SN remain poorly understood. The present study investigated the relationship between dopaminergic neuronal damage, iron content changes, and divalent metal transporter 1 (DMT1) in the midbrain SN of PD rats to explore the relationship between time of iron deposition and DMT1 expression. Frozen midbrain SN sections from model rats were stained with Perls' iron. Results showed massive loss of tyrosine hydroxylase (TH)-positive cells in the SN and increased DMT1 expression in model group rats. No obvious iron deposition was observed in the SN during early stages after damage, but significant iron deposition was detected at 8 weeks post-injury. Results demonstrate that the loss of TH-positive cells in the SN appeared simultaneously with increased DMT1 expression. Extensive iron deposition occurred at 8 weeks post injury, which could be regarded as an early time window of iron deposition.展开更多
BACKGROUND: Human amniotic epithelial cells (HAECs) can differentiate into neurons, astrocytes and oligodendrocytes. They biologically secrete many active neurotrophins and have the capacity to metabolize dopamine ...BACKGROUND: Human amniotic epithelial cells (HAECs) can differentiate into neurons, astrocytes and oligodendrocytes. They biologically secrete many active neurotrophins and have the capacity to metabolize dopamine enzymes. These features underlie a theoretical basis for the treatment of Parkinson's disease (PD). OBJECTIVE: To investigate the survival and differentiation of transplanted HAECs in the lateral ventricle of PD model rats, and to explore its effect on circling behavior, as well as levels of dopamine (DA), the metabolite homovanillic acid, dihydroxyphenyl acetic acid, 5-hydroxyindoleacetic acid, and 5-hydroxytryptamine in the striatum. DESIGN, TIME AND SETTING: A randomized, controlled, animal study was performed at the Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, and Shanghai Celstar Institute of Biotechnology from May 2007 to December 2008. MATERIALS: HAECs were derived from the placental chorion following caesarean delivery at the Shanghai International Matemal and Child Health Hospital. 6-hydroxydopamine (6-OHDA), and mouse anti-human Vimentin monoclonal antibody were purchased from Sigma, USA; mouse anti-human nestin and tyrosine hydroxylase (TH) monoclonal antibodies were purchased from Chemicon, USA. METHODS: A total of 114 healthy, adult, Sprague Dawley rats were randomly assigned to two groups: PD model [n = 90, stereotactic microinjection of 2 μL 6-OHDA (3.5 μg/uL) into the striatum] and control (n = 24, no treatment). The 51 successful PD model rats were randomly divided into 3 subgroups (n = 17): HAEC, PBS, and model. The HAEC and PBS groups were respectively injected with 10 μL PBS solution containing 1 × 10^5/mL HAECs or 10 pL PBS into the lateral ventricle. The model group was not treated. MAIN OUTCOME MEASURES: TH protein expression in the striatum was evaluated by immunohistochemistry 5 weeks after HAEC transplantation. At 10 weeks, HAEC survival in the lateral ventricle was investigated by immunofluorescent staining; differentiation of HAECs in the lateral and third ventricles was examined by TH immunohistochemistry; concentrations of DA, homovanillic acid, dihydroxyphenyl acetic acid, 5-hydroxyindoleacetic acid, and 5-hydroxytryptamine in the striatum, as well as DA concentration in the cerebrospinal fluid, were measured with high-performance liquid chromatography-electrochemical detection. Circling behavior of PD model rats was consecutively observed for 10 weeks following intraperitoneal injection of amphetamine 1 week after successful model establishment. RESULTS: tn the HAEC group, the number of TH-positive cells significantly increased in the striatum, and circling behavior significantly decreased, compared with the PBS and model groups (P 〈 0.01). In addition, monoamine concentrations in the striatum, as well as DA concentrations in the cerebrospinal fluid, significantly increased, compared with the PBS group (P 〈 0.05-0.01). Moreover, a large number of nestin-, vimentin-, and TH-positive cells were observed in the lateral and third ventricles following HAEC injection.CONCLUSION: HAECs survived for 10 weeks with no overgrowth following transplantation into the lateral ventricle of PD model rats. Moreover, the cells differentiated into dopaminergic neurons, which increased DA secretion. HAEC transplantation improved cycling behavior in PD model rats.展开更多
BACKGROUND: Previous researches suggested that expression level of calbindin D28K mRNA decreased in substantia nigra (SN) of model rats with Parkinson disease (PD), and this might be related to the decrease of an...BACKGROUND: Previous researches suggested that expression level of calbindin D28K mRNA decreased in substantia nigra (SN) of model rats with Parkinson disease (PD), and this might be related to the decrease of anti-degeneration potentials of dopaminergic neurons. OBJECTIVE: To observe expression changes of calbindin D28K in SN dopaminergic neurons during their degeneration and death in midbrain of PD model rats. DESIGN: Completely randomized grouping design SETTING: Department of Neurobiology, Xuzhou Medical College MATERIALS" A total of 92 healthy male SD rats, with the age of 3 months, weighing 200-250 g, were selected from Experimental Animal Center of Xuzhou Medical College [certification: SCXK (su) 2003-0003]. Calbindin D28K(CB), tyroxine hydroxylase (TH), ABC kit, 6-hydroxydopamine (6-OHDA) and Nissl dyes were provided by Sigma Company, and sheep serum was provided by Beijing Zhongshan Company. METHODS: The experiment was carried out in the Neurobiological Center of Xuzhou Medical College from October 2003 to October 2004. ① With lot method, rats were divided into blank control group (n=28), experimental control group (n=-28) and experimental group (n=36). Rats in experimental group were injected with 6-OHDA at right corpus striatum for PD modeling; rats in experimental control group were injected with saline at the same site; rats in blank control group did not give any injections.② On the 7^th, 14^th, 21^st and 28^th days, SN segments on right midbrain from every 5 rats in experimental group were fixed, embedded with paraffin and cut into successively coronary pieces. Rats in other two groups were treated with the same methods and then stained with Nissl to show neuronal form. Meanwhile, CB and TH antibodies staining with immunohistochemistry were used to show CB containing dopaminergic neurons and dopaminergic neurons, and cells were calculated and observed under optic microscope. ③ On the 14^th and 28^th days, every 4 rats in experimental group and every 4 rats in control group were selected to obtain their brains and separate SN on the injured side. Western blot was used to detect expression of calbindin D28K, protein band was scanned with imaging equipment, and data were analyzed with LabWorks software. MAIN OUTCOME MEASURES:① On the 7^th, 14^th, 21^st and 28^th days, Nissl staining results of SN neurons and immunohistochemical staining results of CB and TH antibodies; ② On the 14^th and 28^th days, Western blot results of calbindin D28K in SN neurons, RESULTS; Among 92 rats, 2 rats in experimental group died after 1 day due to 6-OHDA injection and other 90 rats were involved in the final analysis. ①Nissl staining results: On the 7^th day of 6-OHDA injection, most neuronal somas on right SN pars compacta were shown as deep pycnosis or lysis breakage; on the 14^th and 21^st days, amount of neurons was decreased remarkably; on the 28^th day, most neurons in SN pars compacta disappeared. ② Results of immunohistochemical staining: Amount of positive neurons of calbindin D28K in right SN pars compacta was not changed on the 7^th day after 6-OHDA injection; on the 14^th day, the amount was higher in experimental group than that in both control groups (P 〈 0.01) and was decreased till the 21^st day, but it was still higher than that in the two control groups (P 〈 0.05); on the 28^th day, positive neurons of calbindin D28K nearly disappeared, and the amount was lower than that in the two control groups (P 〈 0.01). In addition, on the 7^th day after 6-OHDA injection into corpus striatum, positive TH neurons decreased 24% in right SN, and there was significant difference from that in control groups; on the 14^th, 21^st and 28^th days, positive TH neurons decreased 37%, 46% and 64%, respectively. ③ Western blot results: On the 14'h day after 6-OHDA injection into corpus striatum, expression of calbindin D28K in right SN was higher in experimental group than that in both control groups (P 〈 0.05); however, on the 28^th day, the expression was lower than that in the two control groups (P 〈 0.01 ). CONCLUSION : During degeneration and death of dopaminergic neurons, CB expression in SN pars compacta increases firstly and decreased gradually.展开更多
Melanins are widely used in medicine, pharmacology and cosmetics. Different technologies have been used to obtain melanin including: chemical synthesis based on oxidation of tyrosine and its derivatives; extraction f...Melanins are widely used in medicine, pharmacology and cosmetics. Different technologies have been used to obtain melanin including: chemical synthesis based on oxidation of tyrosine and its derivatives; extraction from animal materials; alkaline extraction from plant material; and microbiological synthesis. A few number of works have been published that were focused on purification of water insoluble 3,4-dihy- droxy-phenylalanine-melanins (Kukulianskaia et al., 2002). The majority of synthetic and natural melanins are insoluble in wa- ter that significantly complicates preparation of pharmacolog- ical and cosmetic preparations. Obtaining of low-cost soluble biotechnological melanin can speed up application of melanin in medicine and other fields. For the first time, melanin-syn-thesizing strain with high level of pigment synthesis - Bacillus thuringiensis was obtained. The ecologically safe technology of biosynthesis, isolation and purification of the bacterial melanin has been elaborated.展开更多
Parkinson’s disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta.Many studies have been performed based on the supplementation of lost dopaminergic ...Parkinson’s disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta.Many studies have been performed based on the supplementation of lost dopaminergic neurons to treat Parkinson’s disease.The initial strategy for cell replacement therapy used human fetal ventral midbrain and human embryonic stem cells to treat Parkinson’s disease,which could substantially alleviate the symptoms of Parkinson’s disease in clinical practice.However,ethical issues and tumor formation were limitations of its clinical application.Induced pluripotent stem cells can be acquired without sacrificing human embryos,which eliminates the huge ethical barriers of human stem cell therapy.Another widely considered neuronal regeneration strategy is to directly reprogram fibroblasts and astrocytes into neurons,without the need for intermediate proliferation states,thus avoiding issues of immune rejection and tumor formation.Both induced pluripotent stem cells and direct reprogramming of lineage cells have shown promising results in the treatment of Parkinson’s disease.However,there are also ethical concerns and the risk of tumor formation that need to be addressed.This review highlights the current application status of cell reprogramming in the treatment of Parkinson’s disease,focusing on the use of induced pluripotent stem cells in cell replacement therapy,including preclinical animal models and progress in clinical research.The review also discusses the advancements in direct reprogramming of lineage cells in the treatment of Parkinson’s disease,as well as the controversy surrounding in vivo reprogramming.These findings suggest that cell reprogramming may hold great promise as a potential strategy for treating Parkinson’s disease.展开更多
BACKGROUND: Synphilin-1 has been shown to be involved in the pathogenesis of Parkinson's disease (PD), and superoxide dismutase (SOD) reduction might induce PD onset. To date, the precise effect of synphilin-1 o...BACKGROUND: Synphilin-1 has been shown to be involved in the pathogenesis of Parkinson's disease (PD), and superoxide dismutase (SOD) reduction might induce PD onset. To date, the precise effect of synphilin-1 on SOD expression remains poorly understood. OBJECTIVE: To explore the influence of synphilin-1 small interfering RNA (siRNA) on SOD expression in a rat model of PD. DESIGN, TIME AND SETTING: A randomized, controlled, animal experiment was performed at the Laboratory of Neurology, Affiliated Hospital of Qingdao University Medical School from June to October 2008. MATERIALS: 6-hydroxydopamine was purchased from Wuhan Boster, China. METHODS: A total of 40 male, Wistar rats were randomly assigned to PD, siRNA, siRNA negative control, and control groups, with 10 rats in each group. Rats from the PD, siRNA, and siRNA negative control groups were injected with 6-hydroxydopamine into the right substantia nigra to establish PD models. In addition, synphilin-1 siRNA and siRNA negative control sequences were separately injected into the right substantia nigra of siRNA, and siRNA negative control groups. The control group rats were treated with a mixture of ascorbic acid and normal saline. MAIN OUTCOME MEASURES: Synphilin-1 and SOD protein and mRNA expression in the substantia nigra was detected by immunohistochemistry and in situ hybridization. RESULTS: Synphilin-1 and SOD protein and mRNA expression were significantly decreased in PD and siRNA negative control groups (P 〈 0.05). However, the siRNA group exhibited opposite effects. CONCLUSION: Synphilin-1 resulted in altered SOD expression, which suggested a protective role for synphilin-1 siRNA in an animal model of PD.展开更多
Parkinson’s disease (PD) is a common neurodegenerative disease with unclear pathogenesis. Currently, there are no disease-modifying neuron-protecting drugs to slow down the neuronal degeneration. Mutations in the leu...Parkinson’s disease (PD) is a common neurodegenerative disease with unclear pathogenesis. Currently, there are no disease-modifying neuron-protecting drugs to slow down the neuronal degeneration. Mutations in the leucine-rich repeat kinase 2 (LRRK2) cause genetic forms of PD and contribute to sporadic PD as well. Disruption of LRRK2 kinase functions has become one of the potential mechanisms underlying disease-linked mutation-induced neuronal degeneration. To further characterize the pharmacological effects of a reported LRRK2 kinase inhibitor, LDN-73794, in vitro cell models and a LRRK2 Drosophila PD model were used. LDN-73794 reduced LRRK2 kinase activity in vitro and in vivo. Moreover, LDN-73794 increased survival, improved locomotor activity, and suppressed DA neuron loss in LRRK2 transgenic flies. These results suggest that inhibition of LRRK2 kinase activity can be a potential therapeutic strategy for PD intervention and LDN-73794 could be a potential lead compound for developing neuroprotective therapeutics.展开更多
BACKGROUND: Previous researches found that animal models with Parkinson disease (PD) could be established by injecting 6-hydroxydopamine (6-OHDA) into medial forebrain bundle (MFB), substantia nigra compacta (...BACKGROUND: Previous researches found that animal models with Parkinson disease (PD) could be established by injecting 6-hydroxydopamine (6-OHDA) into medial forebrain bundle (MFB), substantia nigra compacta (SNC) and caudate-putamen complex (CPU) of the nigrostriatal pathway. OBJECTIVE : To compare behavioral, biochemica 6-OHDA injections in the areas of MFB, SNC and DESIGN: Controlled observational study and histological properties of these rats undergoing the CPU respectively. SEI-IING: Department of Neurology, First Affiliated Hospital of Guangxi Medical University MATERIALS: A total of 64 adult female SD rats weighing 180-230 g were provided by the Animal Experimental Center of Guangxi Medical University. 6-OHDA (Sigma Company, USA); Brain solid positioner (Standard model 51600, Stoelting Co., IL, USA); rotational monitoring of little animal (type QL-1, USA); high liquid chromatography (HLC, Waters Company). METHOOS: The experiment was carried out in the Medical Experimental Center of Guangxi Medical University from February to December 2005. ① According to digital table, 64 SD rats were divided into MFB group, SNC group, CPU group and control group with 16 in each group. On the basis of the brain atlas of Paxinos, rats in the first three groups were injected with 5 μL 6-OHDA into right MFB (0 mm of line of incisor tooth, A/P 4.4 mm, L/R 1.2 mm, ON -7.8 mm), SNC (line of incisor tooth just equal to horizon, A/P -4.8 mm, L/R 1.6 mm, ON -7.8 mm) and CPU (0 mm of line of incisor tooth, A/P 1.2 mm, L/R 2.7 mm, ON -5.4 mm), respectively. The rats in control group were injected with 5 μL ascorbic acid solution (2 g/L). One week after operation, 0.1 g/L apomorphine (Apo, 0.05 mg/kg) was subcutaneously injected into neck and then rotational behavior induced by Apo was recorded once a week for 8 weeks. The PD models were considered successful only when rotational times more than or equal to 7 times per minute. Eight weeks after operation, micro-perfusion was used to obtain micro-perfusate in bilateral CPU and contents of 3,4-dihydroxyphenylacetic acid (3,4-DOPAC) and homovanillic acid (HVA) were also measured. In addition, amount of tyrosine hydroxylase positive cells (TH*) in SNC was counted with immuno- histochemical staining. MAIN OUTCOME MEASURES : ① Successful rate of PD models; ② contents of dopamine and its metabolite in MFB, SNC and CPU groups and TH* amount. RESULTS: All 64 SD rats were involved in the final analysis. ③ Successful rate and rotational behavior: One week after operation, there were 6 successful models both in SNC and MFB groups; in the 2^nd week, there were 6 both in SNC and MFB groups and 1 in CPU group; in the 3^nd week, there were 1 in MFB group and 3 in CPU group; in the 4^nd week, there were 3 in CPU group. Otherwise, no successful case was found out in the next 3 weeks. Abnormal rotational behavior was not observed in control group. Four weeks after operation, successful rates were 81% (13/16) in MFB group, 75% (12/16) in SNC group and 44% (7/16) in CPU group.② Contents of 3, 4-DOPAC and HVA: Eight weeks after operation, contents in the SNC area of the injured side were lower than those on non-lesion side (P 〈 0.01).③Changes of TH+ amount: Eight weeks after operation, TH+ amount in the SNC area of the lesion side was lower than that on non-lesion side (P 〈 0.01 ). CONCLUSION: Injecting 6-OHDA into MFB, SNC and CPU can damage dopaminergic cells and establish successful PD models.展开更多
The goal of this study was to increase the dopamine content and reduce dopaminergic metabolites in the brain of Parkinson’s disease rats. Using high-performance liquid chromatography, we found that dopamine and dopam...The goal of this study was to increase the dopamine content and reduce dopaminergic metabolites in the brain of Parkinson’s disease rats. Using high-performance liquid chromatography, we found that dopamine and dopaminergic metabolite(dihydroxyphenylacetic acid and homovanillic acid) content in the midbrain of Parkinson’s disease rats was increased after neural stem cell transplantation + Zhichan decoction, compared with neural stem cell transplantation alone. Our genetic algorithm results show that dihydroxyphenylacetic acid and homovanillic acid levels achieve global optimization. Neural stem cell transplantation + Zhichan decoction increased dihydroxyphenylacetic acid levels up to 10-fold, while transplantation alone resulted in a 3-fold increment. Homovanillic acid levels showed no apparent change. Our experimental findings show that after neural stem cell transplantation in Parkinson’s disease rats, Zhichan decoction can promote differentiation of neural stem cells into dopaminergic neurons.展开更多
Melatonin can attenuate cardiac microvascular ischemia/reperfusion injury,but it remains unclear whether melatonin can also ameliorate cerebral microvascular abnormalities.Rat models of Alzheimer’s disease were estab...Melatonin can attenuate cardiac microvascular ischemia/reperfusion injury,but it remains unclear whether melatonin can also ameliorate cerebral microvascular abnormalities.Rat models of Alzheimer’s disease were established by six intracerebroventricular injections of amyloidbeta 1–42,administered once every other day.Melatonin(30 mg/kg)was intraperitoneally administered for 13 successive days,with the first dose given 24 hours prior to the first administration of amyloid-beta 1–42.Melatonin ameliorated learning and memory impairments in the Morris water maze test,improved the morphology of microvessels in the cerebral cortex and hippocampus,increased microvessel density,alleviated pathological injuries of cerebral neurons,and decreased the expression of vascular endothelial growth factor and vascular endothelial growth factor receptors 1 and 2.These findings suggest that melatonin can improve microvessel abnormalities in the cerebral cortex and hippocampus by lowering the expression of vascular endothelial growth factor and its receptors,thereby improving the cognitive function of patients with Alzheimer’s disease.This study was approved by the Animal Care and Use Committee of Jinzhou Medical University,China(approval No.2019015)on December 6,2018.展开更多
Parkinson’s disease(PD) is an age-related neurodegenerative disease for which the characteristic motor symptoms emerge after an extensive loss of dopamine containing neurons.The cell bodies of these neurons are pre...Parkinson’s disease(PD) is an age-related neurodegenerative disease for which the characteristic motor symptoms emerge after an extensive loss of dopamine containing neurons.The cell bodies of these neurons are present in the substantia nigra,with the nerve terminals being in the striatum.Both innate and adaptive immune responses may contribute to dopaminergic neurodegeneration and disease progression is potentially linked to these.Studies in the last twenty years have indicated an important role for neuroinflammation in PD through degeneration of the nigrostriatal dopaminergic pathway.Characteristic of neuroinflammation is the activation of brain glial cells,principally microglia and astrocytes that release various soluble factors.Many of these factors are proinflammatory and neurotoxic and harmful to nigral dopaminergic neurons.Recent studies have identified several different agents with immunomodulatory properties that protected dopaminergic neurons from degeneration and death in animal models of PD.All of the agents were effective in reducing the motor deficit and alleviating dopaminergic neurotoxicity and,when measured,preventing the decrease of dopamine upon being administered therapeutically after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,6-hydroxydopamine,rotenone-lesioning or delivery of adeno-associated virus-α-synuclein to the ventral midbrain of animals.Some of these agents were shown to exert an anti-inflammatory action,decrease oxidative stress,and reduce lipid peroxidation products.Activation of microglia and astrocytes was also decreased,as well as infiltration of T cells into the substantia nigra.Pretreatment with fingolimod,tanshinoine I,dimethyl fumarate,thalidomide,or cocaine-and amphetamine-regulated transcript peptide as a preventive strategy ameliorated motor deficits and nigral dopaminergic neurotoxicity in brain-lesioned animals.Immunomodulatory agents could be used to treat patients with early clinical signs of the disease or potentially even prior to disease onset in those identified as having pre-disposing risk,including genetic factors.展开更多
Parkinson’s disease(PD)relates to defective mitochondrial quality control in the dopaminergic motor network.Genetic studies have revealed that PINK1 and Parkin mutations are indicative of a heightened propensity to P...Parkinson’s disease(PD)relates to defective mitochondrial quality control in the dopaminergic motor network.Genetic studies have revealed that PINK1 and Parkin mutations are indicative of a heightened propensity to PD onset,pinpointing mitophagy and inflammation as the culprit pathways involved in neuronal loss in the substantia nigra(SNpc).In a reciprocal manner,LRRK2 functions in the regulation of basal flux and inflammatory responses responsible for PINK1/Parkin-dependent mitophagy activation.Pharmacological intervention in these diseasemodifying pathways may facilitate the development of novel PD therapeutics,despite the current lack of an established drug evaluation model.As such,we reviewed the feasibility of employing the versatile global Pink1knockout(KO)rat model as a self-sufficient,spontaneous PD model for investigating both disease etiology and drug pharmacology.These rats retain clinical features encompassing basal mitophagic flux changes with PD progression.We demonstrate the versatility of this PD rat model based on the incorporation of additional experimental insults to recapitulate the proinflammatory responses observed in PD patients.展开更多
Dental pulp stem cells are dental pulp-derived mesenchymal stem cells that originate from the neural crest.They exhibit greater potential for the treatment of nervous system diseases than other types of stem cells bec...Dental pulp stem cells are dental pulp-derived mesenchymal stem cells that originate from the neural crest.They exhibit greater potential for the treatment of nervous system diseases than other types of stem cells because of their neurogenic differentiation capability and their ability to secrete multiple neurotrophic factors.Few studies have reported Alzheimer’s disease treatment using dental pulp stem cells.Rat models of Alzheimer’s disease were established by injecting amyloid-β1–42 into the hippocampus.Fourteen days later,5×106 dental pulp stem cells were injected into the hippocampus.Immunohistochemistry and western blot assays showed that dental pulp stem cell transplantation increased the expression of neuron-related doublecortin,NeuN,and neurofilament 200 in the hippocampus,while the expression of amyloid-βwas decreased.Moreover,cognitive and behavioral abilities were improved.These findings indicate that dental pulp stem cell transplantation in rats can improve cognitive function by regulating the secretion of neuron-related proteins,which indicates a potential therapeutic effect for Alzheimer’s disease.This study was approved by the Animal Ethics Committee of Harbin Medical University,China(approval No.KY2017-132)on February 21,2017.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
Biophysical computational models are complementary to experiments and theories,providing powerful tools for the study of neurological diseases.The focus of this review is the dynamic modeling and control strategies of...Biophysical computational models are complementary to experiments and theories,providing powerful tools for the study of neurological diseases.The focus of this review is the dynamic modeling and control strategies of Parkinson’s disease(PD).In previous studies,the development of parkinsonian network dynamics modeling has made great progress.Modeling mainly focuses on the cortex-thalamus-basal ganglia(CTBG)circuit and its sub-circuits,which helps to explore the dynamic behavior of the parkinsonian network,such as synchronization.Deep brain stimulation(DBS)is an effective strategy for the treatment of PD.At present,many studies are based on the side effects of the DBS.However,the translation from modeling results to clinical disease mitigation therapy still faces huge challenges.Here,we introduce the progress of DBS improvement.Its specific purpose is to develop novel DBS treatment methods,optimize the treatment effect of DBS for each patient,and focus on the study in closed-loop DBS.Our goal is to review the inspiration and insights gained by combining the system theory with these computational models to analyze neurodynamics and optimize DBS treatment.展开更多
Parkinson's disease (PD) is disorder affecting more than a common neurodegenerative 1% people above 60 years of age worldwide, manifesting as the impaired motor function such as tremors, rigidity, akinesia/bradykin...Parkinson's disease (PD) is disorder affecting more than a common neurodegenerative 1% people above 60 years of age worldwide, manifesting as the impaired motor function such as tremors, rigidity, akinesia/bradykinesia and postural inefficiency with a reduced life expectancy (Dorsey et al., 2007). PD is believed to be the end result of the progressive death of dopaminergic neurons in the substantia nigra pars compacta (SNc).展开更多
Diagnostics and rehabilitation of Parkinson’s disease (PD) presents the current information pertaining to etiology, early biomarkers for diagnostics, novel methods to evaluate symptoms, multidisciplinary rehabilitati...Diagnostics and rehabilitation of Parkinson’s disease (PD) presents the current information pertaining to etiology, early biomarkers for diagnostics, novel methods to evaluate symptoms, multidisciplinary rehabilitation, new applications of brain imaging and invasive methods to the study of PD. Researchers have only recently begun to focus on the non-motor symptoms of PD, which are poorly recognized and inadequately treated by clinicians. The non-motor symptoms of PD have a significant impact on patient quality of life and mortality, and include cognitive impairments, autonomic, gastrointestinal, and sensory symptoms. Indepth discussion of the use of imaging tools to study disease mechanisms is also provided, with emphasis on the abnormal network organization in parkinsonism. Deep brain stimulation management is a paradigm-shifting therapy for PD, essential tremor and dystonia. In the recent years, new approaches of early diagnostics, training programmes and treatments have vastly improved the lives of people with PD, substantially reducing symptoms and significantly delaying disability. PD results primarily from the death of dopaminergic neurons in the substantia nigra. Current PD medications treat symptoms;none halt or retard dopaminergic neuron degeneration. The main obstacle to developing neuroprotective therapies is a limited understanding of the key molecular mechanisms that provoke neurodegeneration. The discovery of PD genes has led to the hypothesis that misfolding of proteins and dysfunction of the ubiquitin-proteasome pathway are pivotal to PD pathogenesis. Previously implicated culprits in PD neurodegeneration, mitochondrial dysfunction and oxidative stress, may also act in part by causing the accumulation of misfolded proteins, in addition to producing other deleterious events in dopaminergic neurons. Neurotoxin-based models have been important in elucidating the molecular cas-cade of cell death in dopaminergic neurons. PD models based on the manipulation of PD genes should prove valuable in elucidating important aspects of the disease, such as selective vulnerability of substantia nigra dopaminergic neurons to the degenerative process.展开更多
Parkinson's disease(PD) is the second most common age-related neurodegenerative disorder, with the clinical main symptoms caused by a loss of dopaminergic neurons in the substantia nigra, corpus striatum and brain ...Parkinson's disease(PD) is the second most common age-related neurodegenerative disorder, with the clinical main symptoms caused by a loss of dopaminergic neurons in the substantia nigra, corpus striatum and brain cortex. Over 90% of patients with PD have sporadic PD and occur in people with no known family history of the disorder. Currently there is no cure for PD. Treatment with medications to increase dopamine relieves the symptoms but does not slow down or reverse the damage to neurons in the brain. Increasing evidence points to inflammation as a chief mediator of PD with inflammatory response mechanisms, involving microglia and leukocytes, activated following loss of dopaminergic neurons. Oxidative stress is also recognized as one of the main causes of PD, and excessive reactive oxygen species(ROS) and reactive nitrogen species can lead to dopaminergic neuron vulnerability and eventual death. Micro RNAs control a range of physiological and pathological functions, and may serve as potential targets for intervention against PD to mitigate damage to the brain. Several studies have demonstrated that micro RNAs can regulate oxidative stress and prevent ROS-mediated damage to dopaminergic neurons, suggesting that specific micro RNAs may be putative targets for novel therapeutic strategies in PD. Recent human and animal studies have identified a large number of dysregulated micro RNAs in PD brain tissue samples, many of which were downregulated. The dysregulated micro RNAs affect downstream targets such as SNCA, PARK2, LRRK2, TNFSF13 B, LTA, SLC5 A3, PSMB2, GSR, GBA, LAMP-2 A, HSC. Apart from one study, none of the studies reviewed had used agomirs or antagomirs to reverse the levels of downregulated or upregulated micro RNAs, respectively, in mouse models of PD or with isolated human or mouse dopaminergic cells. Further large-scale studies of brain tissue samples collected with short postmortem interval from human PD patients are warranted to provide more information on the micro RNA profiles in different brain regions and to test for gender differences.展开更多
文摘Parkinson’s disease is chara cterized by the loss of dopaminergic neurons in the substantia nigra pars com pacta,and although restoring striatal dopamine levels may improve symptoms,no treatment can cure or reve rse the disease itself.Stem cell therapy has a regenerative effect and is being actively studied as a candidate for the treatment of Parkinson’s disease.Mesenchymal stem cells are considered a promising option due to fewer ethical concerns,a lower risk of immune rejection,and a lower risk of teratogenicity.We performed a meta-analysis to evaluate the therapeutic effects of mesenchymal stem cells and their derivatives on motor function,memory,and preservation of dopamine rgic neurons in a Parkinson’s disease animal model.We searched bibliographic databases(PubMed/MEDLINE,Embase,CENTRAL,Scopus,and Web of Science)to identify articles and included only pee r-reviewed in vivo interve ntional animal studies published in any language through J une 28,2023.The study utilized the random-effect model to estimate the 95%confidence intervals(CI)of the standard mean differences(SMD)between the treatment and control groups.We use the systematic review center for laboratory animal expe rimentation’s risk of bias tool and the collaborative approach to meta-analysis and review of animal studies checklist for study quality assessment.A total of 33studies with data from 840 Parkinson’s disease model animals were included in the meta-analysis.Treatment with mesenchymal stem cells significantly improved motor function as assessed by the amphetamine-induced rotational test.Among the stem cell types,the bone marrow MSCs with neurotrophic factor group showed la rgest effect size(SMD[95%CI]=-6.21[-9.50 to-2.93],P=0.0001,I^(2)=0.0%).The stem cell treatment group had significantly more tyrosine hydroxylase positive dopamine rgic neurons in the striatum([95%CI]=1.04[0.59 to 1.49],P=0.0001,I^(2)=65.1%)and substantia nigra(SMD[95%CI]=1.38[0.89 to 1.87],P=0.0001,I^(2)=75.3%),indicating a protective effect on dopaminergic neurons.Subgroup analysis of the amphetamine-induced rotation test showed a significant reduction only in the intracranial-striatum route(SMD[95%CI]=-2.59[-3.25 to-1.94],P=0.0001,I^(2)=74.4%).The memory test showed significant improvement only in the intravenous route(SMD[95%CI]=4.80[1.84 to 7.76],P=0.027,I^(2)=79.6%).Mesenchymal stem cells have been shown to positively impact motor function and memory function and protect dopaminergic neurons in preclinical models of Parkinson’s disease.Further research is required to determine the optimal stem cell types,modifications,transplanted cell numbe rs,and delivery methods for these protocols.
基金the Scientific Research Common Program of Beijing Municipal Commission of Education,No.KM200610025008
文摘BACKGROUND: Inflammatory injury induced by microglial activation plays an important role in the occurrence and development of Parkinson's disease (PD). However, few studies have examined the relationship between microglia and substantia nigra damage or dopaminergic neuron loss in animals with rotenone-induced PD.OBJECTIVE: To explore the relationship between activated microglia and loss of the substantia nigra, and the changes in concentration and dose of rotenone in the brain of rats with rotenone-induced PD.DESIGN, TIME AND SETTING: The neuropathological experiment was performed at the School of Traditional Chinese Medicine, Capital Medical University, China, from July 2007 to July 2008. MATERIALS: Rotenone was purchased from Sigma, USA. METHODS: The Parkinson's model was induced by injection of a rotenone oily-emulsion (2 mg/kg daily) subcutaneously into the back of 58 male adult Wistar rats for 3-6 weeks. Another three rats served as normal controls.MAIN OUTCOME MEASURES: Neurobehavioral changes were observed and recorded following rotenone treatment. Tyrosine hydroxylase and complement receptor OX42 were separately analyzed by immunohistochemical staining within 4 weeks following stopping rotenone treatment. Rotenone content was measured using high performance liquid chromatography in the cerebellum of rats that scored 2.4-6.RESULTS: Rotenone induced a loss of dopaminergic neurons in the substantia nigra as well as microglial activation, with increased behavior scores. Dopaminergic loss was still ongoing even when rotenone was stopped. Dopaminergic neuronal degeneration in the substantia nigra was initially 6%, but was 85% at 2 weeks after scoring, and degeneration depended on activated microglia. Rotenone was detected in the cerebellum at concentrations between 78.9 μg/L and 309.6 μg/L. CONCLUSION: Nigrostriatal dopaminergic degeneration paralleled the microglial activation. Rotenone absorbed into the brain in its original form initiated pathological injury in the substantia niara of PD rats.
基金the Scientific Research Common Program of Beijing Municipal Commission of Education,No.KM200610025008
文摘Extensive iron deposition has been observed in the midbrain substantia nigra (SN) of Parkinson's disease (PD) patients, but the mechanisms of iron deposition in the SN remain poorly understood. The present study investigated the relationship between dopaminergic neuronal damage, iron content changes, and divalent metal transporter 1 (DMT1) in the midbrain SN of PD rats to explore the relationship between time of iron deposition and DMT1 expression. Frozen midbrain SN sections from model rats were stained with Perls' iron. Results showed massive loss of tyrosine hydroxylase (TH)-positive cells in the SN and increased DMT1 expression in model group rats. No obvious iron deposition was observed in the SN during early stages after damage, but significant iron deposition was detected at 8 weeks post-injury. Results demonstrate that the loss of TH-positive cells in the SN appeared simultaneously with increased DMT1 expression. Extensive iron deposition occurred at 8 weeks post injury, which could be regarded as an early time window of iron deposition.
基金Supported by: the Major State Basic Research Development Program of China (973 Program), No.2005CB522604the National Natural Science Foundation of China, No. 30271325
文摘BACKGROUND: Human amniotic epithelial cells (HAECs) can differentiate into neurons, astrocytes and oligodendrocytes. They biologically secrete many active neurotrophins and have the capacity to metabolize dopamine enzymes. These features underlie a theoretical basis for the treatment of Parkinson's disease (PD). OBJECTIVE: To investigate the survival and differentiation of transplanted HAECs in the lateral ventricle of PD model rats, and to explore its effect on circling behavior, as well as levels of dopamine (DA), the metabolite homovanillic acid, dihydroxyphenyl acetic acid, 5-hydroxyindoleacetic acid, and 5-hydroxytryptamine in the striatum. DESIGN, TIME AND SETTING: A randomized, controlled, animal study was performed at the Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, and Shanghai Celstar Institute of Biotechnology from May 2007 to December 2008. MATERIALS: HAECs were derived from the placental chorion following caesarean delivery at the Shanghai International Matemal and Child Health Hospital. 6-hydroxydopamine (6-OHDA), and mouse anti-human Vimentin monoclonal antibody were purchased from Sigma, USA; mouse anti-human nestin and tyrosine hydroxylase (TH) monoclonal antibodies were purchased from Chemicon, USA. METHODS: A total of 114 healthy, adult, Sprague Dawley rats were randomly assigned to two groups: PD model [n = 90, stereotactic microinjection of 2 μL 6-OHDA (3.5 μg/uL) into the striatum] and control (n = 24, no treatment). The 51 successful PD model rats were randomly divided into 3 subgroups (n = 17): HAEC, PBS, and model. The HAEC and PBS groups were respectively injected with 10 μL PBS solution containing 1 × 10^5/mL HAECs or 10 pL PBS into the lateral ventricle. The model group was not treated. MAIN OUTCOME MEASURES: TH protein expression in the striatum was evaluated by immunohistochemistry 5 weeks after HAEC transplantation. At 10 weeks, HAEC survival in the lateral ventricle was investigated by immunofluorescent staining; differentiation of HAECs in the lateral and third ventricles was examined by TH immunohistochemistry; concentrations of DA, homovanillic acid, dihydroxyphenyl acetic acid, 5-hydroxyindoleacetic acid, and 5-hydroxytryptamine in the striatum, as well as DA concentration in the cerebrospinal fluid, were measured with high-performance liquid chromatography-electrochemical detection. Circling behavior of PD model rats was consecutively observed for 10 weeks following intraperitoneal injection of amphetamine 1 week after successful model establishment. RESULTS: tn the HAEC group, the number of TH-positive cells significantly increased in the striatum, and circling behavior significantly decreased, compared with the PBS and model groups (P 〈 0.01). In addition, monoamine concentrations in the striatum, as well as DA concentrations in the cerebrospinal fluid, significantly increased, compared with the PBS group (P 〈 0.05-0.01). Moreover, a large number of nestin-, vimentin-, and TH-positive cells were observed in the lateral and third ventricles following HAEC injection.CONCLUSION: HAECs survived for 10 weeks with no overgrowth following transplantation into the lateral ventricle of PD model rats. Moreover, the cells differentiated into dopaminergic neurons, which increased DA secretion. HAEC transplantation improved cycling behavior in PD model rats.
基金Scientific and Technological Project of State Ministry of Education, No. 204055 the Natural Science Foundation of Educational Bureau of Jiangsu Province, No. 02KJB310009
文摘BACKGROUND: Previous researches suggested that expression level of calbindin D28K mRNA decreased in substantia nigra (SN) of model rats with Parkinson disease (PD), and this might be related to the decrease of anti-degeneration potentials of dopaminergic neurons. OBJECTIVE: To observe expression changes of calbindin D28K in SN dopaminergic neurons during their degeneration and death in midbrain of PD model rats. DESIGN: Completely randomized grouping design SETTING: Department of Neurobiology, Xuzhou Medical College MATERIALS" A total of 92 healthy male SD rats, with the age of 3 months, weighing 200-250 g, were selected from Experimental Animal Center of Xuzhou Medical College [certification: SCXK (su) 2003-0003]. Calbindin D28K(CB), tyroxine hydroxylase (TH), ABC kit, 6-hydroxydopamine (6-OHDA) and Nissl dyes were provided by Sigma Company, and sheep serum was provided by Beijing Zhongshan Company. METHODS: The experiment was carried out in the Neurobiological Center of Xuzhou Medical College from October 2003 to October 2004. ① With lot method, rats were divided into blank control group (n=28), experimental control group (n=-28) and experimental group (n=36). Rats in experimental group were injected with 6-OHDA at right corpus striatum for PD modeling; rats in experimental control group were injected with saline at the same site; rats in blank control group did not give any injections.② On the 7^th, 14^th, 21^st and 28^th days, SN segments on right midbrain from every 5 rats in experimental group were fixed, embedded with paraffin and cut into successively coronary pieces. Rats in other two groups were treated with the same methods and then stained with Nissl to show neuronal form. Meanwhile, CB and TH antibodies staining with immunohistochemistry were used to show CB containing dopaminergic neurons and dopaminergic neurons, and cells were calculated and observed under optic microscope. ③ On the 14^th and 28^th days, every 4 rats in experimental group and every 4 rats in control group were selected to obtain their brains and separate SN on the injured side. Western blot was used to detect expression of calbindin D28K, protein band was scanned with imaging equipment, and data were analyzed with LabWorks software. MAIN OUTCOME MEASURES:① On the 7^th, 14^th, 21^st and 28^th days, Nissl staining results of SN neurons and immunohistochemical staining results of CB and TH antibodies; ② On the 14^th and 28^th days, Western blot results of calbindin D28K in SN neurons, RESULTS; Among 92 rats, 2 rats in experimental group died after 1 day due to 6-OHDA injection and other 90 rats were involved in the final analysis. ①Nissl staining results: On the 7^th day of 6-OHDA injection, most neuronal somas on right SN pars compacta were shown as deep pycnosis or lysis breakage; on the 14^th and 21^st days, amount of neurons was decreased remarkably; on the 28^th day, most neurons in SN pars compacta disappeared. ② Results of immunohistochemical staining: Amount of positive neurons of calbindin D28K in right SN pars compacta was not changed on the 7^th day after 6-OHDA injection; on the 14^th day, the amount was higher in experimental group than that in both control groups (P 〈 0.01) and was decreased till the 21^st day, but it was still higher than that in the two control groups (P 〈 0.05); on the 28^th day, positive neurons of calbindin D28K nearly disappeared, and the amount was lower than that in the two control groups (P 〈 0.01). In addition, on the 7^th day after 6-OHDA injection into corpus striatum, positive TH neurons decreased 24% in right SN, and there was significant difference from that in control groups; on the 14^th, 21^st and 28^th days, positive TH neurons decreased 37%, 46% and 64%, respectively. ③ Western blot results: On the 14'h day after 6-OHDA injection into corpus striatum, expression of calbindin D28K in right SN was higher in experimental group than that in both control groups (P 〈 0.05); however, on the 28^th day, the expression was lower than that in the two control groups (P 〈 0.01 ). CONCLUSION : During degeneration and death of dopaminergic neurons, CB expression in SN pars compacta increases firstly and decreased gradually.
文摘Melanins are widely used in medicine, pharmacology and cosmetics. Different technologies have been used to obtain melanin including: chemical synthesis based on oxidation of tyrosine and its derivatives; extraction from animal materials; alkaline extraction from plant material; and microbiological synthesis. A few number of works have been published that were focused on purification of water insoluble 3,4-dihy- droxy-phenylalanine-melanins (Kukulianskaia et al., 2002). The majority of synthetic and natural melanins are insoluble in wa- ter that significantly complicates preparation of pharmacolog- ical and cosmetic preparations. Obtaining of low-cost soluble biotechnological melanin can speed up application of melanin in medicine and other fields. For the first time, melanin-syn-thesizing strain with high level of pigment synthesis - Bacillus thuringiensis was obtained. The ecologically safe technology of biosynthesis, isolation and purification of the bacterial melanin has been elaborated.
基金supported by the National Natural Science Foundation of China,No.31960120Yunnan Science and Technology Talent and Platform Plan,No.202105AC160041(both to ZW).
文摘Parkinson’s disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta.Many studies have been performed based on the supplementation of lost dopaminergic neurons to treat Parkinson’s disease.The initial strategy for cell replacement therapy used human fetal ventral midbrain and human embryonic stem cells to treat Parkinson’s disease,which could substantially alleviate the symptoms of Parkinson’s disease in clinical practice.However,ethical issues and tumor formation were limitations of its clinical application.Induced pluripotent stem cells can be acquired without sacrificing human embryos,which eliminates the huge ethical barriers of human stem cell therapy.Another widely considered neuronal regeneration strategy is to directly reprogram fibroblasts and astrocytes into neurons,without the need for intermediate proliferation states,thus avoiding issues of immune rejection and tumor formation.Both induced pluripotent stem cells and direct reprogramming of lineage cells have shown promising results in the treatment of Parkinson’s disease.However,there are also ethical concerns and the risk of tumor formation that need to be addressed.This review highlights the current application status of cell reprogramming in the treatment of Parkinson’s disease,focusing on the use of induced pluripotent stem cells in cell replacement therapy,including preclinical animal models and progress in clinical research.The review also discusses the advancements in direct reprogramming of lineage cells in the treatment of Parkinson’s disease,as well as the controversy surrounding in vivo reprogramming.These findings suggest that cell reprogramming may hold great promise as a potential strategy for treating Parkinson’s disease.
基金the Young and Middle-Aged Scientists Research Foundation of Shandong Province, No. 200503021
文摘BACKGROUND: Synphilin-1 has been shown to be involved in the pathogenesis of Parkinson's disease (PD), and superoxide dismutase (SOD) reduction might induce PD onset. To date, the precise effect of synphilin-1 on SOD expression remains poorly understood. OBJECTIVE: To explore the influence of synphilin-1 small interfering RNA (siRNA) on SOD expression in a rat model of PD. DESIGN, TIME AND SETTING: A randomized, controlled, animal experiment was performed at the Laboratory of Neurology, Affiliated Hospital of Qingdao University Medical School from June to October 2008. MATERIALS: 6-hydroxydopamine was purchased from Wuhan Boster, China. METHODS: A total of 40 male, Wistar rats were randomly assigned to PD, siRNA, siRNA negative control, and control groups, with 10 rats in each group. Rats from the PD, siRNA, and siRNA negative control groups were injected with 6-hydroxydopamine into the right substantia nigra to establish PD models. In addition, synphilin-1 siRNA and siRNA negative control sequences were separately injected into the right substantia nigra of siRNA, and siRNA negative control groups. The control group rats were treated with a mixture of ascorbic acid and normal saline. MAIN OUTCOME MEASURES: Synphilin-1 and SOD protein and mRNA expression in the substantia nigra was detected by immunohistochemistry and in situ hybridization. RESULTS: Synphilin-1 and SOD protein and mRNA expression were significantly decreased in PD and siRNA negative control groups (P 〈 0.05). However, the siRNA group exhibited opposite effects. CONCLUSION: Synphilin-1 resulted in altered SOD expression, which suggested a protective role for synphilin-1 siRNA in an animal model of PD.
文摘Parkinson’s disease (PD) is a common neurodegenerative disease with unclear pathogenesis. Currently, there are no disease-modifying neuron-protecting drugs to slow down the neuronal degeneration. Mutations in the leucine-rich repeat kinase 2 (LRRK2) cause genetic forms of PD and contribute to sporadic PD as well. Disruption of LRRK2 kinase functions has become one of the potential mechanisms underlying disease-linked mutation-induced neuronal degeneration. To further characterize the pharmacological effects of a reported LRRK2 kinase inhibitor, LDN-73794, in vitro cell models and a LRRK2 Drosophila PD model were used. LDN-73794 reduced LRRK2 kinase activity in vitro and in vivo. Moreover, LDN-73794 increased survival, improved locomotor activity, and suppressed DA neuron loss in LRRK2 transgenic flies. These results suggest that inhibition of LRRK2 kinase activity can be a potential therapeutic strategy for PD intervention and LDN-73794 could be a potential lead compound for developing neuroprotective therapeutics.
基金Foundation for the Returned Overseas Chinese Scholars of Guangxi Zhuang Autonomous Region, No. 0448017
文摘BACKGROUND: Previous researches found that animal models with Parkinson disease (PD) could be established by injecting 6-hydroxydopamine (6-OHDA) into medial forebrain bundle (MFB), substantia nigra compacta (SNC) and caudate-putamen complex (CPU) of the nigrostriatal pathway. OBJECTIVE : To compare behavioral, biochemica 6-OHDA injections in the areas of MFB, SNC and DESIGN: Controlled observational study and histological properties of these rats undergoing the CPU respectively. SEI-IING: Department of Neurology, First Affiliated Hospital of Guangxi Medical University MATERIALS: A total of 64 adult female SD rats weighing 180-230 g were provided by the Animal Experimental Center of Guangxi Medical University. 6-OHDA (Sigma Company, USA); Brain solid positioner (Standard model 51600, Stoelting Co., IL, USA); rotational monitoring of little animal (type QL-1, USA); high liquid chromatography (HLC, Waters Company). METHOOS: The experiment was carried out in the Medical Experimental Center of Guangxi Medical University from February to December 2005. ① According to digital table, 64 SD rats were divided into MFB group, SNC group, CPU group and control group with 16 in each group. On the basis of the brain atlas of Paxinos, rats in the first three groups were injected with 5 μL 6-OHDA into right MFB (0 mm of line of incisor tooth, A/P 4.4 mm, L/R 1.2 mm, ON -7.8 mm), SNC (line of incisor tooth just equal to horizon, A/P -4.8 mm, L/R 1.6 mm, ON -7.8 mm) and CPU (0 mm of line of incisor tooth, A/P 1.2 mm, L/R 2.7 mm, ON -5.4 mm), respectively. The rats in control group were injected with 5 μL ascorbic acid solution (2 g/L). One week after operation, 0.1 g/L apomorphine (Apo, 0.05 mg/kg) was subcutaneously injected into neck and then rotational behavior induced by Apo was recorded once a week for 8 weeks. The PD models were considered successful only when rotational times more than or equal to 7 times per minute. Eight weeks after operation, micro-perfusion was used to obtain micro-perfusate in bilateral CPU and contents of 3,4-dihydroxyphenylacetic acid (3,4-DOPAC) and homovanillic acid (HVA) were also measured. In addition, amount of tyrosine hydroxylase positive cells (TH*) in SNC was counted with immuno- histochemical staining. MAIN OUTCOME MEASURES : ① Successful rate of PD models; ② contents of dopamine and its metabolite in MFB, SNC and CPU groups and TH* amount. RESULTS: All 64 SD rats were involved in the final analysis. ③ Successful rate and rotational behavior: One week after operation, there were 6 successful models both in SNC and MFB groups; in the 2^nd week, there were 6 both in SNC and MFB groups and 1 in CPU group; in the 3^nd week, there were 1 in MFB group and 3 in CPU group; in the 4^nd week, there were 3 in CPU group. Otherwise, no successful case was found out in the next 3 weeks. Abnormal rotational behavior was not observed in control group. Four weeks after operation, successful rates were 81% (13/16) in MFB group, 75% (12/16) in SNC group and 44% (7/16) in CPU group.② Contents of 3, 4-DOPAC and HVA: Eight weeks after operation, contents in the SNC area of the injured side were lower than those on non-lesion side (P 〈 0.01).③Changes of TH+ amount: Eight weeks after operation, TH+ amount in the SNC area of the lesion side was lower than that on non-lesion side (P 〈 0.01 ). CONCLUSION: Injecting 6-OHDA into MFB, SNC and CPU can damage dopaminergic cells and establish successful PD models.
基金financially supported by the National Natural Science Foundation of China,No.30772870
文摘The goal of this study was to increase the dopamine content and reduce dopaminergic metabolites in the brain of Parkinson’s disease rats. Using high-performance liquid chromatography, we found that dopamine and dopaminergic metabolite(dihydroxyphenylacetic acid and homovanillic acid) content in the midbrain of Parkinson’s disease rats was increased after neural stem cell transplantation + Zhichan decoction, compared with neural stem cell transplantation alone. Our genetic algorithm results show that dihydroxyphenylacetic acid and homovanillic acid levels achieve global optimization. Neural stem cell transplantation + Zhichan decoction increased dihydroxyphenylacetic acid levels up to 10-fold, while transplantation alone resulted in a 3-fold increment. Homovanillic acid levels showed no apparent change. Our experimental findings show that after neural stem cell transplantation in Parkinson’s disease rats, Zhichan decoction can promote differentiation of neural stem cells into dopaminergic neurons.
基金This study was supported by the National Natural Science Foundation of China,No.81370462(to JB)the Climbing Scholars Support Plan of Liaoning Province of China(to JB)+1 种基金the Principal’s Fund of Liaoning Medical University of China,No.20140107(to PW)the Natural Science Foundation of Liaoning Province of China,No.20180551185(to PW).
文摘Melatonin can attenuate cardiac microvascular ischemia/reperfusion injury,but it remains unclear whether melatonin can also ameliorate cerebral microvascular abnormalities.Rat models of Alzheimer’s disease were established by six intracerebroventricular injections of amyloidbeta 1–42,administered once every other day.Melatonin(30 mg/kg)was intraperitoneally administered for 13 successive days,with the first dose given 24 hours prior to the first administration of amyloid-beta 1–42.Melatonin ameliorated learning and memory impairments in the Morris water maze test,improved the morphology of microvessels in the cerebral cortex and hippocampus,increased microvessel density,alleviated pathological injuries of cerebral neurons,and decreased the expression of vascular endothelial growth factor and vascular endothelial growth factor receptors 1 and 2.These findings suggest that melatonin can improve microvessel abnormalities in the cerebral cortex and hippocampus by lowering the expression of vascular endothelial growth factor and its receptors,thereby improving the cognitive function of patients with Alzheimer’s disease.This study was approved by the Animal Care and Use Committee of Jinzhou Medical University,China(approval No.2019015)on December 6,2018.
文摘Parkinson’s disease(PD) is an age-related neurodegenerative disease for which the characteristic motor symptoms emerge after an extensive loss of dopamine containing neurons.The cell bodies of these neurons are present in the substantia nigra,with the nerve terminals being in the striatum.Both innate and adaptive immune responses may contribute to dopaminergic neurodegeneration and disease progression is potentially linked to these.Studies in the last twenty years have indicated an important role for neuroinflammation in PD through degeneration of the nigrostriatal dopaminergic pathway.Characteristic of neuroinflammation is the activation of brain glial cells,principally microglia and astrocytes that release various soluble factors.Many of these factors are proinflammatory and neurotoxic and harmful to nigral dopaminergic neurons.Recent studies have identified several different agents with immunomodulatory properties that protected dopaminergic neurons from degeneration and death in animal models of PD.All of the agents were effective in reducing the motor deficit and alleviating dopaminergic neurotoxicity and,when measured,preventing the decrease of dopamine upon being administered therapeutically after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,6-hydroxydopamine,rotenone-lesioning or delivery of adeno-associated virus-α-synuclein to the ventral midbrain of animals.Some of these agents were shown to exert an anti-inflammatory action,decrease oxidative stress,and reduce lipid peroxidation products.Activation of microglia and astrocytes was also decreased,as well as infiltration of T cells into the substantia nigra.Pretreatment with fingolimod,tanshinoine I,dimethyl fumarate,thalidomide,or cocaine-and amphetamine-regulated transcript peptide as a preventive strategy ameliorated motor deficits and nigral dopaminergic neurotoxicity in brain-lesioned animals.Immunomodulatory agents could be used to treat patients with early clinical signs of the disease or potentially even prior to disease onset in those identified as having pre-disposing risk,including genetic factors.
基金supported by the KIZ-CUHK Joint Lab of Bioresources and Molecular Research of Common Diseases(4750378)the VC Discretionary Fund provided to the Hong Kong Branch of Chinese Academy of Science Center for Excellence in Animal Evolution and Genetics(Acc 8601011)partially by the State Key Laboratory CUHKJinan MOE Key Laboratory for Regenerative medicine(2622009)。
文摘Parkinson’s disease(PD)relates to defective mitochondrial quality control in the dopaminergic motor network.Genetic studies have revealed that PINK1 and Parkin mutations are indicative of a heightened propensity to PD onset,pinpointing mitophagy and inflammation as the culprit pathways involved in neuronal loss in the substantia nigra(SNpc).In a reciprocal manner,LRRK2 functions in the regulation of basal flux and inflammatory responses responsible for PINK1/Parkin-dependent mitophagy activation.Pharmacological intervention in these diseasemodifying pathways may facilitate the development of novel PD therapeutics,despite the current lack of an established drug evaluation model.As such,we reviewed the feasibility of employing the versatile global Pink1knockout(KO)rat model as a self-sufficient,spontaneous PD model for investigating both disease etiology and drug pharmacology.These rats retain clinical features encompassing basal mitophagic flux changes with PD progression.We demonstrate the versatility of this PD rat model based on the incorporation of additional experimental insults to recapitulate the proinflammatory responses observed in PD patients.
基金This study was supported by Yu Weihan Fund for Distinguished Young Scholars of Harbin Medical University of China,No.002000013(to XMZ).
文摘Dental pulp stem cells are dental pulp-derived mesenchymal stem cells that originate from the neural crest.They exhibit greater potential for the treatment of nervous system diseases than other types of stem cells because of their neurogenic differentiation capability and their ability to secrete multiple neurotrophic factors.Few studies have reported Alzheimer’s disease treatment using dental pulp stem cells.Rat models of Alzheimer’s disease were established by injecting amyloid-β1–42 into the hippocampus.Fourteen days later,5×106 dental pulp stem cells were injected into the hippocampus.Immunohistochemistry and western blot assays showed that dental pulp stem cell transplantation increased the expression of neuron-related doublecortin,NeuN,and neurofilament 200 in the hippocampus,while the expression of amyloid-βwas decreased.Moreover,cognitive and behavioral abilities were improved.These findings indicate that dental pulp stem cell transplantation in rats can improve cognitive function by regulating the secretion of neuron-related proteins,which indicates a potential therapeutic effect for Alzheimer’s disease.This study was approved by the Animal Ethics Committee of Harbin Medical University,China(approval No.KY2017-132)on February 21,2017.
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Project supported by the National Natural Science Foundation of China(Nos.11932003 and 11772019)。
文摘Biophysical computational models are complementary to experiments and theories,providing powerful tools for the study of neurological diseases.The focus of this review is the dynamic modeling and control strategies of Parkinson’s disease(PD).In previous studies,the development of parkinsonian network dynamics modeling has made great progress.Modeling mainly focuses on the cortex-thalamus-basal ganglia(CTBG)circuit and its sub-circuits,which helps to explore the dynamic behavior of the parkinsonian network,such as synchronization.Deep brain stimulation(DBS)is an effective strategy for the treatment of PD.At present,many studies are based on the side effects of the DBS.However,the translation from modeling results to clinical disease mitigation therapy still faces huge challenges.Here,we introduce the progress of DBS improvement.Its specific purpose is to develop novel DBS treatment methods,optimize the treatment effect of DBS for each patient,and focus on the study in closed-loop DBS.Our goal is to review the inspiration and insights gained by combining the system theory with these computational models to analyze neurodynamics and optimize DBS treatment.
基金supported by funding from CSIR network project(BSC0115)
文摘Parkinson's disease (PD) is disorder affecting more than a common neurodegenerative 1% people above 60 years of age worldwide, manifesting as the impaired motor function such as tremors, rigidity, akinesia/bradykinesia and postural inefficiency with a reduced life expectancy (Dorsey et al., 2007). PD is believed to be the end result of the progressive death of dopaminergic neurons in the substantia nigra pars compacta (SNc).
文摘Diagnostics and rehabilitation of Parkinson’s disease (PD) presents the current information pertaining to etiology, early biomarkers for diagnostics, novel methods to evaluate symptoms, multidisciplinary rehabilitation, new applications of brain imaging and invasive methods to the study of PD. Researchers have only recently begun to focus on the non-motor symptoms of PD, which are poorly recognized and inadequately treated by clinicians. The non-motor symptoms of PD have a significant impact on patient quality of life and mortality, and include cognitive impairments, autonomic, gastrointestinal, and sensory symptoms. Indepth discussion of the use of imaging tools to study disease mechanisms is also provided, with emphasis on the abnormal network organization in parkinsonism. Deep brain stimulation management is a paradigm-shifting therapy for PD, essential tremor and dystonia. In the recent years, new approaches of early diagnostics, training programmes and treatments have vastly improved the lives of people with PD, substantially reducing symptoms and significantly delaying disability. PD results primarily from the death of dopaminergic neurons in the substantia nigra. Current PD medications treat symptoms;none halt or retard dopaminergic neuron degeneration. The main obstacle to developing neuroprotective therapies is a limited understanding of the key molecular mechanisms that provoke neurodegeneration. The discovery of PD genes has led to the hypothesis that misfolding of proteins and dysfunction of the ubiquitin-proteasome pathway are pivotal to PD pathogenesis. Previously implicated culprits in PD neurodegeneration, mitochondrial dysfunction and oxidative stress, may also act in part by causing the accumulation of misfolded proteins, in addition to producing other deleterious events in dopaminergic neurons. Neurotoxin-based models have been important in elucidating the molecular cas-cade of cell death in dopaminergic neurons. PD models based on the manipulation of PD genes should prove valuable in elucidating important aspects of the disease, such as selective vulnerability of substantia nigra dopaminergic neurons to the degenerative process.
文摘Parkinson's disease(PD) is the second most common age-related neurodegenerative disorder, with the clinical main symptoms caused by a loss of dopaminergic neurons in the substantia nigra, corpus striatum and brain cortex. Over 90% of patients with PD have sporadic PD and occur in people with no known family history of the disorder. Currently there is no cure for PD. Treatment with medications to increase dopamine relieves the symptoms but does not slow down or reverse the damage to neurons in the brain. Increasing evidence points to inflammation as a chief mediator of PD with inflammatory response mechanisms, involving microglia and leukocytes, activated following loss of dopaminergic neurons. Oxidative stress is also recognized as one of the main causes of PD, and excessive reactive oxygen species(ROS) and reactive nitrogen species can lead to dopaminergic neuron vulnerability and eventual death. Micro RNAs control a range of physiological and pathological functions, and may serve as potential targets for intervention against PD to mitigate damage to the brain. Several studies have demonstrated that micro RNAs can regulate oxidative stress and prevent ROS-mediated damage to dopaminergic neurons, suggesting that specific micro RNAs may be putative targets for novel therapeutic strategies in PD. Recent human and animal studies have identified a large number of dysregulated micro RNAs in PD brain tissue samples, many of which were downregulated. The dysregulated micro RNAs affect downstream targets such as SNCA, PARK2, LRRK2, TNFSF13 B, LTA, SLC5 A3, PSMB2, GSR, GBA, LAMP-2 A, HSC. Apart from one study, none of the studies reviewed had used agomirs or antagomirs to reverse the levels of downregulated or upregulated micro RNAs, respectively, in mouse models of PD or with isolated human or mouse dopaminergic cells. Further large-scale studies of brain tissue samples collected with short postmortem interval from human PD patients are warranted to provide more information on the micro RNA profiles in different brain regions and to test for gender differences.