X-box-binding protein 1-modified neural stem cells for treatment of Parkinson’s disease

X-box-binding protein 1-transfected neural stem cells were transplanted into the right lateral ventricles of rats with rotenone-induced Parkinson’s disease. The survival capacities and differentiation rates of cells expressing the dopaminergic marker tyrosine hydroxylase were higher in X-box-binding protein 1-transfected neural stem cells compared to non-transfected cells. Moreover, dopamine and 3,4-dihydroxyphenylacetic acid levels in the substantia nigra were significantly increased, α-synuclein expression was decreased, and neurological behaviors were significantly ameliorated in rats following transplantation of X-box-binding protein 1-transfected neural stem cells. These results indicate that transplantation of X-box-binding protein 1-transfected neural stem cells can promote stem cell survival and differentiation into dopaminergic neurons, increase dopamine and 3,4-dihydroxyphenylacetic acid levels, reduce α-synuclein aggregation in the substantia nigra, and improve the symptoms of Parkinson’s disease in rats.     

Intracerebroventricular transplanted bone marrow stem cells survive and migrate into the brain of rats with Parkinson’s disease

In this study,6-hydroxydopamine was stereotaxically injected into the right substantia nigra compact and ventral tegmental area of rats to establish Parkinson’s disease models.The rats then received a transplantation of bone marrow stromal cells that were previously isolated,cultured and labeled with 5-bromo-2’-deoxyuridine in vitro.Transplantation of the bone marrow stromal cells significantly de-creased apomorphine-induced rotation time and the escape latency in the Morris water maze test as compared with rats with untreated Parkinson’s disease.Immunohistochemical staining showed that,5-bromo-2’-deoxyuridine-immunoreactive cells were present in the lateral ventricular wall and the choroid plexus 1 day after transplantation.These immunoreactive cells migrated to the surrounding areas of the lateral cerebral ventricle along the corpus callosum.The results indicated that bone marrow stromal cells could migrate to tissues surround the cerebral ventricle via the cerebrospinal fluid circulation and fuse with cells in the brain,thus altering the phenotype of cells or forming neuron-like cells or astrocytes capable of expressing neuron-specific proteins.Taken together,the present findings indicate that bone marrow stromal cells transplanted intracerebroventricularly could survive,migrate and significantly improve the rotational behavior and cognitive function of rats with experimentally induced Parkinson’s disease.     

Zhichan decoction induces differentiation of dopaminergic neurons in Parkinson’s disease rats after neural stem cell transplantation

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.     

Distribution and localization of fibroblast growth factor-8 in rat brain and nerve cells during neural stem/progenitor cell differentiation

The present study explored the distribution and localization of fibroblast growth factor-8 and its potential receptor,fibroblast growth factor receptor-3,in adult rat brain in vivo and in nerve cells during differentiation of neural stem/progenitor cells in vitro.Immunohistochemistry was used to examine the distribution of fibroblast growth factor-8 in adult rat brain in vivo.Localization of fibroblast growth factor-8 and fibroblast growth factor receptor-3 in cells during neural stem/progenitor cell differentiation in vitro was detected by immunofluorescence.Flow cytometry and immunofluorescence were used to evaluate the effect of an anti-fibroblast growth factor-8 antibody on neural stem/progenitor cell differentiation and expansion in vitro.Results from this study confirmed that fibroblast growth factor-8 was mainly distributed in adult midbrain,namely the substantia nigra,compact part,dorsal tier,substantia nigra and reticular part,but was not detected in the forebrain comprising the caudate putamen and striatum.Unusual results were obtained in retrosplenial locations of adult rat brain.We found that fibroblast growth factor-8 and fibroblast growth factor receptor-3 were distributed on the cell membrane and in the cytoplasm of nerve cells using immunohistochemistry and immunofluorescence analyses.We considered that the distribution of fibroblast growth factor-8 and fibroblast growth factor receptor-3 in neural cells corresponded to the characteristics of fibroblast growth factor-8,a secretory factor.Addition of an anti-fibroblast growth factor-8 antibody to cultures significantly affected the rate of expansion and differentiation of neural stem/progenitor cells.In contrast,addition of recombinant fibroblast growth factor-8 to differentiation medium promoted neural stem/progenitor cell differentiation and increased the final yields of dopaminergic neurons and total neurons.Our study may help delineate the important roles of fibroblast growth factor-8 in brain activities and neural stem/progenitor cell differentiation.     

Stem cell transplantation for treating Parkinson's disease Literature analysis based on the Web of Science

OBJECTIVE:To identify global research trends of stem cell transplantation for treating Parkinson’s disease using a bibliometric analysis of the Web of Science.DATA RETRIEVAL:We performed a bibliometric analysis of data retrievals for stem cell transplantation for treating Parkinson’s disease from 2002 to 2011 using the Web of Science.SELECTION CRITERIA:Inclusion criteria:(a) peer-reviewed articles on stem cell transplantation for treating Parkinson’s disease which were published and indexed in the Web of Science;(b) type of articles:original research articles,reviews,meeting abstracts,proceedings papers,book chapters,editorial material and news items;(c) year of publication:2002-2011.Exclusion criteria:(a) articles that required manual searching or telephone access;(b) we excluded documents that were not published in the public domain;(c) we excluded a number of corrected papers from the total number of articles.MAIN OUTCOME MEASURES:(1) Type of literature;(2) annual publication output;(3) distribution according to journals;(4) distribution according to subject areas;(5) distribution according to country;(6) distribution according to institution;(7) comparison of countries that published the most papers on stem cell transplantation from different cell sources for treating Parkinson’s disease;(8) comparison of institutions that published the most papers on stem cell transplantation from different cell sources for treating Parkinson’s disease in the Web of Science from 2002 to 2011;(9) comparison of studies on stem cell transplantation from different cell sources for treating Parkinson’s disease RESULTS:In total,1 062 studies on stem cell transplantation for treating Parkinson’s disease appeared in the Web of Science from 2002 to 2011,almost one third of which were from American authors and institutes.The number of studies on stem cell transplantation for treating Parkinson’s disease had gradually increased over the past 10 years.Papers on stem cell transplantation for treating Parkinson’s disease appeared in journals such as Stem Cells and Experimental Neurology.Although the United States published more articles addressing neural stem cell and embryonic stem cell transplantation for treating Parkinson’s disease,China ranked first for articles published on bone marrow mesenchymal stem cell transplantation for treating Parkinson’s disease.CONCLUSION:From our analysis of the literature and research trends,we found that stem cell transplantation for treating Parkinson’s disease may offer further benefits in regenerative medicine.     

Are human dental papilla-derived stem cell and human brain-derived neural stem cell transplantations suitable for treatment of Parkinson's disease?

Transplantation of neural stem cells has been reported as a possible approach for replacing impaired dopaminergic neurons. In this study, we tested the efficacy of early-stage human dental papilla-derived stem cells and human brain-derived neural stem cells in rat models of 6-hydroxydopamine-induced Parkinson’s disease. Rats received a unilateral injection of 6-hydroxydopamine into right medial forebrain bundle, followed 3 weeks later by injections of PBS, early-stage human dental papilla-derived stem cells, or human brain-derived neural stem cells into the ipsilateral striatum. All of the rats in the human dental papilla-derived stem cell group died from tumor formation at around 2 weeks following cell transplantation. Postmortem examinations revealed homogeneous malignant tumors in the striatum of the human dental papilla-derived stem cell group. Stepping tests revealed that human brain-derived neural stem cell transplantation did not improve motor dysfunction. In apomorphine-induced rotation tests, neither the human brain-derived neural stem cell group nor the control groups (PBS injection) demonstrated significant changes. Glucose metabolism in the lesioned side of striatum was reduced by human brain-derived neural stem cell transplantation. [18 F]-FP-CIT PET scans in the striatum did not demonstrate a significant increase in the human brain-derived neural stem cell group. Tyrosine hydroxylase (dopaminergic neuronal marker) staining and G protein-activated inward rectifier potassium channel 2 (A9 dopaminergic neuronal marker) were positive in the lesioned side of striatum in the human brain-derived neural stem cell group. The use of early-stage human dental papilla-derived stem cells confirmed its tendency to form tumors. Human brain-derived neural stem cells could be partially differentiated into dopaminergic neurons, but they did not secrete dopamine.     

Verbascoside promotes the regeneration of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra

Tyrosine hydroxylase is a key enzyme in dopamine biosynthesis. Change in tyrosine hydroxylase expression in the nigrostriatal system is closely related to the occurrence and development of Parkinson’s disease. Verbascoside, an extract from Radix Rehmanniae Praeparata has been shown to be clinically effective in treating Parkinson’s disease. However, the underlying mechanisms remain unclear. It is hypothesized that the effects of verbascoside on Parkinson’s disease are related to tyrosine hydroxylase expression change in the nigrostriatal system. Rat models of Parkinson’s disease were established and verbascoside (60 mg/kg) was administered intraperitoneally once a day. After 6 weeks of verbascoside treatment, rat rotational behavior was alleviated; tyrosine hydroxylase mRNA and protein expression and the number of tyrosine hydroxylase-immunoreactive neurons in the rat right substantia nigra were signiifcantly higher than the Parkinson’s model group. These ifndings suggest that the mechanism by which verbascoside treats Parkinson’s disease is related to the regeneration of tyrosine hy-droxylase-immunoreactive neurons in the substantia nigra.     

Anchanling reduces pathology in a lactacystin-induced Parkinson’s disease model

A rat model of Parkinson’s disease was induced by injecting lactacystin stereotaxically into the left mesencephalic ventral tegmental area and substantia nigra pars compacta. After rats were intragastrically perfused with Anchanling, a Chinese medicine, mainly composed of magnolol, for 5 weeks, when compared with Parkinson’s disease model rats, tyrosine hydroxylase expression was increased, α-synuclein and ubiquitin expression was decreased, substantia nigra cell apoptosis was reduced, and apomorphine-induced rotational behavior was improved. Results suggested that Anchanling can ameliorate Parkinson’s disease pathology possibly by enhancing degradation activity of the ubiquitin-proteasome system.     

Gastrodin inhibits neuroinflammation in rotenone-induced Parkinson's disease model rats

The present study showed that the latency of rats moving on a vertical grid was significantly prolonged,and the number of rats sliding down from the declined plane was increased remarkably,in rotenone-induced Parkinson’s disease model rats compared with control rats.The moving latency recovered to normal levels,but the number of slides was significantly increased at 28 days after model establishment.The slope test is a meaningful approach to evaluate the symptoms of Parkinson’s disease model rats treated with rotenone.In addition,loss of substantia nigral dopaminergic neurons in model rats was observed at 1 day after the model was established,and continued gradually at 14 and 28 days.The expression of tyrosine hydroxylase-positive cells was significantly increased in gastrodin-treated rats at 14 days.Significant numbers of activated microglia cells were observed in model rats at 14 and 28 days;treatment of rats with Madopar at 28 days suppressed microglial activation.Treatment of rats with gastrodin or Madopar at 28 days significantly reduced interleukin-1β expression.The loss of substantia nigral dopaminergic neurons paralleled the microglial activation in Parkinson’s disease model rats treated with rotenone.The inflammatory factors tumor necrosis factor-α and interleukin-1β are involved in the substantia nigral damage.Gastrodin could protect dopaminergic neurons via inhibition of interleukin-1β expression and neuroinflammation in the substantia nigra.     

Cell transplantation for Parkinson‘s disease

The motor symptoms of Parkinson‘s disease (PD) can be improved by cell transplantation,which has caught general attention from the field of the therapy for PD recently. In this paper, we summarize the cell-based therapy for PD.DATA SOURCES: A search for English literature related to the cellular transplantation of PD from January 1979to July 2006 was conducted in Medline with the key words of “Parkinson‘s disease, cell transplantation,embryonic stem cells, neural stem cells“.STUDY SELECTTON: Data were checked in the first trial, and literatures about PD and cell transplantation were selected. Inclusive criteria: ① PD; ② Cell transplantation. Exclusive criteria: repetitive researches.DATA EXTRACTTON: A total of 100 papers related to cellular transplant and PD were collected and 41literatures were in accordance with the inclusive criteria.DATA SYNTHESIS: PD is a neural degeneration disease that threatens the health of the aged people, and most traditional therapeusis cannot delay its pathological proceeding. Cell transplantation is becoming popular as a new therapeutic tool, and the cells used to transplant mainly included dopamine-secreting cells, fetal ventral mesencephalic cells, embryonic stem cells and neural stem cells up to now. Animal experiment and clinical test demonstrate that cell transplantation can relieve the motor symptoms of Parkinson‘s disease obviously, but there are some problems need to be solved.CONCLUSTON: Cell transplantation has visible therapeutic efficacy on PD. Following the improvement of technique, and we have enough cause to credit that cell therapy may cure PD in the future.     

Protective effects of kidney-tonifying Chinese herbal preparation on substantia nigra neurons in a mouse model of Parkinson’s disease

The Chinese herbs Herba Epimedii, Fructus Ligustri Lucidi and Rhizoma Polygonati were injected into Parkinson’s disease mice established via intraperitoneal injection of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride. The selective monoamine oxidase B inhibitor selegiline was used as a positive control drug. After successive administration for 4 weeks, Herba Epimedii could downregulate the expression of caspase-3 and increase the brain-derived neurotrophic factor level, as well as increase tyrosine hydroxylase activity in the substantia nigra of Parkinson’s disease mouse models. Rhizoma Polygonati could downregulate the expression of caspase-3 and FasL, and increase neural growth factor and brain-derived neurotrophic factor levels. Fructus Ligustri Lucidi could downregulate caspase-3 expression. Rhizoma Polygonati and Fructus Ligustri Lucidi did not produce obvious effects on tyrosine hydroxylase activity. Herba Epimedii and Fructus Ligustri Lucidi yielded similar effects on apoptosis-promoting factors to those elicited by selegiline. Herba Epimedii and Rhizoma Polygonati significantly increased the levels of neurotrophic factors compared with selegiline. Herba Epimedii significantly increased tyrosine hydroxylase activity compared with selegiline. It is indicated that the kidney-tonifying Chinese herbal preparation can downregulate the expression of apoptosis-promoting factors, increase neurotrophic factors levels in the substantia nigra and striatum, as well as increase tyrosine hydroxylase activity in the substantia nigra of Parkinson’s disease mouse models, thereby exerting a stronger or similar neuroprotective effects compared with selegiline.     

Baicalin and deferoxamine alleviate iron accumulation in different brain regions of Parkinson’s disease rats

Previous studies found that iron accumulates in the substantia nigra of Parkinson’s disease patients. However, it is still unclear whether other brain regions have iron accumulation as well. In this experiment, rats with rotenone-induced Parkinson’s disease were treated by gastric perfusion of baicalin or intraperitoneal injection of deferoxamine. Immunohistochemical staining demonstrated that iron accumulated not only in the substantia nigra pars compacta, but also significantly in the striatum globus pallidus, the dentate gyrus granular layer of the hippocampus, the dentate-interpositus and the facial nucleus of the cerebellum. Both baicalin and deferoxamine, which are iron chelating agents, significantly inhibited iron deposition in these brain areas, and substantially reduced the loss of tyrosine hydroxylase-positive cells. These chelators also reduced iron content in the substantia nigra. In addition to the substantia nigra, iron deposition was observed in other brain regions as well. Both baicalin and deferoxamine significantly inhibited iron accumulation in different brain regions, and had a protective effect on dopaminergic neurons.     

Why psychosis is frequently associated with Parkinson's disease?

Psychosis is a common non-motor symptom of Parkinson’s disease whose pathogenesis remains poorly understood.Parkinson’s disease in conjunction with psychosis has been shown to induce injury to extracorticospinal tracts as well as within some cortical areas.In this study,Parkinson’s disease patients with psychosis who did not receive antipsychotic treatment and those without psychosis underwent diffusion tensor imaging.Results revealed that in Parkinson’s disease patients with psychosis,damage to the left frontal lobe,bilateral occipital lobe,left cingulated gyrus,and left hippocampal white-matter fibers were greater than damage to the substantia nigra or the globus pallidus.Damage to white-matter fibers in the right frontal lobe and right cingulate gyrus were also more severe than in the globus pallidus,but not the substantia nigra.Damage to frontal lobe and cingulate gyrus white-matter fibers was more apparent than that to occipital or hippocampal fiber damage.Compared with Parkinson’s disease patients without psychosis,those with psychosis had significantly lower fractional anisotropy ratios of left frontal lobe,bilateral occipital lobe,left cingulated gyrus,and left hippocampus to ipsilateral substantia nigra or globus pallidus,indicating more severe damage to white-matter fibers.These results suggest that psychosis associated with Parkinson’s disease is probably associated with an imbalance in the ratio of white-matter fibers between brain regions associated with psychiatric symptoms(frontal lobe,occipital lobe,cingulate gyrus,and hippocampus) and those associated with the motor symptoms of Parkinson’s disease(the substantia nigra and globus pallidus).The relatively greater damage to white-matter fibers in psychiatric symptom-related brain regions than in extracorticospinal tracts might explain why psychosis often occurs in Parkinson’s disease patients.     

A novel method for evaluating brain function and microstructural changes in Parkinson's disease

In this study,microstructural brain damage in Parkinson’s disease patients was examined using diffusion tensor imaging and tract-based spatial statistics.The analyses revealed the presence of neuronal damage in the substantia nigra and putamen in the Parkinson’s disease patients.Moreover,disease symptoms worsened with increasing damage to the substantia nigra,confirming that the substantia nigra and basal ganglia are the main structures affected in Parkinson’s disease.We also found that microstructural damage to the putamen,caudate nucleus and frontal lobe positively correlated with depression.Based on the tract-based spatial statistics,various white matter tracts appeared to have microstructural damage,and this correlated with cognitive disorder and depression.Taken together,our results suggest that diffusion tensor imaging and tract-based spatial statistics can be used to effectively study brain function and microstructural changes in patients with Parkinson’s disease.Our novel findings should contribute to our understanding of the histopathological basis of cognitive dysfunction and depression in Parkinson’s disease.     

Total saponins of Panax ginseng effects on proliferation and differentiation of human embryonic neural stem cells and in a Parkinson's disease mouse model

BACKGROUND:Total saponins of Panax ginseng(TSPG) exhibits neuroprotection against Parkinson's disease in the substantia nigra. OBJECTIVE:To investigate the effects of TSPG on human embryonic neural stem cells(NSCs) proliferation and differentiation into dopaminergic neurons using in vitro studies,and to observe NSC differentiation in a mouse model of Parkinson's disease,as well as behavioral changes before and after transplantation. DESIGN,TIME AND SETTING:In vitro neural cell biology trial and in vivo r...     

Directional induction of dopaminergic neurons from neural stem cells using substantia nigra homogenates and basic fibroblast growth factor

To date, complex components of available reagents have been used for directional induction of neural stem cells into dopaminergic neurons, resulting in a poor ability to repeat experiments. This study sought to investigate whether a homogenate of the substantia nigra of adult rats and/or basic fibroblast growth factor could directionally induce neural stem cells derived from the subventricular zone of embryonic rats to differentiate into dopaminergic neurons. Tyrosine hydroxylase-positive cells were observed exclusively after induction with the homogenate supernatant of the substantia nigra from adult rats and basic fibroblast growth factor for 48 hours in vitro. However, in the groups treated with homogenate supernatant or basic fibroblast growth factor alone, tyrosine hydroxylase expression was not observed. Moreover, the content of dopamine in the culture medium of subventricular zone neurons was significantly increased at 48 hours after induction with the homogenate supernatant of the substantia nigra from adult rats and basic fibroblast growth factor. Experimental findings indicate that the homogenate supernatant of the substantia nigra from adult rats and basic fibroblast growth factor could directionally induce neural stem cells derived from the subventricular zone of embryonic rats to differentiate into dopaminergic neurons in the substantia nigra with the ability to secrete dopamine.     

Cell reprogramming therapy for Parkinson's disease

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. Howeve...