A Combination of NT-4/5 and GDNF Is Favorable for Cultured Human Nigral Neural Progenitor Cells

Idiopathic Parkinson’s disease (PD) is a progressive neurodegenerative disorder, clinically manifested by cardinal motor symptoms including tremor at rest, bradykinesia, and muscle rigidity. Transplantation of dopaminergic (DAergic) neurons is an experimental therapy for PD, however, it is limited by suboptimal integration and low survival of grafts. Pretreatment of donor tissue may offer a strategy to improve properties of transplanted DAergic neurons and thereby clinical outcome. We have previously shown that a combination of neurotrophin-4/5 (NT-4/5) and glial cell line-derived neurotrophic factor (GDNF) demonstrated additive effects on rat ventral mesencephalic (VM) tissue. The present study investigated the effects of NT-4/5 and GDNF as single factors, or in combination on DAergic neurons, in organotypic explant cultures of fetal human ventral mesencephalon. For that purpose, free-floating roller-tube cultures were prepared from VM and the equally sized pieces grown for 1 week in the presence or absence of neurotrophic factors. Both neurotrophic factors increased dopamine content in the culture medium and in the number of tyrosine hydroxylase immunoreactive neurons, most prominently after combined GDNF + NT-4/5 treatment. Culture volumes did not differ between groups while content of lactate dehydrogenase in the culture medium was moderately reduced in all treated groups. In conclusion, we identified that a combination of GDNF and NT-4/5 robustly promoted differentiation and survival of human fetal VM DAergic neurons, an observation with potential promising impact for cell replacement approaches in PD.

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Potential Role of Caffeine in the Treatment of Parkinson’s Disease

The Open Neurology Journal ◽

10.2174/1874205x01610010042 ◽

2016 ◽

Vol 10 (1) ◽

pp. 42-58 ◽

Cited By ~ 8

Author(s):

Mohsin H.K. Roshan ◽

Amos Tambo ◽

Nikolai P. Pace

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Randomized Clinical Trials ◽

Neurodegenerative Disorder ◽

Lewy Bodies ◽

Substantia Nigra Pars Compacta ◽

Muscle Rigidity ◽

Therapeutic Effects ◽

Motor Symptoms ◽

Wide Range

Parkinson’s disease [PD] is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting 1% of the population over the age of 55. The underlying neuropathology seen in PD is characterised by progressive loss of dopaminergic neurons in the substantia nigra pars compacta with the presence of Lewy bodies. The Lewy bodies are composed of aggregates of α-synuclein. The motor manifestations of PD include a resting tremor, bradykinesia, and muscle rigidity. Currently there is no cure for PD and motor symptoms are treated with a number of drugs including levodopa [L-dopa]. These drugs do not delay progression of the disease and often provide only temporary relief. Their use is often accompanied by severe adverse effects. Emerging evidence from bothin vivoandin vitrostudies suggests that caffeine may reduce parkinsonian motor symptoms by antagonising the adenosine A2Areceptor, which is predominately expressed in the basal ganglia. It is hypothesised that caffeine may increase the excitatory activity in local areas by inhibiting the astrocytic inflammatory processes but evidence remains inconclusive. In addition, the co-administration of caffeine with currently available PD drugs helps to reduce drug tolerance, suggesting that caffeine may be used as an adjuvant in treating PD. In conclusion, caffeine may have a wide range of therapeutic effects which are yet to be explored, and therefore warrants further investigation in randomized clinical trials.

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Intranigral Grafts of Fetal Ventral Mesencephalic Tissue in Adult 6-Hydroxydopamine-Lesioned Rats can Induce Behavioral Recovery

Cell Transplantation ◽

10.1177/096368979700600309 ◽

1997 ◽

Vol 6 (3) ◽

pp. 267-276 ◽

Cited By ~ 4

Author(s):

R.E. Johnston ◽

Jill B. Becker

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cyclosporine A ◽

Ventral Mesencephalon ◽

Behavioral Recovery ◽

Treatment Conditions ◽

Movement Sequence ◽

Ventral Mesencephalic ◽

6 Hydroxydopamine ◽

Disease Specific

Intrastriatal grafts of fetal ventral mesencephalon in rats with unilateral 6-hydroxydopamine lesions can reduce and even reverse rotational behavior in response to direct and indirect dopamine agonists. These grafts can ameliorate deficits on simple spontaneous behaviors, but do not improve complex behaviors that require the skilled integration of the use of both paws. We report here that rats with grafts into the DA-depleted substantia nigra, that receive cyclosporine A, can experience recovery on spontaneous behaviors that mimic those observed in Parkinson's disease. Specific cyclosporine A treatment conditions can differentially affect whether intranigral grafts normalize paw use during initiation or termination of a movement sequence. These findings may have important implications for the treatment of Parkinson's disease.

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cytoNet: Network Analysis of Cell Communities

10.1101/180273 ◽

2017 ◽

Cited By ~ 3

Author(s):

Arun S. Mahadevan ◽

Byron L. Long ◽

Chenyue Wendy Hu ◽

David T. Ryan ◽

George L. Britton ◽

...

Keyword(s):

Neurotrophic Factors ◽

Neural Progenitor Cells ◽

Individual Cell ◽

Morphological Response ◽

Cellular Behavior ◽

Quantitative Manner ◽

Cell Cycle Dynamics ◽

Cell Phenotypes ◽

The Brain ◽

Microscopy Images

We introduce cytoNet, a method to characterize multicellular topology from microscopy images. Accessible over the web, cytoNet quantifies the spatial relationships in cell communities using principles of graph theory, and evaluates the effect of cell-cell interactions on individual cell phenotypes. We demonstrate cytoNet’s capabilities in two applications relevant to regenerative medicine: quantifying the morphological response of endothelial cells to neurotrophic factors present in the brain after injury, and characterizing cell cycle dynamics of differentiating neural progenitor cells. The framework introduced here can be used to study complex cell communities in a quantitative manner, leading to a deeper understanding of environmental effects on cellular behavior.

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D-serine supplement ameliorates MPP+-induced neurotoxicity via attenuating DAPK1-associated pathway in Parkinson's disease models

10.21203/rs.3.rs-892540/v1 ◽

2021 ◽

Author(s):

Wenli Zhang ◽

Xueying Sun ◽

Jun Liu ◽

Yuanwen Peng ◽

Yuanhua Qin ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Disorder ◽

Neuronal Cells ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Morphological Observation ◽

Dopamine Content ◽

Acetylcholine Level ◽

Related Pathway

Abstract Background: D-serine is reported to modulate neurotransmission via regulating the activation of N-methyl-D-aspartate receptor 1 (NMDAR1) in a narrow range, and dysfunction or dysregulation of NMDAR1 contributes to the pathophysiology of Parkinson's disease (PD), a chronic and progressive neurodegenerative disorder. This study aims to further elucidate the action mechanism of D-serine/NMDAR1 in PD. Methods and Results: At animal level, we found D-Serine and NMDAR1 were cooperatively distributed in mouse brains. Compared to the control mice, a dramatic increase in D-serine content and NMDAR1 expression was revealed in striatum, whereas a significant reduction was found in cortex, hippocampus, cerebellum and brainstem in PD mice. Thus, the tissue-specific D-serine/NMDAR1 was suspected to be associated with PD. Based on the decreased levels of NMDAR1 and D-serine in the MPP+-treated glioma cells, a D-serine supplement was introduced. We found that D-serine supplement enhanced NMDAR1 expression, and triggered neuronal cells to be rescued supporting by parkinsonian parameters including morphological observation, a decreased ROS level, an increased dopamine content, and a declined acetylcholine level. Additionally, a decreased calcium, reduced DAPK1 expression, and raised Bcl2 level were found in neuronal cells supplied with D-serine. Conclusions: We speculated that D-Serine attenuated neuronal cell death via inhibiting DAPK1-related pathway. Additionally, D-serine was confirmed to display an ability to ameliorate the MPTP injury using the MPTP-administrated mice injected with D-serine. Unlike the previous description, D-serine displays a protective effect on neuronal cells. Overall, our finding highlights D-serine as a strong enhancer for NMDAR1 expression and a candidate for PD therapy. This opens up an innovative perspective for neurobiological therapy using D-serine augmentation.

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Microcarrier Enhanced Survival of Human and Rat Fetal Ventral Mesencephalon Cells Implanted in the Rat Striatum

Cell Transplantation ◽

10.1177/096368979700600608 ◽

1997 ◽

Vol 6 (6) ◽

pp. 579-584 ◽

Cited By ~ 7

Author(s):

Samuel Saporta ◽

Cesario Borlongan ◽

Joann Moore ◽

Elizabeth Mejia-Millan ◽

Stacey L. Jones ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Chromaffin Cells ◽

Rat Striatum ◽

Ventral Mesencephalon ◽

Poor Survival ◽

Systemic Immunosuppression ◽

Ventral Mesencephalic ◽

Transplant Site ◽

Mesencephalic Cells

The transplantation of tissue containing dopamine-producing cells into the mammalian central nervous system is an emerging treatment for Parkinson's disease, despite relatively poor survival of implanted tissue. Recent evidence has suggested that Cytodex microcarriers enhance the survival of dopaminergic rat chromaffin cells transplanted into the rat striatum in the absence of immunosuppression. The current study was undertaken to evaluate the survival of rat and human fetal ventral mesencephalic neurons (VM) implanted alone or after attachment to microcarriers in the striatum of rats without immunosuppression. Rat fetal VM neurons demonstrated enhanced survival in the rat striatum when transplanted on microcarriers, compared to their transplantation alone during the 3-mo period examined in the present study. Transplants of human fetal VM neurons on microcarriers also survived remarkably well in the rat striatum without systemic immunosuppression. In contrast, human fetal VM cells transplanted alone into the rat striatum did not survive without systemic immunosuppression. There was no evidence of TH fiber sprouting in the vicinity of any transplant site. These data indicated that Cytodex microcarriers provide enhanced survival of both rat allograft and human xenograft fetal mesencephalic cells in the rat striatum without the necessity of systemic immunosuppression, perhaps by inducing a unique neuron–glia environment.

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Levodopa Therapy for Parkinson's Disease: History, Current Status and Perspectives

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200722153156 ◽

2020 ◽

Vol 19 (8) ◽

pp. 572-583

Author(s):

Helle Bogetofte ◽

Arezo Alamyar ◽

Morten Blaabjerg ◽

Morten Meyer

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Side Effects ◽

Dopaminergic Neurons ◽

Neurodegenerative Disorder ◽

Neuroprotective Effect ◽

Substantia Nigra Pars Compacta ◽

Current Status ◽

Current Evidence ◽

Muscle Rigidity

Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by a preferential degeneration of dopaminergic neurons in the substantia nigra pars compacta. This results in a profound decrease of striatal dopamine (DA) levels, which in turn leads to the cardinal motor symptoms of PD; muscle rigidity, hypo- and bradykinesia and resting tremor. Even 50 years after its initial use, the DA precursor levodopa (L-dopa), is still the most effective medical therapy for the symptomatic treatment of PD. Long-term L-dopa treatment is however, unfortunately associated with undesirable side effects such as motor fluctuations and dyskinesias. Furthermore, despite the disease alleviating effects of L-dopa, it is still discussed whether L-dopa has a neurotoxic or neuroprotective effect on dopaminergic neurons. Here we review the history of L-dopa, including its discovery, development and current use in the treatment of PD. We furthermore review current evidence of the L-dopa-induced side effects and perspectives of L-dopa treatment in PD compared to other established treatments such as DA-agonists and the inhibitors of catechol-o-methyltransferase and monoamine oxidase B.

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Rat mesenchymal stem cells increase tyrosine hydroxylase expression and dopamine content in ventral mesencephalic cells in vitro

Cell Biology International ◽

10.1016/j.cellbi.2008.08.014 ◽

2008 ◽

Vol 32 (11) ◽

pp. 1433-1438 ◽

Cited By ~ 22

Author(s):

Guang-Zhen Jin ◽

Su-Jin Cho ◽

Eu-Gene Choi ◽

Young-S. Lee ◽

Xian-Feng Yu ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tyrosine Hydroxylase ◽

Dopamine Content ◽

Ventral Mesencephalic ◽

Mesencephalic Cells

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Differential Dissection of the Rat E16 Ventral Mesencephalon and Survival and Reinnervation of the 6-Ohda-Lesioned Striatum by a Subset of Aldehyde Dehydrogenase-Positive th Neurons

Cell Transplantation ◽

10.1177/096368979700600307 ◽

1997 ◽

Vol 6 (3) ◽

pp. 239-248 ◽

Cited By ~ 15

Author(s):

Nadia S.K. Haque ◽

Celeste J. Leblanc ◽

Ole Isacson

Keyword(s):

Aldehyde Dehydrogenase ◽

Functional Recovery ◽

Dopaminergic Neurons ◽

Histological Evaluation ◽

Ventral Mesencephalon ◽

Th Cells ◽

Immunohistochemical Markers ◽

Normal Projection ◽

Ventral Mesencephalic ◽

Projection Pattern

The retinoic acid-generating enzyme, aldehyde dehydrogenase (AHD), is expressed in a subpopulation of dopaminergic neurons found in the substantia nigra. Using AHD and tyrosine hydroxylase (TH) as immunohistochemical markers, we determined whether differential dissection of the embryonic (E16) ventral mesencephalon (VM) into its lateral and medial portions contributed equally to the number of TH cells surviving transplantation, if grafted AHD/TH neurons reinnervate the host striatum according to their normal projection patterns, and examined the functional recovery caused by the implanted cells as assessed by amphetamine-induced rotation in a 6-OHDA-lesioned model of Parkinson's disease. The embryonic tissue was transplanted as solid pieces injected via a 20-gauge lumbar puncture needle into the center of the deafferented striatum. Groups received either one complete ventral mesencephalic piece (VM), two medial pieces of ventral mesencephalic tissue (MVM), or two lateral pieces of ventral mesencephalic tissue (LVM). Both VM and MVM groups showed a significant decrease in amphetamine-induced rotation over time and, there was no difference in the degree of reduction observed between the two groups. Histological evaluation of the transplants revealed a much larger total number of surviving TH cells in grafts from the VM and MVM groups compared to the LVM group. Surviving AHD/TH neurons were found in all groups. Whereas TH staining of the transplanted striatum displayed a halo of graft-derived fibers all around the transplant and integration of these fibers into the host neuropil, AHD staining showed a preferential reinnervation of the dorsolateral striatum corresponding to the normal projection pattern of AHD/TH neurons. In summary, selective dissection of the embryonic ventral mesencephalon is possible, functional recovery as assessed by amphetamineinduced rotation in animals transplanted with MVM is similar to that seen in animals grafted with VM, and AHD/TH neurons have a selective reinnervation pattern in the PD transplantation paradigm. These findings may have implications for the grafting of fetal mesencephalic tissue in PD patients.

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Viral vector delivery of neurotrophic factors for Parkinson's disease therapy

Expert Reviews in Molecular Medicine ◽

10.1017/erm.2015.6 ◽

2015 ◽

Vol 17 ◽

Cited By ~ 20

Author(s):

Martin J. Kelly ◽

Gerard W. O'Keeffe ◽

Aideen M. Sullivan

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Clinical Trials ◽

Neurotrophic Factors ◽

Neurotrophic Factor ◽

Dopaminergic Neurons ◽

Viral Vectors ◽

Viral Vector ◽

Neurodegenerative Disorder ◽

The Brain

Parkinson's disease (PD) is a neurodegenerative disorder characterised by the progressive loss of midbrain dopaminergic neurons, which causes motor impairments. Current treatments involve dopamine replacement to address the disease symptoms rather than its cause. Factors that promote the survival of dopaminergic neurons have been proposed as novel therapies for PD. Several dopaminergic neurotrophic factors (NTFs) have been examined for their ability to protect and/or restore degenerating dopaminergic neurons, both in animal models and in clinical trials. These include glial cell line-derived neurotrophic factor, neurturin, cerebral dopamine neurotrophic factor and growth/differentiation factor 5. Delivery of these NTFs via injection or infusion to the brain raises several practical problems. A new delivery approach for NTFs involves the use of recombinant viral vectors to enable long-term expression of these factors in brain cells. Vectors used include those based on adenoviruses, adeno-associated viruses and lentiviruses. Here we review progress to date on the potential of each of these four NTFs as novel therapeutic strategies for PD, as well as the challenges that have arisen, from pre-clinical analysis to clinical trials. We conclude by discussing recently-developed approaches to optimise the delivery of NTF-carrying viral vectors to the brain.

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