scholarly journals Transplantation of Foetal Ventral Mesencephalic Grafts in Parkinson’s Disease: A Still Evolving Concept with New Regulatory Challenges

10.5772/16851 ◽  
2011 ◽  
Author(s):  
Sven Mollers ◽  
Mate Dobrossy ◽  
Guido Nikkhah
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ventral Mesencephalic ◽  
Regulatory Challenges

scholarly journals Foetal Cell Transplantation for Parkinson’s Disease: Focus on Graft-Induced Dyskinesia

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Elisabetta Tronci ◽  
Camino Fidalgo ◽  
Manolo Carta
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Transplantation ◽  
Open Label ◽  
Double Blind ◽  
Clinical Investigations ◽  
Serotonin Neurons ◽  
Ventral Mesencephalic ◽  
Preclinical And Clinical Studies ◽  
Foetal Cell

Transplantation of dopamine- (DA-) rich foetal ventral mesencephalic cells emerged as a promising therapy for Parkinson’s disease (PD), as it allowed significant improvement of motor symptoms in several PD patients in open-label studies. However, double-blind clinical trials have been largely disappointing. The general agreement in the field is that the lack of standardization of tissue collection and preparation, together with the absence of postsurgical immunosuppression, played a key role in the failure of these studies. Moreover, a further complication that emerged in previous studies is the appearance of the so-called graft-induced dyskinesia (GID), in a subset of grafted patients, which resembles dyskinesia induced by L-DOPA but in the absence of medication. Preclinical evidence pointed to the serotonin neurons as possible players in the appearance of GID. In agreement, clinical investigations have shown that grafted tissue may contain a large number of serotonin neurons, in the order of half of the DA cells; moreover, the serotonin 5-HT1A receptor agonist buspirone has been found to produce significant dampening of GID in grafted patients. In this paper, we will review the recent preclinical and clinical studies focusing on cell transplantation for PD and on the mechanisms underlying GID.

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

1997 ◽  
Vol 6 (3) ◽  
pp. 267-276 ◽  
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.

scholarly journals Role of Serotonin Neurons in L-DOPA- and Graft-Induced Dyskinesia in a Rat Model of Parkinson's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Eunju Shin ◽  
Elisabetta Tronci ◽  
Manolo Carta
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Work ◽  
Serotonin System ◽  
Serotonin Neurons ◽  
Advanced Stages ◽  
Ventral Mesencephalic ◽  
The One ◽  
Patients Experience

L-DOPA, the most effective drug to treat motor symptoms of Parkinson's disease, causes abnormal involuntary movements, limiting its use in advanced stages of the disease. An increasing body of evidence points to the serotonin system as a key player in the appearance of L-DOPA-induced dyskinesia (LID). In fact, exogenously administered L-DOPA can be taken up by serotonin neurons, converted to dopamine and released as a false transmitter, contributing to pulsatile stimulation of striatal dopamine receptors. Accordingly, destruction of serotonin fibers or silencing serotonin neurons by serotonin agonists could counteract LID in animal models. Recent clinical work has also shown that serotonin neurons are present in the caudate/putamen of patients grafted with embryonic ventral mesencephalic cells, producing intense serotonin hyperinnervation. These patients experience graft-induced dyskinesia (GID), a type of dyskinesia phenotypically similar to the one induced by L-DOPA but independent from its administration. Interestingly, the 5-HT1Areceptor agonist buspirone has been shown to suppress GID in these patients, suggesting that serotonin neurons might be involved in the etiology of GID as for LID. In this paper we will discuss the experimental and clinical evidence supporting the involvement of the serotonin system in both LID and GID.

Viral Vector Mediated Overexpression of Human α-Synuclein in the Nigrostriatal Dopaminergic Neurons: A New Model for Parkinson's Disease

CNS Spectrums ◽  
2005 ◽  
Vol 10 (3) ◽  
pp. 235-244 ◽  
Author(s):  
Matthew Maingay ◽  
Marina Romero-Ramos ◽  
Deniz Kirik
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Viral Vectors ◽  
Viral Vector ◽  
Disease Process ◽  
Deficiency Syndrome ◽  
Toxic Substances ◽  
Testing Strategies ◽  
Ventral Mesencephalic ◽  
The Brain

AbstractParkinson's disease is predominantly a dopamine deficiency syndrome, which is produced in the brain by the loss of cells located in a small area in the ventral midbrain called the substantia nigra. Complete unilateral dopamine lesions, based on the administration of toxic substances (ie, 6-hydroxy-dopamine in rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice and primates) have been extremely useful in testing strategies of replacement. For example, the functional and biochemical impact of the transplanted ventral mesencephalic dopaminergic progenitors has been characterized to a large extent, using the complete lesion model in rats. Over the last decade, however, studies addressing the ability of neurotrophic factors to protect injured dopamine cells prompted researchers to make available partial and progressive lesion models to allow a window of opportunity to interfere the disease progression. Recent findings relating a-synuclein with Parkinson's disease pathology have opened new possibilities to develop alternative models based on the overexpression of this protein using recombinant adeno-associated viral vectors, which is valuable not only for helping to better understand its involvement in the disease process, but also to more closely resemble the neurodegeneration found in Parkinson's disease.

scholarly journals How to improve the survival of the fetal ventral mesencephalic cell transplanted in Parkinson’s disease?

2007 ◽  
Vol 23 (6) ◽  
pp. 377-382 ◽  
Author(s):  
Jia Liu ◽  
Hong-Yun Huang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ventral Mesencephalic

scholarly journals The Effect of Sertoli Cells on Xenotransplantation and Allotransplantation of Ventral Mesencephalic Tissue in a Rat Model of Parkinson’s Disease

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1420
Author(s):  
Yun-Ting Jhao ◽  
Chuang-Hsin Chiu ◽  
Chien-Fu F. Chen ◽  
Ta-Kai Chou ◽  
Yi-Wen Lin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rat Model ◽  
Sertoli Cells ◽  
Dopaminergic Neurons ◽  
Sprague Dawley ◽  
Drug Induced ◽  
In Vivo Evaluation ◽  
Ventral Mesencephalic

Intra-striatal transplantation of fetal ventral mesencephalic (VM) tissue has a therapeutic effect on patients with Parkinson’s disease (PD). Sertoli cells (SCs) possess immune-modulatory properties that benefit transplantation. We hypothesized that co-graft of SCs with VM tissue can attenuate rejection. Hemi-parkinsonian rats were generated by injecting 6-hydroxydopamine into the right medial forebrain bundle of Sprague Dawley (SD) rats. The rats were then intrastriatally transplanted with VM tissue from rats or pigs (rVM or pVM), with/without a co-graft of SCs (rVM+SCs or pVM+SCs). Recovery of dopaminergic function and survival of the grafts were evaluated using the apomorphine-induced rotation test and small animal-positron emission tomography (PET) coupled with [18F] DOPA or [18F] FE-PE2I, respectively. Immunohistochemistry (IHC) examination was used to determine the survival of the grafted dopaminergic neurons in the striatum and to investigate immune-modulatory effects of SCs. The results showed that the rVM+SCs and pVM+SCs groups had significantly improved drug-induced rotational behavior compared with the VM alone groups. PET revealed a significant increase in specific uptake ratios (SURs) of [18F] DOPA and [18F] FE-PE2I in the grafted striatum of the rVM+SCs and pVM+SCs groups as compared to that of the rVM and pVM groups. SC and VM tissue co-graft led to better dopaminergic (DA) cell survival. The co-grafted groups exhibited lower populations of T-cells and activated microglia compared to the groups without SCs. Our results suggest that co-graft of SCs benefit both xeno- and allo-transplantation of VM tissue in a PD rat model. Use of SCs enhanced the survival of the grafted dopaminergic neurons and improved functional recovery. The enhancement may in part be attributable to the immune-modulatory properties of SCs. In addition, [18F]DOPA and [18F]FE-PE2I coupled with PET may provide a feasible method for in vivo evaluation of the functional integrity of the grafted DA cell in parkinsonian rats.

Long-term improvement in patients with severe Parkinson's disease after implantation of fetal ventral mesencephalic tissue in a cavity of the caudate nucleus: 5-year follow up in 10 patients

1997 ◽  
Vol 86 (6) ◽  
pp. 931-942 ◽  
Author(s):  
Juan J. López-Lozano ◽  
Gonzalo Bravo ◽  
Begoña Brera ◽  
Isabel Millán ◽  
Jose Dargallo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Caudate Nucleus ◽  
Adrenal Medulla ◽  
Open Surgery ◽  
Clinical Symptoms ◽  
Content Type ◽  
Ventral Mesencephalic ◽  
Fine Print

✓ Different groups worldwide have observed in recent years that stereotactic implantation of fetal tissue can ameliorate the clinical symptoms of Parkinson's disease. The authors therefore investigated whether implantation of fetal ventral mesencephalic (FVM) tissue via open surgery is also capable of producing an improvement and whether this improvement is transient or long lasting. The authors report their findings in a 5-year follow-up study in 10 patients with Hoehn and Yahr Grade IV or V Parkinson's disease in whom a single FVM graft was implanted in a cavity created in the right caudate nucleus. The results indicate that the implants improved motor function and that clinical recovery persisted in seven of the 10 patients 5 years after implantation. Amelioration was observed in both the on and off phases and was accompanied by a 64% reduction in the levodopa dose and withdrawal of the dopamine agonist. The on phase was prolonged from 39% of the waking day to 72%, with reduced intensity and duration of dyskinesias. All symptoms that were analyzed showed improvement, although they differed in intensity and time of onset. The course of improvement seemed to be stepwise, with significant improvement between 5 and 7 months postimplantation followed by two waves of progress peaking in Months 15 and 36. Withdrawal of cyclosporine in three patients after more than 2 years of administration produced a decline in the patients' clinical conditions. In conclusion, the results indicate that open surgery implantation of FVM tissue in the caudate nucleus improves the clinical condition of parkinsonian patients and that this improvement can persist for at least 5 years. In comparison with two earlier series reported by the authors, which involved implants of perfused adrenal medulla and coimplantation of adrenal medulla and peripheral nerve, the course and pattern of improvement in these implant recipients suggests that their recovery can be attributed to more than one factor.

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