Continuous exposure to glial cell line-derived neurotrophic factor to mature dopaminergic transplants impairs the graft’s ability to improve spontaneous motor behavior in parkinsonian rats

doi:10.1016/j.neuroscience.2006.03.068

Neuroscience

Volume 141, Issue 1, 2006, Pages 521-531

https://doi.org/10.1016/j.neuroscience.2006.03.068 Get rights and content

Abstract

Functional recovery following intrastriatal transplantation of fetal dopaminergic neurons in animal models of Parkinson’s disease is, at least in part, dependent on the number of surviving dopaminergic neurons and the degree of graft-derived dopaminergic reinnervation of the host striatum. In the present study, we analyzed whether continuous exposure of glial cell line-derived neurotrophic factor (GDNF) to mature dopaminergic grafts could further boost the functional outcome of widespread intrastriatal dopaminergic grafts. Rats with dopamine-denervating lesions received multiple intrastriatal transplants of fetal dopaminergic cells and graft-induced behavioral effects were analyzed in drug-induced and spontaneous motor behaviors. At three months after grafting, animals received intrastriatal injections of recombinant lentiviral vectors encoding for either human GDNF or the green fluorescent protein. Continuous exposure of GDNF to the grafts did not boost the functional recovery beyond what was observed in the control animals. Rather, in some of the spontaneous motor behaviors, animals in the GDNF-group showed deterioration as compared with control animals, and this negative effect of GDNF was associated with a down-regulation of the tyrosine hydroxylase enzyme. Based on these and our earlier results, we propose that intrastriatal administration of GDNF at the time of or shortly after grafting is highly effective in initially promoting the cell survival and fiber outgrowth from the grafts. However, once the grafts are mature, GDNF’s ability to boost dopaminergic neurotransmission follows the same dynamics as for the native nigral dopaminergic neurons, which appears to be dependent on the concentration of GDNF. Since rather low doses of glial cell line-derived neurotrophic factor at nanogram levels appear to saturate these effects, it may be critical to adjust GDNF levels using tightly regulated gene expression systems.

Section snippets

Experimental design

In this study we analyzed the long-term effects of recombinant lentiviral vector (rLV) -mediated overexpression of GDNF on the fiber outgrowth and function of ventral mesencephalic (VM) grafts that were transplanted into the striatum several months prior to injection of viral vectors (Fig. 1). The rats received unilateral injections of 6-hydroxydopamine (6-OHDA) into the striatum in order to induce severe DA-denervating lesions, which are restricted to the striatum and leave the limbic and

Functional effects of GDNF-encoding lentiviral vectors on intrastriatal VM grafts

In this study, we analyzed the behavioral and morphological effects of GDNF, expressed long-term in the striatum using viral vector delivery, on mature intrastriatal VM grafts. Animals received severe DA-denervating lesions restricted to the striatum, and were included in the study when they performed ≤two adjusting steps in the stepping test which is indicative of a >80% DA denervation in the striatum. Animals then received intrastriatal transplants of fetal VM cells, which were allowed to

Discussion

The present study was designed to explore the effects of GDNF on the functional impact of fetal VM grafts in a rodent PD model. For this purpose, DA-depleted rats received intrastriatal transplants of fetal DA tissue that were spread over the whole striatum. Three months after transplantation, when graft-induced functional recovery was established, animals received intrastriatal injections of rLVs encoding for GDNF or GFP. Assessment of the motor behaviors at 3 months post–vector transduction

Conclusion

In conclusion, a number of critical issues can be raised for potential use of GDNF in conjunction with fetal nigral grafts. Since immature neuroblasts appear to be highly receptive to the actions of GDNF, this growth factor is likely to have a major impact on fetal nigral grafts at the time of, or shortly after grafting (i.e. within the first weeks after grafting). The major mode of action of GDNF during these first weeks after grafting is to increase cell survival and to induce fiber

Acknowledgments

This work was supported by grants from the Swedish Research Council (K2001-99-XG-13285-02B, K2002-33X-03874-30C, K2003-33P-14788-01A). We thank to Ulla Jarl, Anneli Josefson and Bengt Mattsson for excellent technical support.

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Citation Excerpt :
First identified for its role in the survival and plasticity of embryonic midbrain DA neurons in culture (Lin et al., 1993), glial cell line-derived neurotrophic factor (GDNF) has been shown to increase the survival, plasticity, and metabolism of DA neurons in pre-clinical and clinical studies for PD (for reviews, see Björklund et al., 1997; Kirik et al., 2017; Thompson and Björklund, 2012). Recombinant GDNF protein has also been used to promote the survival of DA progenitors within fetal donor preparations prior to transplantation (Rosenblad et al., 1996), with studies in rodents and non-human primates demonstrating the benefits of prolonged delivery into the host tissue (via infusion) (Ahn et al., 2005; Johansson et al., 1995; Sinclair et al., 1996; Yurek, 1998) or injection of viral vectors) (Elsworth et al., 2008; Georgievska et al., 2004; Kauhausen et al., 2013; Redmond et al., 2009; Thompson et al., 2009; Wakeman et al., 2014; Winkler et al., 2006) for promoting survival, plasticity, and functionally appropriate integration of DA-rich fetal VM tissue grafts. Here, we have assessed the impact of long-term GDNF overexpression on hPSC-derived VM DA progenitor grafts.
Dopaminergic neurons (DAns), generated from human pluripotent stem cells (hPSCs), are capable of functionally integrating following transplantation and have recently advanced to clinical trials for Parkinson’s disease (PD). However, pre-clinical studies have highlighted the low proportion of DAns within hPSC-derived grafts and their inferior plasticity compared to fetal tissue. Here, we examined whether delivery of a developmentally critical protein, glial cell line-derived neurotrophic factor (GDNF), could improve graft outcomes. We tracked the response of DAns implanted into either a GDNF-rich environment or after a delay in exposure. Early GDNF promoted survival and plasticity of non-DAns, leading to enhanced motor recovery in PD rats. Delayed exposure to GDNF promoted functional recovery through increases in DAn specification, DAn plasticity, and DA metabolism. Transcriptional profiling revealed a role for mitogen-activated protein kinase (MAPK)-signaling downstream of GDNF. Collectively, these results demonstrate the potential of neurotrophic gene therapy strategies to improve hPSC graft outcomes.
GDNF-induced cerebellar toxicity: A brief review
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For example, GFRα-1 and GFRα-2 are progressively down-regulated in postnatal spinal motoneurons (Zhang and Huang, 2006), and exposure to toxins such as MPTP and rotenone effects a robust down-regulation of c-RET in neurons (Hirata and Kiuchi, 2007). Also, there are a number of studies reporting that chronic long-term over-expression of GDNF has adverse effects on both intact and Parkinsonian nigrostriatal neurons (Georgievska et al., 2004a,b; Winkler et al., 2006). A potential explanation for the latter findings is a direct negative feedback mechanism involving GDNF receptors.
Recombinant-methionyl human glial cell line-derived neurotrophic factor (GDNF) is known for its neurorestorative and neuroprotective effects in rodent and primate models of Parkinson's disease (PD). When administered locally into the putamen of Parkinsonian subjects, early clinical studies showed its potential promise as a disease-modifying agent. However, the development of GDNF for the treatment of PD has been significantly clouded by findings of cerebellar toxicity after continuous intraputamenal high-dose administration in a 6-month treatment/3-month recovery toxicology study in rhesus monkeys. Specifically, multifocal cerebellar Purkinje cell loss affecting 1–21% of the cerebellar cortex was observed in 4 of 15 (26.7%; 95% confidence interval [CI]: 10.5–52.4%) animals treated at the highest dose level tested (3000 μg/month). No cerebellar toxicity was observed at lower doses (450 and 900 μg/month) in the same study, or at similar or higher doses (up to 10,000 μg/month) in subchronic or chronic toxicology studies testing intermittent intracerebroventricular administration. While seemingly associated with the use of GDNF, the pathogenesis of the cerebellar lesions has not been fully understood to date. This review integrates available information to evaluate potential pathogenic mechanisms and provide a consolidated assessment of the findings. While other explanations are considered, the existing evidence is most consistent with the hypothesis that leakage of GDNF into cerebrospinal fluid during chronic infusions into the putamen down-regulates GDNF receptors on Purkinje cells, and that subsequent acute withdrawal of GDNF generates the observed lesions. The implications of these findings for clinical studies with GDNF are discussed.
Interrogating the aged striatum: Robust survival of grafted dopamine neurons in aging rats produces inferior behavioral recovery and evidence of impaired integration
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The rationale for choosing this population of patients is valid in that these individuals represent the population most in need of alternative therapeutics; nevertheless, the impact of factors associated with the environment of the severely DA-depleted, aged striatum on the overall success of previous cell transplantation trials in PD remains incompletely understood. There have been painstaking efforts both in the clinic and the laboratory to characterize optimal donor cells used for cell transplantation therapy in PD, addressing issues including the source material for grafted cells, donor cell age, density of cell grafts, immune factors, and growth factors (e.g.: Steece-Collier et al., 1990; Annett et al., 1997; Freeman et al., 1995; Sladek et al., 1998; Collier et al., 1999; Freed et al., 2001; Winkler et al., 2006; Torres et al., 2007; Matarredona et al., 2003; Terpstra et al., 2007; Soderstrom et al., 2008; Bjorklund and Kordower, 2013). However, comparatively little has been done to determine the impact of the host environment on transplant success, with most of the attention given to defining the optimal transplant location (Strömberg et al., 1986; Goren et al., 2005; Breysse et al., 2007).
Advanced age is the primary risk factor for Parkinson's disease (PD). In PD patients and rodent models of PD, advanced age is associated with inferior symptomatic benefit following intrastriatal grafting of embryonic dopamine (DA) neurons, a pattern believed to result from decreased survival and reinnervation provided by grafted neurons in the aged host. To help understand the capacity of the aged, parkinsonian striatum to be remodeled with new DA terminals, we used a grafting model and examined whether increasing the number of grafted DA neurons in aged rats would translate to enhanced behavioral recovery. Young (3 months), middle-aged (15 months), and aged (22 months) parkinsonian rats were grafted with proportionately increasing numbers of embryonic ventral mesencephalic (VM) cells to evaluate whether the limitations of the graft environment in subjects of advancing age can be offset by increased numbers of transplanted neurons. Despite robust survival of grafted neurons in aged rats, reinnervation of striatal neurons remained inferior and amelioration of levodopa-induced dyskinesias (LID) was delayed or absent. This study demonstrates that: 1) counter to previous evidence, under certain conditions the aged striatum can support robust survival of grafted DA neurons; and 2) unknown factors associated with the aged striatum result in inferior integration of graft and host, and continue to present obstacles to full therapeutic efficacy of DA cell-based therapy in this model of aging.
Intrastriatal GDNF gene transfer by inducible lentivirus vectors protects dopaminergic neurons in a rat model of parkinsonism
2014, Experimental Neurology
Citation Excerpt :
Although lentivirus-mediated GDNF gene transfer into the brain of animal models of parkinsonism protects DA neurons from neurotoxin-induced cell death (Brizard et al., 2006; Georgievska et al., 2002a; Kordower et al., 2000), long-term overexpression of GDNF gene has been found to be associated with side effects including aberrant sprouting in the areas outside the striatum and down-regulation of tyrosine hydroxylase (TH) in the preserved DA terminals and intact striatum (Georgievska et al., 2002a, 2004b; Rosenblad et al., 2003). Furthermore, Winkler et al. reported that continuous exposure to GDNF impaired the ability of mature nigral transplants to improve spontaneous motor behavior in a rat model of parkinsonism (Winkler et al., 2006). It is therefore required to develop an inducible virus-mediated delivery system to regulate GDNF gene expression avoiding its related side effects.
Glial cell line-derived neurotrophic factor (GDNF) has neuroprotective effects on dopaminergic (DA) neurons both in vivo and in vitro. However, substantial evidence has shown that a long-term overexpression of GDNF gene is often associated with side effects. We previously improved tetracycline (Tet)-On lentivirus system carrying human GDNF (hGDNF) gene, and demonstrated that hGDNF gene expression was tightly regulated and functional in vitro. Here we further examined the efficiency and neuroprotection of Tet-On lentivirus-mediated hGDNF gene regulation in neural progenitor cells (NPCs) and a rat model of parkinsonism. The results showed that hGDNF gene expression was tightly regulated in transduced NPCs. Doxycycline (Dox)-induced hGDNF protected DA neurons from 6-hydroxydopamine (6-OHDA)-induced toxicity in vitro. Intrastriatal injections of Tet-On lentivirus vectors resulted in dramatically increased levels of hGDNF protein in the striatum of rats with Dox-drinking water, when compared to lentivirus-injected and saline-injected rats with normal drinking water, respectively. In addition, hGDNF protected nigral DA neurons and striatal DA fibers, and attenuated d-amphetamine-induced rotational asymmetry in the 6-OHDA lesioned rats. To the best of our knowledge, this is the first report that hGDNF gene transfer by Tet-On lentivirus vectors is tightly regulated in rat brain, and Dox-induced hGDNF is functional in neuroprotection of nigral DA neurons in a rat model of parkinsonism.
Impact of dopamine to serotonin cell ratio in transplants on behavioral recovery and L-DOPA-induced dyskinesia
2011, Neurobiology of Disease
Fetal dopamine (DA) cell transplantation has shown to be efficient in reversing behavioral impairments associated with Parkinson's disease. However, the beneficial effects on motor behavior and L-DOPA-induced dyskinesia have varied greatly in between clinical trials and patients within the same trial. Recently, the inclusion of serotonin (5-HT) neurons in the grafted tissue has been suggested to play an important negative role, in particular, on the effect of L-DOPA-induced dyskinesia. In the present study we have evaluated the influence of different ratios of DA neurons in relation to 5-HT neurons in the graft on spontaneous motor behavior and L-DOPA-induced dyskinesia in a rat model of Parkinson's disease. We show that using the standard dissection method that gives rise to a DA:5-HT ratio in the graft of 2:1 to 1:2 there is significant and consistent improvement in spontaneous motor behavior and reversal of L-DOPA-induced dyskinesia. Increasing the ratio of 5-HT neurons in the graft, to a DA:5-HT ratio of in between 1:3 and 1:10, still induces significant reduction of L-DOPA-induced dyskinesia, suggesting that the detrimental effect of 5-HT neurons on L-DOPA-induced dyskinesia is prevented even by small numbers of DA neurons in the graft. Nonetheless, while the post-synaptic responses were normalized following peripheral L-DOPA delivery in animals with low DA:5-HT ratio, we observed a pharmacological indication of hyperactive pre-synaptic response in these animals. These data suggests that 5-HT cells within a graft are neither detrimental nor beneficial for functional effects of DA-rich transplants; however, in absence of sufficient numbers of DA neurons, the 5-HT neurons may induce negative effects following L-DOPA therapy. In summary, our data indicate that for future clinical trials the inclusion of 5-HT neurons in grafted tissue is not critical as long as there are sufficient numbers of DA cells in the graft.
Zuckerkandl's organ improves long-term survival and function of neural stem cell derived dopaminergic neurons in Parkinsonian rats
2008, Experimental Neurology
Transplantation of neural stem cells (NSC) derived dopamine (DA) neurons has emerged as an alternative approach to fetal neural cell transplantation in Parkinson's disease (PD). However, similar to fetal neural cell, survival of these neurons following transplantation is also limited due to limited striatal reinnervation (graft with dense neuronal core), limited host–graft interaction, poor axonal outgrowth, lack of continuous neurotrophic factors supply and principally an absence of cell adhesion molecules mediated appropriate developmental cues. In the present study, an attempt has been made to increase survival and function of NSC derived DA neurons, by co-grafting with Zuckerkandl's organ (a paraneural organ that expresses neurotrophic factors as well as cell adhesion molecules); to provide continuous NTF support and developmental cues to transplanted DA neurons in the rat model of PD. 24 weeks post transplantation, a significant number of surviving functional NSC derived DA neurons were observed in the co-transplanted group as evident by an increase in the number of tyrosine hydroxylase immunoreactive (TH-IR) neurons, TH-IR fiber density, TH-mRNA expression and TH-protein level at the transplantation site (striatum). Significant behavioral recovery (amphetamine induced stereotypy and locomotor activity) and neurochemical recovery (DA-D2 receptor binding and DA and DOPAC levels at the transplant site) were also observed in the NSC + ZKO co-transplanted group as compared to the NSC or ZKO alone transplanted group. In vivo results were further substantiated by in vitro studies, which suggest that ZKO increases the NSC derived DA neuronal survival, differentiation, DA release and neurite outgrowth as well as protects against 6-OHDA toxicity in co-culture condition. The present study suggests that long-term and continuous NTF support provided by ZKO to the transplanted NSC derived DA neurons, helped in their better survival, axonal arborization and integration with host cells, leading to long-term functional restoration in the rat model of PD.

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Systems neuroscienceContinuous exposure to glial cell line-derived neurotrophic factor to mature dopaminergic transplants impairs the graft’s ability to improve spontaneous motor behavior in parkinsonian rats

Abstract

Section snippets

Experimental design

Functional effects of GDNF-encoding lentiviral vectors on intrastriatal VM grafts

Discussion

Conclusion

Acknowledgments

Brain Res Bull

Int J Dev Neurosci

Neurobiol Dis

Dev Brain Res

Exp Neurol

Brain Res Dev Brain Res

Brain Res

Exp Neurol

Prog Neurobiol

Exp Neurol

Neurobiol Dis

Exp Neurol

Prog Brain Res

Neurobiol Aging

J Neurosci Methods

Neuroscience

Exp Neurol

Exp Neurol

Exp Neurol

Brain Res

Exp Neurol

Prog Brain Res

Trends Neurosci

Brain Res Brain Res Rev

Mesencephalic dopaminergic neurons protected by GDNF from axotomy-induced degeneration in the adult brain

Nature

Intrastriatal injection of an adenoviral vector expressing glial-cell- line-derived neurotrophic factor prevents dopaminergic neuron degeneration and behavioral impairment in a rat model of Parkinson disease

Proc Natl Acad Sci U S A

Intracerebral grafting of neuronal cell suspensions. II. Survival and growth of nigral cell suspensions implanted in different brain sites

Acta Physiol Scand Suppl

Dopaminergic neurons protected from degeneration by GDNF gene therapy

Science

Transplantation in Parkinson’s diseasePET changes correlate with the amount of grafted tissue

Mov Disord

Effect of prior dopamine denervation on survival and fiber outgrowth from intrastriatal fetal mesencephalic grafts

Eur J Neurosci

Continuous low-level glial cell line-derived neurotrophic factor delivery using recombinant adeno-associated viral vectors provides neuroprotection and induces behavioral recovery in a primate model of Parkinson’s disease

J Neurosci

Neuroprotection in the rat Parkinson model by intrastriatal GDNF gene transfer using a lentiviral vector

Neuroreport

Dissociation between short-term increased graft survival and long-term functional improvements in Parkinsonian rats overexpressing glial cell line-derived neurotrophic factor

Eur J Neurosci

Overexpression of glial cell line-derived neurotrophic factor using a lentiviral vector induces time- and dose-dependent downregulation of tyrosine hydroxylase in the intact nigrostriatal dopamine system

J Neurosci

Chronic, controlled GDNF infusion promotes structural and functional recovery in advanced parkinsonian monkeys

Brain

Systems neuroscience
Continuous exposure to glial cell line-derived neurotrophic factor to mature dopaminergic transplants impairs the graft’s ability to improve spontaneous motor behavior in parkinsonian rats