Short-Term GDNF Treatment Provides Long-Term Rescue of Lesioned Nigral Dopaminergic Neurons in a Rat Model of Parkinson’s Disease

Winkler, Christian; Sauer, H.; Lee, Chong S.; Björklund, Anders

doi:10.1523/jneurosci.16-22-07206.1996

Cited by 236 publications

(153 citation statements)

References 25 publications

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“…[5][6][7][8][9][10][11][12] However, when GDNF is administered with a delay after the insult, sparing of DA neurons is only marginal and the magnitude of functional recovery probably reflects the number of DA neurons still surviving and maintaining nigrostriatal connections. 10,[23][24][25] In contrast with previous studies 10,26 in which three or four deposits of 6-OHDA were injected to create more extensive striatal lesions, 6-OHDA was injected at only one site in our model and less damage might have been incurred to nigrostriatal connections. Using adenoviral vectors Kozlowski et al 22 demonstrated that delivering GDNF gene to the SN 1 week after lesioning rescued DA neurons and increased the number of DA neurons maintaining a connection to the striatum.…”

Section: Discussionmentioning

confidence: 90%

Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson's disease

et al. 2002

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Glial cell line-derived neurotrophic factor (GDNF) is a strong candidate agent in the neuroprotective treatment of Parkinson's disease (PD). We investigated whether adeno-associated viral (AAV) vector-mediated delivery of a GDNF gene in a delayed manner could prevent progressive degeneration of dopaminergic (DA) neurons, while preserving a functional nigrostriatal pathway. Four weeks after a unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA), rats received injection of AAV vectors expressing GDNF tagged with FLAG peptide (AAV-GDNFflag) or ␤-galactosidase (AAV-LacZ) into the lesioned striatum. Immunostaining for FLAG demonstrated retrograde transport of GDNFflag to the substantia nigra (SN). The density of tyrosine hydroxylase

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Section: Discussionmentioning

confidence: 90%

Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson's disease

et al. 2002

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“…Extremely promising pre-clinical [5][6][7][8] and open-label clinical trials [9][10][11] , confirming the neuroprotective role of GDNF on dopaminergic neurons, renewed enthusiasm that disease modulating approaches were within reach. Unfortunately, issues related to the delivery of GDNF undoubtedly contributed towards the failure to reach satisfactory clinical outcome measures in a double-blind placebo-controlled study where patients received intra-putamenal infusion of recombinant GDNF via implanted catheters 12, 13 .…”

Section: Text Introductionmentioning

confidence: 99%

Fibrin As a Scaffold for Delivery of GDNF Overexpressing Stem Cells to the Adult Rat Brain

Moloney

Fhlathartaigh

Kulkarni

et al. 2015

ACS Biomater. Sci. Eng.

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Treatment of neurodegenerative disease is entering a new era where direct intracerebral delivery of therapeutic factors aims to restore normality to dysfunctional circuits.Cell-based therapeutic approaches, where virally manipulated mesenchymal stem cells (MSCs) over-expressing glial cell line derived neurotrophic factor (GDNF) are utilised as vehicles to deliver neurotrophic support to the Parkinsonian brain, have shown promising pre-clinical results at preserving dopaminergic neuron integrity. However, poor cell survival following transplantation will hinder clinical progression. One approach to improve MSCs survival following transplantation is to couple the cell engraftment procedure with a scaffold thereby providing a physical substrate upon which to eventually complex pro-survival factors. Evaluation of commercially available, clinically accepted materials with an established safety profile will expedite clinical translation. Therefore, this study sought to determine if a clinically used fibrin scaffold can be utilised as an adjunct to intra-cerebral cell transplantation without evoking an adverse host or stem cell response. Sixteen male SpragueDawley rats received bilateral intra-striatal transplants of 30,000 GDNF-transduced MSCs delivered in either control transplantation medium or a fibrin scaffold. Rats were sacrificed 1, 4, 7, and 14 days post-transplantation. Brains were analysed to determine in situ polymerisation and biodegradability of the fibrin scaffold, GDNF release from transplanted GDNF-MSCs, survival of the GDNF-MSCs graft and the host's immune response to the transplant. This study found that fibrin scaffold was adaptable to intra-cerebral delivery with successful polymerisation of the fibrin scaffold in situ. Inclusion of the fibrin scaffold was not detrimental to cell survival nor did it impede neurotrophin release from entrapped cells.Importantly, the inclusion of the fibrin scaffold was associated with a reduced host astroglial and microglial response compared to cells alone indicative of a favourable biocompatibility profile. Overall, fibrin represents an adaptable scaffold for inclusion in a minimally invasive cell-based therapeutic approach for neurodegenerative diseases.TEXT Introduction:

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“…The effects of GDNF have been studied in animal models of PD. Administered into the striatum or in the substantia nigra (SN) of rats, [3][4][5] GDNF has a neuroprotective effects for DA neurons after striatal lesions. In a primate model of PD, intracerebral injection of GDNF is followed by improved motor function.…”

Section: Introductionmentioning

confidence: 99%

Does neuronal expression of GDNF effectively protect dopaminergic neurons in a rat model of Parkinson's disease?

Thi¹,

Saillour²,

Ferrero³

et al. 2006

Gene Ther

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The transfer of the Glial cell line-derived neurotrophic factor (GDNF) gene to the central nervous system by a recombinant adenoviral vector (Ad) was studied. We constructed the adenovirus vector Ad-NSE-GDNF from which the E1, E3/E4 regions of Ad5 have been deleted and in which the GDNF gene was under the control of a neuron-specific enolase (NSE) promoter. The vector was injected into the striatum of a rat model of Parkinson's disease. We found that (i) the NSE promoter can restrict transgene expression in neurons; (ii) Ad-NSE-GDNF significantly protected dopaminergic (DA) neurons in the substantia nigra (SN) but did not reverse the impairments of amphetamine-induced rotational behavior in lesioned rats.

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Short-Term GDNF Treatment Provides Long-Term Rescue of Lesioned Nigral Dopaminergic Neurons in a Rat Model of Parkinson’s Disease

Cited by 236 publications

References 25 publications

Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson's disease

Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson's disease

Fibrin As a Scaffold for Delivery of GDNF Overexpressing Stem Cells to the Adult Rat Brain

Does neuronal expression of GDNF effectively protect dopaminergic neurons in a rat model of Parkinson's disease?

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