Neurotrophic and neuroprotective efficacy of intranasal GDNF in a rat model of Parkinson’s disease

Migliore, Mattia M.; Ortiz, Robin; Dye, S.; Campbell, R. B.; Amiji, Mansoor M.; Waszczak, Barbara L.

doi:10.1016/j.neuroscience.2014.05.019

Cited by 97 publications

(54 citation statements)

References 55 publications

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“…Activation of the receptor complex in neurons can lead to modification of various signaling events, including p38 MAPK, ERK, protein kinase B (AKT), and PKA (2,22,54). GDNF has been intensively studied as a potential therapeutic agent for neurodegenerative diseases, such as Parkinson's disease (37,55,64,66). In models of neurodegenerative diseases GDNF has positive effects on proliferation of neurons and is necessary for the maintenance of neuronal morphology (7).…”

Section: Gdnf Directly Promotes Barrier Maturation and Proliferation mentioning

confidence: 99%

The glial cell-line derived neurotrophic factor: a novel regulator of intestinal barrier function in health and disease

Meir

Flemming

Burkard

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Regulation of the intestinal epithelial barrier is a differentiated process, which is profoundly deranged in inflammatory bowel diseases. Recent data provide evidence that the glial cell line-derived neurotrophic factor (GDNF) is critically involved in intestinal epithelial wound healing and barrier maturation and exerts antiapoptotic effects under certain conditions. Furthermore, not only the enteric nervous system, but also enterocytes synthesize GDNF in significant amounts, which points to a potential para- or autocrine signaling loop between enterocytes. Apart from direct effects of GDNF on enterocytes, an immunomodulatory role of this protein has been previously assumed because of a significant reduction of inflammation in a model of chronic inflammatory bowel disease after application of GDNF. In this review we summarize the current knowledge of GDNF on intestinal epithelial barrier regulation and discuss the novel role for GDNF as a regulator of intestinal barrier functions in health and disease.

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Section: Gdnf Directly Promotes Barrier Maturation and Proliferation mentioning

confidence: 99%

The glial cell-line derived neurotrophic factor: a novel regulator of intestinal barrier function in health and disease

Meir

Flemming

Burkard

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…This distribution is also consistent with that achieved for intranasally administered radiolabeled IGF1 in rats 74 , peptoid in rats 89 , and B--interferon in cynomolgus monkeys 80 . Additionally, Migliore et al (2014) showed that a single 50 μg dose of GDNF administered intranasally one hour before a unilateral 6--OHDA lesion had a significant neuroprotective effect, as evidenced by a significant increase in tyrosine hydroxylase staining density and dopamine cell counts in the lesioned SN compared to the intact SN 3--4 weeks post--lesion. This effect was somewhat more pronounced with the GDNF liposome preparation than the same GDNF dose in PBS, suggesting that an optimized nanoparticle formulation may improve delivery by the nasal route.…”

Section: Glial Cell Line--derived Neurotrophic Factormentioning

confidence: 98%

“…The most promising and widely cited examples of therapeutic biomolecules shown to reach the brain after intranasal administration have been summarized in our review article 100 and are listed on the right side in the Venn diagram ( Figure 7) and recapitulated below. However, except for GDNF 101 , bFGF 92 , and insulin 102 , none have been tested by the intranasal route in a Parkinson's disease model. …”

Section: Evidence Of Nose--to--brain Transport Of Macromolecules and mentioning

confidence: 99%

“…When three 50 μg doses were given at daily intervals (1 day before, 1 hour before, and one day after 6--OHDA lesioning), the neuroprotective effect of both formulations was greater than with single 50 μg doses (Figure 10). Our lab was the first to demonstrate that intranasal administration of GDNF protein is neuroprotective in a PD model 101 . While this report revealed the potential of intranasal GDNF protein as a neuroprotective strategy for PD, repeated dosing would likely be necessary to maintain GDNF levels in the target brain areas sufficient to arrest disease progression.…”

Section: Glial Cell Line--derived Neurotrophic Factormentioning

confidence: 99%

“…Although many of these agents do reach the brain after intranasal administration (Table 3), none were evaluated by this route in a model of PD, with the exception of insulin 102 , FGF 92 , GDNF 101 and pGDNF_1b NPs 100,160,164 . In addition to those listed in Table 3 …”

Section: Macromolecules With Disease--modifying Potential For Parkinsmentioning

confidence: 99%

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intranasal GDNF gene therapy approach for treating Parkinson's disease

Aly¹

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Abstract:Parkinson's disease (PD) is a progressive neurodegenerative disorder that results from the loss of the A9 nigrostriatal dopamine neurons. The current therapies available for treating PD provide symptomatic relief by replacing or mimicking dopamine in the brain, but do not actually prevent or reverse the loss of these dopaminergic neurons. Glial cell--line derived neurotrophic factor (GDNF) has disease--modifying potential in PD due to its ability to promote the survival of dopamine neurons both in vitro and in vivo. GDNF has been shown to be neuroprotective in several animal models of PD. However, its clinical potential has been limited thus far by its inability to cross the blood--brain barrier (BBB) and the need for invasive intracranial delivery. The main objective of this thesis was to develop an approach to non--invasively deliver a continuous source of GDNF to the brain at levels that are neuroprotective inParkinson's Disease, whilst minimizing systemic exposure. To do so, this project investigated the intranasal delivery of non--viral hGDNF expression plasmids (pGDNF_1b and pUGG) compacted into nanoparticles (NPs). Intranasal delivery allows large therapeutics to circumvent the BBB while avoiding peripheral exposure, while a gene therapy approach would provide a long--term renewable source of GDNF in the brain regions associated with PD. These NPs, developed by Copernicus Therapeutics, Inc., are composed of 10 kDa polyethylene glycol--substituted lysine 30--mers (CK30PEG10k) which unimolecularly compact the plasmid DNA into neutrally charged NPs.The first goal of this project was to determine if intranasal administration of pGDNF_1b DNA NPs produces a neuroprotective and neurotrophic effect on rat substantia nigra (SN)

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Cell and Tissue Instructive Materials for Central Nervous System Repair

Rocha

Silva

Barata‐Antunes

et al. 2020

Adv Funct Materials

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Neurodegenerative disorders and traumatic events affecting the central nervous system (CNS) represent one of the main health problems nowadays. The level of disability and impairment of these patients is very high, both at physiological and psychological level, drastically altering a person's lifestyle. The fact that CNS tissue has a limited capacity of regeneration has hampered the development of possible therapies to these conditions. The specificity of each disease also increases the complexity of creating strategies capable of inducing significant recovery. Therefore, the search for a solution for these problems most likely demands a combinatorial approach that integrates knowledge from different fields. Tissue engineering and regenerative medicine (TERM) concepts merge areas such as biology, chemistry, physics, or biomaterials science, and it is a strong candidate for CNS applications. In particular, the development of cell and tissue instructive materials (CTIMs) can bring new opportunities for the treatment of these conditions. In this review, the authors summarize and discuss the most recent advances in the development of CTIMs for CNS applications, focusing on traumatic conditions such as spinal cord injuy, traumatic brain injuy, but also stroke, and other neurodegenerative diseases such as Alzheimer's and Parkinson's disease as well as multiple sclerosis.

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Neurotrophic and neuroprotective efficacy of intranasal GDNF in a rat model of Parkinson’s disease

Cited by 97 publications

References 55 publications

The glial cell-line derived neurotrophic factor: a novel regulator of intestinal barrier function in health and disease

The glial cell-line derived neurotrophic factor: a novel regulator of intestinal barrier function in health and disease

intranasal GDNF gene therapy approach for treating Parkinson's disease

Cell and Tissue Instructive Materials for Central Nervous System Repair

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