Topographical distribution of [125I]-glial cell line-derived neurotrophic factor in unlesioned and MPTP-lesioned rhesus monkey brain following a bolus intraventricular injection

Lapchak, Paul A.; Araujo, Dalia M.; Hilt, Dana; Jiao, Shoushu; Collin, Fidéline; Miyoshi, Yasuyuki; Ai, Yi; Zhang, Z; Gash, Don M.

doi:10.1016/s0006-8993(97)01495-9

Cited by 27 publications

(23 citation statements)

References 23 publications

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“…2) their occurrence was more prevalent at later time points than at one month. While we do not have a definitive identification of these structures, it is possible that they are associated with extracellular matrix complexes (Lapchak et al, 1998;Ruoslahti, 1996;Venstrom and Reichardt, 1993).…”

Section: Discussionmentioning

confidence: 93%

AAV2-mediated gene transfer of GDNF to the striatum of MPTP monkeys enhances the survival and outgrowth of co-implanted fetal dopamine neurons

Elsworth

Redmond

Léránth

et al. 2008

Experimental Neurology

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Neural transplantation offers the potential of treating Parkinson's disease by grafting fetal dopamine neurons to depleted regions of the brain. However, clinical studies of neural grafting in Parkinson's disease have produced only modest improvements. One of the main reasons for this is the low survival rate of transplanted neurons. The inadequate supply of critical neurotrophic factors in the adult brain is likely to be a major cause of early cell death and restricted outgrowth of fetal grafts placed into the mature striatum. Glial derived neurotrophic factor (GDNF) is a potent neurotrophic factor that is crucial to the survival, outgrowth and maintenance of dopamine neurons, and so is a candidate for protecting grafted fetal dopamine neurons in the adult brain. We found that implantation of adenoassociated virus type 2 encoding GDNF (AAV2-GDNF) in the normal monkey caudate nucleus induced over-expression of GDNF that persisted for at least 6 months after injection. In a 6-month within-animal controlled study, AAV2-GDNF enhanced the survival of fetal dopamine neurons by 4-fold, and increased the outgrowth of grafted fetal dopamine neurons by almost 3-fold in the caudate nucleus of MPTP-treated monkeys, compared with control grafts in the other caudate nucleus. Thus, the addition of GDNF gene therapy to neural transplantation may be a useful strategy to improve treatment for Parkinson's disease.

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Section: Discussionmentioning

confidence: 93%

AAV2-mediated gene transfer of GDNF to the striatum of MPTP monkeys enhances the survival and outgrowth of co-implanted fetal dopamine neurons

Elsworth

Redmond

Léránth

et al. 2008

Experimental Neurology

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“…Heparin binding has been shown to limit the biodistribution of GDNF, thereby affecting its therapeutic targeting following an intracranial injection (Gash et al, 2005; Lapchak et al, 1998). Unlike mature GDNF, both DNSP-5 and DNSP-11 do not bind heparin (Figure 2), thus suggesting that the GDNF prosequence-derived peptides would have enhanced volume of distribution properties when delivered intracranially.…”

Section: Discussionmentioning

confidence: 99%

“…However, GDNF has not advanced beyond phase II clinical trials, primarily due to challenges attributed to the direct intracranial delivery of large proteins (Gash et al, 2005; Lang et al, 2006; Patel and Gill, 2007; Salvatore et al, 2006). Furthermore, GDNF binds heparin with high affinity (Lin et al, 1994; Lin et al, 1993), and likely other heparin-related molecules abundant in the brain matrix (Rickard et al, 2003; Sariola and Saarma, 2003), which hinders its predictable biodistribution following a direct injection (Gash et al, 2005; Lapchak et al, 1998; Patel and Gill, 2007; Piltonen et al, 2009; Salvatore et al, 2006). While additional delivery strategies have been examined to improve GDNF delivery and distribution in vivo , including: convection enhanced delivery (CED) (Fiandaca et al, 2008; Hamilton et al, 2001; Morrison et al, 2007); co-infusion with heparin during CED (Hamilton et al, 2001); removal of the GDNF N-terminal heparin binding domain (Piltonen et al, 2009); viral vector delivery (Kordower et al, 2000; Ramaswamy et al, 2009; Wang et al, 2002); and encapsulated GDNF-producing cells (Lindner et al, 1995; Lindvall and Wahlberg, 2008), an alternate approach to circumvent these delivery and distribution challenges would be to utilize small, neurotrophic-like functional molecules.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the physical and in vitro protective activity of three synthetic peptides derived from the pro- and mature GDNF sequence

et al. 2011

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Recently, a small 11-amino acid amidated peptide, dopamine neuron stimulating peptide-11 (DNSP-11), was shown to exert neurotrophic-like actions on primary dopaminergic neurons and in parkinsonian rat models. This suggests smaller neurotrophic molecules may be deliverable and modifiable for therapeutic use. Here we evaluate the molecular and cellular protection properties of DNSP-11 and two other amidated-peptides, a 5-mer (DNSP-5) and a 17-mer (DNSP-17), hypothesized to be endoproteolytically processed from the pro- and mature glial cell line-derived neurotrophic factor (GDNF) protein sequence, respectively. Far-UV circular dichroism spectra show that the three DNSPs are soluble and act independently in vitro. Reverse phase HPLC and mass spectrometry analysis show that the three peptides are stable for one month at a variety of storage and experimental conditions. To gain insight into the DNSPs biodistribution properties in the brain, we used affinity chromatography to show that DNSP-17 binds heparin equally as tight as GDNF, whereas DNSP-5 and DNSP-11 do not bind heparin, which should facilitate their delivery in vivo. Finally, we present data showing that DNSP-11 provides dose-dependent protection of HEK-293 cells from staurosporine and 3-nitropropionate (3-NP) cytotoxicity, thereby supporting its broad mitochondrial-protective properties.

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“…This has been recently attributed to its propargyl moiety, which is a very poor inhibitor of MAOÀA and B [34] and has been shown to possess neurorescue activity and increase GDNF and BDNF mRNA by a mechanism involving nuclear factorÀkappaB (NFÀjB) activation [18,24]. A limited availability of neurotrophic factors (GDNF, BDNF) has been suggested to contribute to the mechanism of DA neurodegeneration in PD [35] while they promote DA neurorescue in the mice and nonÀhuman MPTP models [36][37][38][39][40][41]. GDNF has failed to show a similar response in PD subjects [42], mainly because of lack of transport across blood brain barrier.…”

Section: Future Implicationsmentioning

confidence: 99%

Rasagiline Promotes Regeneration of Substantia Nigra Dopaminergic Neurons in Post-MPTP-induced Parkinsonism via Activation of Tyrosine Kinase Receptor Signaling Pathway

2007

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The anti-Parkinson drug rasagiline (Azilect), an irreversible and selective monoamine oxidase (MAO)-B inhibitor, was shown to possess neuroprotective activities, involving multiple survival pathways among them the up-regulation of protein kinase C (PKC)alpha, PKCepsilon, the anti-apoptotic Bcl-2, Bcl-xL, and Bcl-w and the induction of brain-derived- and glial cell line-derived neurotrophic factors (BDNF, GDNF). More recently, employing conventional neurochemical techniques, as well as transcriptomic and proteomic screening tools, combined with a biology-based clustering method, it was shown that rasagiline also possesses neurorescue/neurogenesis activity in mice midbrain dopaminergic neurons when given chronically, post-MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). This action was attributed to the activation of cell signaling mediators associated with neurotrophic factors responsive-tyrosine kinase receptor (Trk) pathway, including ShcC, SOS, AF6, Rin1, and Ras and the increase in the Trk-downstream effecter phosphatidylinositol 3 kinase (PI3K) protein and its substrate, Akt/PKB. It is interesting to determine whether a similar effect is seen in Parkinsonian patients after long-term treatment with rasagiline, which may have implications as a possible disease modifying agent.

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Topographical distribution of [125I]-glial cell line-derived neurotrophic factor in unlesioned and MPTP-lesioned rhesus monkey brain following a bolus intraventricular injection

Cited by 27 publications

References 23 publications

AAV2-mediated gene transfer of GDNF to the striatum of MPTP monkeys enhances the survival and outgrowth of co-implanted fetal dopamine neurons

AAV2-mediated gene transfer of GDNF to the striatum of MPTP monkeys enhances the survival and outgrowth of co-implanted fetal dopamine neurons

Evaluation of the physical and in vitro protective activity of three synthetic peptides derived from the pro- and mature GDNF sequence

Rasagiline Promotes Regeneration of Substantia Nigra Dopaminergic Neurons in Post-MPTP-induced Parkinsonism via Activation of Tyrosine Kinase Receptor Signaling Pathway

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