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Increased antiparkinson efficacy of the combined administration of VEGF- and GDNF-loaded nanospheres in a partial lesion model of Parkinson's disease.

Herrán E, Requejo C, Ruiz-Ortega JA, Aristieta A, Igartua M, Bengoetxea H, Ugedo L, Pedraz JL, Lafuente JV, Hernández RM - Int J Nanomedicine (2014)

Bottom Line: The NS particle size was about 200 nm and the simultaneous addition of VEGF NS and GDNF NS resulted in significant protection of the PC-12 cell line against 6-OHDA in vitro.The results showed that VEGF NS and GDNF NS significantly decreased the number of amphetamine-induced rotations at the end of the study.In addition, tyrosine hydroxylase immunohistochemical analysis in the striatum and the external substantia nigra confirmed a significant enhancement of neurons in the VEGF NS and GDNF NS treatment group.

View Article: PubMed Central - PubMed

Affiliation: NanoBioCel Group, Laboratory of Pharmaceutics, University of the Basque Country (UPV/EHU), School of Pharmacy, Vitoria, Spain ; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria, Spain.

ABSTRACT
Current research efforts are focused on the application of growth factors, such as glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF), as neuroregenerative approaches that will prevent the neurodegenerative process in Parkinson's disease. Continuing a previous work published by our research group, and with the aim to overcome different limitations related to growth factor administration, VEGF and GDNF were encapsulated in poly(lactic-co-glycolic acid) nanospheres (NS). This strategy facilitates the combined administration of the VEGF and GDNF into the brain of 6-hydroxydopamine (6-OHDA) partially lesioned rats, resulting in a continuous and simultaneous drug release. The NS particle size was about 200 nm and the simultaneous addition of VEGF NS and GDNF NS resulted in significant protection of the PC-12 cell line against 6-OHDA in vitro. Once the poly(lactic-co-glycolic acid) NS were implanted into the striatum of 6-OHDA partially lesioned rats, the amphetamine rotation behavior test was carried out over 10 weeks, in order to check for in vivo efficacy. The results showed that VEGF NS and GDNF NS significantly decreased the number of amphetamine-induced rotations at the end of the study. In addition, tyrosine hydroxylase immunohistochemical analysis in the striatum and the external substantia nigra confirmed a significant enhancement of neurons in the VEGF NS and GDNF NS treatment group. The synergistic effect of VEGF NS and GDNF NS allows for a reduction of the dose by half, and may be a valuable neurogenerative/neuroreparative approach for treating Parkinson's disease.

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Related in: MedlinePlus

Histological evaluation of the treatments in the SN.Notes: (A) Schematic illustration of the SN with the “external SN” delimited. This area is topologically related to the lesioned area of striatum and includes SNL, a part of the SNR, and half of the SNC. (B) Picture of whole SN and delimited “external SN”. Scale bar =1 mm. (C) Density of dopaminergic neurons in “external SN”. The results are expressed as a percentage of lesioned hemisphere compared to the non-lesioned one (control). Data are shown as the mean ± standard error of the mean (n=6–8) (#P<0.05 GDNF NS group versus sham group; ***P<0.001 VEGF NS and GDNF NS group versus sham and empty NS groups). (D) Photomicrographs of SN immunostained for tyrosine hydroxylase from a representative intact hemisphere (control) and 6-OHDA lesioned hemispheres from the different experimental groups. Scale bar =1 mm.Abbreviations: 6-OHDA, 6-hydroxydopamine; GDNF, glial cell line-derived neurotrophic factor; NS, nanospheres; SN, substantia nigra; SNC, SN pars compacta; SNL, SN lateral; SNR, SN pars reticulata; SNE, SN externa; VEGF, vascular endothelial growth factor.
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f6-ijn-9-2677: Histological evaluation of the treatments in the SN.Notes: (A) Schematic illustration of the SN with the “external SN” delimited. This area is topologically related to the lesioned area of striatum and includes SNL, a part of the SNR, and half of the SNC. (B) Picture of whole SN and delimited “external SN”. Scale bar =1 mm. (C) Density of dopaminergic neurons in “external SN”. The results are expressed as a percentage of lesioned hemisphere compared to the non-lesioned one (control). Data are shown as the mean ± standard error of the mean (n=6–8) (#P<0.05 GDNF NS group versus sham group; ***P<0.001 VEGF NS and GDNF NS group versus sham and empty NS groups). (D) Photomicrographs of SN immunostained for tyrosine hydroxylase from a representative intact hemisphere (control) and 6-OHDA lesioned hemispheres from the different experimental groups. Scale bar =1 mm.Abbreviations: 6-OHDA, 6-hydroxydopamine; GDNF, glial cell line-derived neurotrophic factor; NS, nanospheres; SN, substantia nigra; SNC, SN pars compacta; SNL, SN lateral; SNR, SN pars reticulata; SNE, SN externa; VEGF, vascular endothelial growth factor.

Mentions: Further evidence of this improvement was found when neuron density of the SN was analyzed. Stereological study showed changes in whole SN neuron density, demonstrating that VEGF NS and GDNF NS increased the density of dopaminergic neurons in a satisfactory way. Moreover, these changes were significantly higher among groups when the “external SN” was considered (Figure 6A and B). The results obtained from the analysis of this specific area showed a considerable increase in neuron density in the VEGF NS and GDNF NS-treated group, the neuronal density being 43% of that of the contralateral side, compared to only 11% in the sham cases (P<0.001 with respect to sham and empty NS groups, one-way ANOVA [Figure 6C]). This improvement can be clearly observed in the serial pictures of Figure 6D.


Increased antiparkinson efficacy of the combined administration of VEGF- and GDNF-loaded nanospheres in a partial lesion model of Parkinson's disease.

Herrán E, Requejo C, Ruiz-Ortega JA, Aristieta A, Igartua M, Bengoetxea H, Ugedo L, Pedraz JL, Lafuente JV, Hernández RM - Int J Nanomedicine (2014)

Histological evaluation of the treatments in the SN.Notes: (A) Schematic illustration of the SN with the “external SN” delimited. This area is topologically related to the lesioned area of striatum and includes SNL, a part of the SNR, and half of the SNC. (B) Picture of whole SN and delimited “external SN”. Scale bar =1 mm. (C) Density of dopaminergic neurons in “external SN”. The results are expressed as a percentage of lesioned hemisphere compared to the non-lesioned one (control). Data are shown as the mean ± standard error of the mean (n=6–8) (#P<0.05 GDNF NS group versus sham group; ***P<0.001 VEGF NS and GDNF NS group versus sham and empty NS groups). (D) Photomicrographs of SN immunostained for tyrosine hydroxylase from a representative intact hemisphere (control) and 6-OHDA lesioned hemispheres from the different experimental groups. Scale bar =1 mm.Abbreviations: 6-OHDA, 6-hydroxydopamine; GDNF, glial cell line-derived neurotrophic factor; NS, nanospheres; SN, substantia nigra; SNC, SN pars compacta; SNL, SN lateral; SNR, SN pars reticulata; SNE, SN externa; VEGF, vascular endothelial growth factor.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4043720&req=5

f6-ijn-9-2677: Histological evaluation of the treatments in the SN.Notes: (A) Schematic illustration of the SN with the “external SN” delimited. This area is topologically related to the lesioned area of striatum and includes SNL, a part of the SNR, and half of the SNC. (B) Picture of whole SN and delimited “external SN”. Scale bar =1 mm. (C) Density of dopaminergic neurons in “external SN”. The results are expressed as a percentage of lesioned hemisphere compared to the non-lesioned one (control). Data are shown as the mean ± standard error of the mean (n=6–8) (#P<0.05 GDNF NS group versus sham group; ***P<0.001 VEGF NS and GDNF NS group versus sham and empty NS groups). (D) Photomicrographs of SN immunostained for tyrosine hydroxylase from a representative intact hemisphere (control) and 6-OHDA lesioned hemispheres from the different experimental groups. Scale bar =1 mm.Abbreviations: 6-OHDA, 6-hydroxydopamine; GDNF, glial cell line-derived neurotrophic factor; NS, nanospheres; SN, substantia nigra; SNC, SN pars compacta; SNL, SN lateral; SNR, SN pars reticulata; SNE, SN externa; VEGF, vascular endothelial growth factor.
Mentions: Further evidence of this improvement was found when neuron density of the SN was analyzed. Stereological study showed changes in whole SN neuron density, demonstrating that VEGF NS and GDNF NS increased the density of dopaminergic neurons in a satisfactory way. Moreover, these changes were significantly higher among groups when the “external SN” was considered (Figure 6A and B). The results obtained from the analysis of this specific area showed a considerable increase in neuron density in the VEGF NS and GDNF NS-treated group, the neuronal density being 43% of that of the contralateral side, compared to only 11% in the sham cases (P<0.001 with respect to sham and empty NS groups, one-way ANOVA [Figure 6C]). This improvement can be clearly observed in the serial pictures of Figure 6D.

Bottom Line: The NS particle size was about 200 nm and the simultaneous addition of VEGF NS and GDNF NS resulted in significant protection of the PC-12 cell line against 6-OHDA in vitro.The results showed that VEGF NS and GDNF NS significantly decreased the number of amphetamine-induced rotations at the end of the study.In addition, tyrosine hydroxylase immunohistochemical analysis in the striatum and the external substantia nigra confirmed a significant enhancement of neurons in the VEGF NS and GDNF NS treatment group.

View Article: PubMed Central - PubMed

Affiliation: NanoBioCel Group, Laboratory of Pharmaceutics, University of the Basque Country (UPV/EHU), School of Pharmacy, Vitoria, Spain ; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria, Spain.

ABSTRACT
Current research efforts are focused on the application of growth factors, such as glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF), as neuroregenerative approaches that will prevent the neurodegenerative process in Parkinson's disease. Continuing a previous work published by our research group, and with the aim to overcome different limitations related to growth factor administration, VEGF and GDNF were encapsulated in poly(lactic-co-glycolic acid) nanospheres (NS). This strategy facilitates the combined administration of the VEGF and GDNF into the brain of 6-hydroxydopamine (6-OHDA) partially lesioned rats, resulting in a continuous and simultaneous drug release. The NS particle size was about 200 nm and the simultaneous addition of VEGF NS and GDNF NS resulted in significant protection of the PC-12 cell line against 6-OHDA in vitro. Once the poly(lactic-co-glycolic acid) NS were implanted into the striatum of 6-OHDA partially lesioned rats, the amphetamine rotation behavior test was carried out over 10 weeks, in order to check for in vivo efficacy. The results showed that VEGF NS and GDNF NS significantly decreased the number of amphetamine-induced rotations at the end of the study. In addition, tyrosine hydroxylase immunohistochemical analysis in the striatum and the external substantia nigra confirmed a significant enhancement of neurons in the VEGF NS and GDNF NS treatment group. The synergistic effect of VEGF NS and GDNF NS allows for a reduction of the dose by half, and may be a valuable neurogenerative/neuroreparative approach for treating Parkinson's disease.

Show MeSH
Related in: MedlinePlus