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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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Behavioral study: amphetamine and apomorphine rotational tests.Notes: (A) The results obtained from the amphetamine rotational behavior test after NS administration. GDNF NS group versus sham group show statistically significant differences (*P<0.05). The VEGF NS and GDNF NS group versus sham and empty NS groups showed statistically significant differences (***P<0.001). (B) Data obtained from the apomorphine rotational behavior test 14 weeks after NS implantation. The VEGF NS and GDNF NS-treated group exhibited the best behavioral recovery (*P<0.05, VEGF NS and GDNF NS versus empty NS; **P<0.01, VEGF NS and GDNF NS versus sham). The data are shown as the mean ± standard deviation (n=6–8).Abbreviations: GDNF, glial cell line-derived neurotrophic factor; NS, nanospheres; VEGF, vascular endothelial growth factor.
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f4-ijn-9-2677: Behavioral study: amphetamine and apomorphine rotational tests.Notes: (A) The results obtained from the amphetamine rotational behavior test after NS administration. GDNF NS group versus sham group show statistically significant differences (*P<0.05). The VEGF NS and GDNF NS group versus sham and empty NS groups showed statistically significant differences (***P<0.001). (B) Data obtained from the apomorphine rotational behavior test 14 weeks after NS implantation. The VEGF NS and GDNF NS-treated group exhibited the best behavioral recovery (*P<0.05, VEGF NS and GDNF NS versus empty NS; **P<0.01, VEGF NS and GDNF NS versus sham). The data are shown as the mean ± standard deviation (n=6–8).Abbreviations: GDNF, glial cell line-derived neurotrophic factor; NS, nanospheres; VEGF, vascular endothelial growth factor.

Mentions: In the amphetamine-induced behavioral experiments, no differences were found in the initial number of rotations between groups, as shown in Figure 4A. After a unilateral 6-OHDA lesion, the animals receiving only the vehicle administration did not show significant recovery of the rotational behavior at any time (sham: 10.15±2.19 ipsilateral turns/minute at 0 weeks to 11.57±2.49 turns/minute at 10 weeks). Rats receiving empty NS, VEGF NS, and GDNF NS treatments showed a slight reduction in rotations at the end of the study (week 10). GDNF NS implantation, in particular, showed a statistical reduction in the number of rotations when compared with sham group (empty NS: 9.71±2.92 turns/minute; VEGF NS: 6.37±2.11 turns/minute; GDNF NS: 4.43±2.75 turns/minute; P<0.05 GDNF NS with respect to sham group, Student’s t-test). In addition, we observed that striatal implantation of the combined VEGF NS and GDNF NS treatment at half the dose of the factors administered individually achieved the best behavioral results and significantly reduced the number of rotations (VEGF NS and GDNF NS: 0.87±0.53 turns/minute) when compared to the empty NS and sham groups (P<0.001 with respect to empty NS and sham groups, Student’s t-test [Figure 4A]).


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)

Behavioral study: amphetamine and apomorphine rotational tests.Notes: (A) The results obtained from the amphetamine rotational behavior test after NS administration. GDNF NS group versus sham group show statistically significant differences (*P<0.05). The VEGF NS and GDNF NS group versus sham and empty NS groups showed statistically significant differences (***P<0.001). (B) Data obtained from the apomorphine rotational behavior test 14 weeks after NS implantation. The VEGF NS and GDNF NS-treated group exhibited the best behavioral recovery (*P<0.05, VEGF NS and GDNF NS versus empty NS; **P<0.01, VEGF NS and GDNF NS versus sham). The data are shown as the mean ± standard deviation (n=6–8).Abbreviations: GDNF, glial cell line-derived neurotrophic factor; NS, nanospheres; VEGF, vascular endothelial growth factor.
© Copyright Policy
Related In: Results  -  Collection

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

f4-ijn-9-2677: Behavioral study: amphetamine and apomorphine rotational tests.Notes: (A) The results obtained from the amphetamine rotational behavior test after NS administration. GDNF NS group versus sham group show statistically significant differences (*P<0.05). The VEGF NS and GDNF NS group versus sham and empty NS groups showed statistically significant differences (***P<0.001). (B) Data obtained from the apomorphine rotational behavior test 14 weeks after NS implantation. The VEGF NS and GDNF NS-treated group exhibited the best behavioral recovery (*P<0.05, VEGF NS and GDNF NS versus empty NS; **P<0.01, VEGF NS and GDNF NS versus sham). The data are shown as the mean ± standard deviation (n=6–8).Abbreviations: GDNF, glial cell line-derived neurotrophic factor; NS, nanospheres; VEGF, vascular endothelial growth factor.
Mentions: In the amphetamine-induced behavioral experiments, no differences were found in the initial number of rotations between groups, as shown in Figure 4A. After a unilateral 6-OHDA lesion, the animals receiving only the vehicle administration did not show significant recovery of the rotational behavior at any time (sham: 10.15±2.19 ipsilateral turns/minute at 0 weeks to 11.57±2.49 turns/minute at 10 weeks). Rats receiving empty NS, VEGF NS, and GDNF NS treatments showed a slight reduction in rotations at the end of the study (week 10). GDNF NS implantation, in particular, showed a statistical reduction in the number of rotations when compared with sham group (empty NS: 9.71±2.92 turns/minute; VEGF NS: 6.37±2.11 turns/minute; GDNF NS: 4.43±2.75 turns/minute; P<0.05 GDNF NS with respect to sham group, Student’s t-test). In addition, we observed that striatal implantation of the combined VEGF NS and GDNF NS treatment at half the dose of the factors administered individually achieved the best behavioral results and significantly reduced the number of rotations (VEGF NS and GDNF NS: 0.87±0.53 turns/minute) when compared to the empty NS and sham groups (P<0.001 with respect to empty NS and sham groups, Student’s t-test [Figure 4A]).

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