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Both systemic and local application of granulocyte-colony stimulating factor (G-CSF) is neuroprotective after retinal ganglion cell axotomy.

Frank T, Schlachetzki JC, Göricke B, Meuer K, Rohde G, Dietz GP, Bähr M, Schneider A, Weishaupt JH - BMC Neurosci (2009)

Bottom Line: We thus evaluated G-CSF as a neuroprotectant for RGCs and found a dose-dependent neuroprotective effect of G-CSF on axotomized RGCs when given subcutaneously.As stem stell mobilization had previously been discussed as a possible contributor to the neuroprotective effects of G-CSF, we compared the local treatment of RGCs by injection of G-CSF into the vitreous body with systemic delivery by subcutaneous application.We thus show that G-CSF neuroprotection is at least partially independent of potential systemic effects and provide further evidence that the clinically applicable G-CSF could become a treatment option for both neurodegenerative diseases and glaucoma.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, University Medical Center Göttingen, Göttingen, Germany. tobias.frank@med.uni-goettingen.de

ABSTRACT

Background: The hematopoietic Granulocyte-Colony Stimulating Factor (G-CSF) plays a crucial role in controlling the number of neutrophil progenitor cells. Its function is mediated via the G-CSF receptor, which was recently found to be expressed also in the central nervous system. In addition, G-CSF provided neuroprotection in models of neuronal cell death. Here we used the retinal ganglion cell (RGC) axotomy model to compare effects of local and systemic application of neuroprotective molecules.

Results: We found that the G-CSF receptor is robustly expressed by RGCs in vivo and in vitro. We thus evaluated G-CSF as a neuroprotectant for RGCs and found a dose-dependent neuroprotective effect of G-CSF on axotomized RGCs when given subcutaneously. As stem stell mobilization had previously been discussed as a possible contributor to the neuroprotective effects of G-CSF, we compared the local treatment of RGCs by injection of G-CSF into the vitreous body with systemic delivery by subcutaneous application. Both routes of application reduced retinal ganglion cell death to a comparable extent. Moreover, G-CSF enhanced the survival of immunopurified RGCs in vitro.

Conclusion: We thus show that G-CSF neuroprotection is at least partially independent of potential systemic effects and provide further evidence that the clinically applicable G-CSF could become a treatment option for both neurodegenerative diseases and glaucoma.

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G-CSF protects RGCs after optic nerve transection. Subcutaneous daily injection of G-CSF (B, C) dose-dependently attenuated RGC apoptosis after optic nerve transection when compared to vehicle injection (A, C). 14 days after optic nerve transection reduction in RGC loss was statistically significant at a dose of 40 μg/kg bodyweight s.c. when the first injection was performed approximately 2 h after the optic nerve transection. Starting G-CSF injection one day before axotomy (40 μg/kg + 1 d) resulted in a slight, but non-significant increase in RGC numbers compared to treatment starting after the lesion. Panels (A) and (B) show an eccentricity at one half of the retinal radius. * p < 0.05 (20 vs. 40 μg/kg bodyweight); ** p < 0.01 (40 μg/kg or 40 μg/kg + 1 d vs. vehicle); n.s. = not significant. Data are given as mean ± S.E.M.
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Figure 2: G-CSF protects RGCs after optic nerve transection. Subcutaneous daily injection of G-CSF (B, C) dose-dependently attenuated RGC apoptosis after optic nerve transection when compared to vehicle injection (A, C). 14 days after optic nerve transection reduction in RGC loss was statistically significant at a dose of 40 μg/kg bodyweight s.c. when the first injection was performed approximately 2 h after the optic nerve transection. Starting G-CSF injection one day before axotomy (40 μg/kg + 1 d) resulted in a slight, but non-significant increase in RGC numbers compared to treatment starting after the lesion. Panels (A) and (B) show an eccentricity at one half of the retinal radius. * p < 0.05 (20 vs. 40 μg/kg bodyweight); ** p < 0.01 (40 μg/kg or 40 μg/kg + 1 d vs. vehicle); n.s. = not significant. Data are given as mean ± S.E.M.

Mentions: Based on the positive G-CSFR immunoreactivity on RGCs, we asked whether G-CSF is able to prevent RGC degeneration following axotomy due to optic nerve transection. Similar to earlier data [37,38], we observed 420.6 ± 58.4 surviving RGCs/mm2 14 days after optic nerve transection and daily subcutaneous vehicle injection (see material and methods; Fig. 2A, C). Based on G-CSF dosing in previous in vivo neuroprotection experiments [3,22], we then applied a daily dose of 20 or 40 μg/kg bodyweight (BW) G-CSF subcutaneously, with the first injection approximately 2 h after axotomy. While application of 20 μg/kg BW showed a non-significantly enhanced survival of RGCs (578.9 ± 52.0 surviving RGCs/mm2; table 1, Fig. 2B), a dose of 40 μg/kg BW G-CSF s.c. resulted in a highly significant neuroprotective effect (742.3 ± 25.8 RGCs/mm2; p < 0.001; table 1, Fig. 2B, C).


Both systemic and local application of granulocyte-colony stimulating factor (G-CSF) is neuroprotective after retinal ganglion cell axotomy.

Frank T, Schlachetzki JC, Göricke B, Meuer K, Rohde G, Dietz GP, Bähr M, Schneider A, Weishaupt JH - BMC Neurosci (2009)

G-CSF protects RGCs after optic nerve transection. Subcutaneous daily injection of G-CSF (B, C) dose-dependently attenuated RGC apoptosis after optic nerve transection when compared to vehicle injection (A, C). 14 days after optic nerve transection reduction in RGC loss was statistically significant at a dose of 40 μg/kg bodyweight s.c. when the first injection was performed approximately 2 h after the optic nerve transection. Starting G-CSF injection one day before axotomy (40 μg/kg + 1 d) resulted in a slight, but non-significant increase in RGC numbers compared to treatment starting after the lesion. Panels (A) and (B) show an eccentricity at one half of the retinal radius. * p < 0.05 (20 vs. 40 μg/kg bodyweight); ** p < 0.01 (40 μg/kg or 40 μg/kg + 1 d vs. vehicle); n.s. = not significant. Data are given as mean ± S.E.M.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2691410&req=5

Figure 2: G-CSF protects RGCs after optic nerve transection. Subcutaneous daily injection of G-CSF (B, C) dose-dependently attenuated RGC apoptosis after optic nerve transection when compared to vehicle injection (A, C). 14 days after optic nerve transection reduction in RGC loss was statistically significant at a dose of 40 μg/kg bodyweight s.c. when the first injection was performed approximately 2 h after the optic nerve transection. Starting G-CSF injection one day before axotomy (40 μg/kg + 1 d) resulted in a slight, but non-significant increase in RGC numbers compared to treatment starting after the lesion. Panels (A) and (B) show an eccentricity at one half of the retinal radius. * p < 0.05 (20 vs. 40 μg/kg bodyweight); ** p < 0.01 (40 μg/kg or 40 μg/kg + 1 d vs. vehicle); n.s. = not significant. Data are given as mean ± S.E.M.
Mentions: Based on the positive G-CSFR immunoreactivity on RGCs, we asked whether G-CSF is able to prevent RGC degeneration following axotomy due to optic nerve transection. Similar to earlier data [37,38], we observed 420.6 ± 58.4 surviving RGCs/mm2 14 days after optic nerve transection and daily subcutaneous vehicle injection (see material and methods; Fig. 2A, C). Based on G-CSF dosing in previous in vivo neuroprotection experiments [3,22], we then applied a daily dose of 20 or 40 μg/kg bodyweight (BW) G-CSF subcutaneously, with the first injection approximately 2 h after axotomy. While application of 20 μg/kg BW showed a non-significantly enhanced survival of RGCs (578.9 ± 52.0 surviving RGCs/mm2; table 1, Fig. 2B), a dose of 40 μg/kg BW G-CSF s.c. resulted in a highly significant neuroprotective effect (742.3 ± 25.8 RGCs/mm2; p < 0.001; table 1, Fig. 2B, C).

Bottom Line: We thus evaluated G-CSF as a neuroprotectant for RGCs and found a dose-dependent neuroprotective effect of G-CSF on axotomized RGCs when given subcutaneously.As stem stell mobilization had previously been discussed as a possible contributor to the neuroprotective effects of G-CSF, we compared the local treatment of RGCs by injection of G-CSF into the vitreous body with systemic delivery by subcutaneous application.We thus show that G-CSF neuroprotection is at least partially independent of potential systemic effects and provide further evidence that the clinically applicable G-CSF could become a treatment option for both neurodegenerative diseases and glaucoma.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, University Medical Center Göttingen, Göttingen, Germany. tobias.frank@med.uni-goettingen.de

ABSTRACT

Background: The hematopoietic Granulocyte-Colony Stimulating Factor (G-CSF) plays a crucial role in controlling the number of neutrophil progenitor cells. Its function is mediated via the G-CSF receptor, which was recently found to be expressed also in the central nervous system. In addition, G-CSF provided neuroprotection in models of neuronal cell death. Here we used the retinal ganglion cell (RGC) axotomy model to compare effects of local and systemic application of neuroprotective molecules.

Results: We found that the G-CSF receptor is robustly expressed by RGCs in vivo and in vitro. We thus evaluated G-CSF as a neuroprotectant for RGCs and found a dose-dependent neuroprotective effect of G-CSF on axotomized RGCs when given subcutaneously. As stem stell mobilization had previously been discussed as a possible contributor to the neuroprotective effects of G-CSF, we compared the local treatment of RGCs by injection of G-CSF into the vitreous body with systemic delivery by subcutaneous application. Both routes of application reduced retinal ganglion cell death to a comparable extent. Moreover, G-CSF enhanced the survival of immunopurified RGCs in vitro.

Conclusion: We thus show that G-CSF neuroprotection is at least partially independent of potential systemic effects and provide further evidence that the clinically applicable G-CSF could become a treatment option for both neurodegenerative diseases and glaucoma.

Show MeSH
Related in: MedlinePlus