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Insulin-like growth factor-I protects axotomized rat retinal ganglion cells from secondary death via PI3-K-dependent Akt phosphorylation and inhibition of caspase-3 In vivo.
J Neurosci. 2000 Jan 15; 20(2):2-8.JN

Abstract

Recently we have shown that the majority of retinal ganglion cells (RGCs) dies via activation of caspase-3 after transection of the optic nerve (ON) in the adult rat. In the present study we investigated whether insulin-like growth factor-I (IGF-I), an important factor in retinal development, prevents secondary death of RGCs after axotomy. Moreover, we studied potential intracellular mechanisms of IGF-mediated neuroprotection in more detail. Our results indicate that intraocular application of IGF-I protects RGCs from death after ON transection in a dose-dependent manner. We show reduced caspase-3 activity as one possible neuroprotective mechanism of IGF-I treatment in vivo. Caspase-3 mRNA expression remained unchanged. Because caspase inhibition can be mediated by Akt in vitro, we examined phosphorylation of Akt after axotomy and under IGF treatment. Western blot analysis revealed decreased Akt phosphorylation after axotomy without treatment and an increased phosphorylation of Akt under treatment with IGF-I. This strong increase could be reduced by simultaneous injection of wortmannin (WM), a potent inhibitor of phosphatidylinositol 3-kinase (PI3-K). To prove the pathway suggested by these experiments as relevant for the in vivo situation, we assessed the number of RGCs 14 d after ON transection under a combined treatment strategy of IGF-I and WM. As expected, WM significantly reduced the neuroprotective effects of IGF-I. In summary, we show for the first time in vivo that IGF is neuroprotective via PI3-K-dependent Akt phosphorylation and by inhibition of caspase-3.

Authors+Show Affiliations

Department of Neurology, Medical School, University of Tübingen, 72076 Tübingen, Germany. pkermer@burnham-inst.orgNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10632601

Citation

Kermer, P, et al. "Insulin-like Growth factor-I Protects Axotomized Rat Retinal Ganglion Cells From Secondary Death Via PI3-K-dependent Akt Phosphorylation and Inhibition of Caspase-3 in Vivo." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 20, no. 2, 2000, pp. 2-8.
Kermer P, Klöcker N, Labes M, et al. Insulin-like growth factor-I protects axotomized rat retinal ganglion cells from secondary death via PI3-K-dependent Akt phosphorylation and inhibition of caspase-3 In vivo. J Neurosci. 2000;20(2):2-8.
Kermer, P., Klöcker, N., Labes, M., & Bähr, M. (2000). Insulin-like growth factor-I protects axotomized rat retinal ganglion cells from secondary death via PI3-K-dependent Akt phosphorylation and inhibition of caspase-3 In vivo. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 20(2), 2-8.
Kermer P, et al. Insulin-like Growth factor-I Protects Axotomized Rat Retinal Ganglion Cells From Secondary Death Via PI3-K-dependent Akt Phosphorylation and Inhibition of Caspase-3 in Vivo. J Neurosci. 2000 Jan 15;20(2):2-8. PubMed PMID: 10632601.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Insulin-like growth factor-I protects axotomized rat retinal ganglion cells from secondary death via PI3-K-dependent Akt phosphorylation and inhibition of caspase-3 In vivo. AU - Kermer,P, AU - Klöcker,N, AU - Labes,M, AU - Bähr,M, PY - 2000/1/13/pubmed PY - 2000/1/13/medline PY - 2000/1/13/entrez SP - 2 EP - 8 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 20 IS - 2 N2 - Recently we have shown that the majority of retinal ganglion cells (RGCs) dies via activation of caspase-3 after transection of the optic nerve (ON) in the adult rat. In the present study we investigated whether insulin-like growth factor-I (IGF-I), an important factor in retinal development, prevents secondary death of RGCs after axotomy. Moreover, we studied potential intracellular mechanisms of IGF-mediated neuroprotection in more detail. Our results indicate that intraocular application of IGF-I protects RGCs from death after ON transection in a dose-dependent manner. We show reduced caspase-3 activity as one possible neuroprotective mechanism of IGF-I treatment in vivo. Caspase-3 mRNA expression remained unchanged. Because caspase inhibition can be mediated by Akt in vitro, we examined phosphorylation of Akt after axotomy and under IGF treatment. Western blot analysis revealed decreased Akt phosphorylation after axotomy without treatment and an increased phosphorylation of Akt under treatment with IGF-I. This strong increase could be reduced by simultaneous injection of wortmannin (WM), a potent inhibitor of phosphatidylinositol 3-kinase (PI3-K). To prove the pathway suggested by these experiments as relevant for the in vivo situation, we assessed the number of RGCs 14 d after ON transection under a combined treatment strategy of IGF-I and WM. As expected, WM significantly reduced the neuroprotective effects of IGF-I. In summary, we show for the first time in vivo that IGF is neuroprotective via PI3-K-dependent Akt phosphorylation and by inhibition of caspase-3. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/10632601/Insulin_like_growth_factor_I_protects_axotomized_rat_retinal_ganglion_cells_from_secondary_death_via_PI3_K_dependent_Akt_phosphorylation_and_inhibition_of_caspase_3_In_vivo_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=10632601 DB - PRIME DP - Unbound Medicine ER -