Simvastatin promotes heat shock protein 27 expression and Akt activation in the rat retina and protects axotomized retinal ganglion cells in vivo

Kretz, Alexandra; Schmeer, Christian; Tausch, Svetlana; Isenmann, Stefan

doi:10.1016/j.nbd.2005.08.003

Cited by 78 publications

(69 citation statements)

References 54 publications

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“…This method of RGC labeling has been commonly used to quantify these cells, and although some RGCs may degenerate immediately after axotomy, a number of studies have observed virtually no RGC loss during first 3-4 days after the surgery. [52][53][54][55] As in this study, RGCs were counted 2 days after axotomy, we believe that the effect of this procedure on the RGC numbers at that time is not significant.…”

Section: Rgc Countingmentioning

confidence: 77%

Redox proteins thioredoxin 1 and thioredoxin 2 support retinal ganglion cell survival in experimental glaucoma

et al. 2008

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We investigated the neuroprotective effect of thioredoxin 1 (Trx1) and thioredoxin 2 (Trx2) which play critical roles in the regulation of oxidative stress on retinal ganglion cells (RGCs) in a rat glaucoma model. Expression of Trx1 and Trx2 and Trx-interacting protein (Txnip) was observed in the RGC layer (GCL), nerve fiber layer and inner nuclear layer. Txnip-, Trx1-and Trx2-expressing cells in the GCL were primarily colocalized with RGCs. The increased Txnip protein level was observed 2 and 5 weeks after glaucoma induction. Trx1 level decreased 2 weeks after glaucoma induction and more prominently after 5 weeks. No change in Trx2 levels was detected. The effects of Trx1 and Trx2 overexpression on RGC survival were evaluated 5 weeks after glaucoma induction. In nontransfected and EGFP-transfected (used as a negative control) retinas, RGC loss was approximately 27% compared with control. The loss of RGCs in Trx1-and Trx2-transfected retinas was approximately 15 and 17%, respectively. Thus, Trx1 and Trx2 preserved 45 and 37% of cells, respectively that were destined to die in glaucomatous retinas. The results of this study provide evidence for the involvement of oxidative stress in RGC degeneration in experimental glaucoma and point to potential strategies to reduce its impact.

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Section: Rgc Countingmentioning

confidence: 77%

Redox proteins thioredoxin 1 and thioredoxin 2 support retinal ganglion cell survival in experimental glaucoma

et al. 2008

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“…Additional investigation into the potential role of p70S6K and 4E-BP1 in atorvastatin-induced neurite outgrowth would be of great interest. Activated Akt phosphorylates GSK-3β at Ser9 to inactivate its kinase activity [17] ; thus, GSK-3β activity is inversely correlated with PI3K/Akt signaling activity [49] . Some studies have observed GSK-3β phosphorylation following Akt activation and subsequently neurite outgrowth [50,51] .…”

Section: Discussionmentioning

confidence: 99%

“…GSK-3β, which is inactivated upon phosphorylation by Akt, is implicated in the regulation of microtubule dynamics by phosphorylating MAPs, including adenomatosis polyposis coli (APC), MAP1, and MAP2 [52] . Phosphorylation of MAPs is a key step in the regulatation of neurite initiation, growth, and branching in hippocampal neurons [17] . Decreased activity of GSK-3β reduces phosphorylation of MAP2, a step that can enhance microtubule polymerization and dendritic growth [53] .…”

Section: Discussionmentioning

confidence: 99%

“…Incubation of the cultured cortical neurons with atorvastatin (10 μmol/L) for 48 h increased the phosphorylation of 4E-BP1. Furthermore, atorvastatininduced increases in the phosphorylation of 4E-BP1 was completely blocked by LY294002 (30 µmol/L) and rapamycin Atorvastatin increases neurite outgrowth through the Akt/GSK3β pathway Signaling via the Akt/GSK-3β pathway can regulate neurite morphology by regulating phosphorylation of MAP2 [17] . Akt phosphorylates GSK-3β to inactivate it.…”

Section: Atorvastatin Promotes Neurite Outgrowth Via the Pi3k-akt Patmentioning

confidence: 96%

“…The serine/threonine protein kinase GSK-3β is a key substrate. Activated Akt phosphorylates at GSK-3β at Ser-9 to inactivate its kinase activity [17] . It has been reported that statins can induce the phosphorylation of Akt [3,18,19] .…”

Section: Introductionmentioning

confidence: 99%

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Atorvastatin enhances neurite outgrowth in cortical neurons in vitro via up-regulating the Akt/mTOR and Akt/GSK-3β signaling pathways

et al. 2012

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Aim: To investigate whether atorvastatin can promote formation of neurites in cultured cortical neurons and the signaling mechanisms responsible for this effect. Methods: Cultured rat cerebral cortical neurons were incubated with atorvastatin (0.05-10 μmol/L) for various lengths of time. For pharmacological experiments, inhibitors were added 30 min prior to addition of atorvastatin. Control cultures received a similar amount of DMSO. Following the treatment period, phase-contrast digital images were taken. Digital images of neurons were analyzed for total neurite branch length (TNBL), neurite number, terminal branch number, and soma area by SPOT Advanced Imaging software. After incubation with atorvastatin for 48 h, the levels of phosphorylated 3-phosphoinoside-dependent protein kinase-1 (PDK1), phospho-Akt, phosphorylated mammalian target of rapamycin (mTOR), phosphorylated 4E-binding protein 1 (4E-BP1), p70S6 kinase (p70S6K), and glycogen synthase kinase-3β (GSK-3β) in the cortical neurons were evaluated using Western blotting analyses. Results: Atorvastatin (0.05-10 µmol/L) resulted in dose-dependent increase in neurite number and length in these neurons. Pretreatment of the cortical neurons with phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 (30 µmol/L) and wortmannin (5 µmol/L), Akt inhibitor tricribine (1 µmol/L) or mTOR inhibitor rapamycin (100 nmol/L) blocked the atorvastatin-induced increase in neurite outgrowth, suggesting that atorvastatin promoted neurite outgrowth via activating the PI3K/Akt/mTOR signaling pathway. Atorvastatin (10 µmol/L) significantly increased the levels of phosphorylated PDK1, Akt and mTOR in the cortical neurons, which were prevented by LY294002 (30 µmol/L). Moreover, atorvastatin (10 µmol/L) stimulated the phosphorylation of 4E-BP1 and p70S6K, the substrates of mTOR, in the cortical neurons. In addition, atorvastatin (10 µmol/L) significantly increased the phosphorylated GSK-3β level in the cortical neurons, which was prevented by both LY294002 and tricribine. Conclusion: These results suggest that activation of both the PI3K/Akt/mTOR and Akt/GSK-3β signaling pathways is responsible for the atorvastatin-induced neurite outgrowth in cultured cortical neurons.

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Association of Statin Use and High Serum Cholesterol Levels With Risk of Primary Open-Angle Glaucoma

et al. 2019

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The use of statins (hydroxymethylglutaryl coenzyme A inhibitors) has been associated with a lower risk of primary open-angle glaucoma (POAG); however, results have been conflicting, and little is known about the association between high cholesterol levels and POAG. OBJECTIVE To assess the association of elevated cholesterol levels and statin use with incident POAG. DESIGN, SETTING, AND PARTICIPANTS This study used data collected biennially from participants aged 40 years or older who were free of glaucoma and reported eye examinations, within 3 population-based cohorts: the Nurses' Health Study (N = 50 710; followed up from 2000 to 2014), the Nurses' Health Study 2 (N = 62 992; 1999-2015), and the Health Professionals Follow-up Study (N = 23 081; 2000-2014). Incident cases of POAG were confirmed by medical record review. The analyses were performed in January and November 2019. EXPOSURES Biennially updated self-reported information on elevated cholesterol level status, serum cholesterol levels, and duration of statin use. MAIN OUTCOMES AND MEASURES Multivariable-adjusted relative risks (RRs) and 95% CIs were estimated using Cox proportional hazards regression models on pooled data, with stratification by cohort. RESULTS Among the 136 783 participants in the 3 cohorts (113 702 women and 23 081 men), 887 incident cases of POAG were identified. A 20-mg/dL increase in total serum cholesterol was not associated with risk of POAG (RR, 1.02 [95% CI, 0.98-1.07]; P = .32). Any self-reported history of elevated cholesterol was not associated with risk of POAG (RR, 1.11 [95% CI, 0.94-1.31]). A history of any statin use was not associated with risk of POAG (RR, 0.93 [95% CI, 0.80-1.10]). Use of statins for 5 or more years vs never use of statins was not associated with risk of POAG (RR, 0.93 [95% CI, 0.75-1.15]; P = .49 for linear trend). CONCLUSIONS AND RELEVANCE Among adults aged 40 years or older, higher self-reported total serum cholesterol levels and statin use compared with never use of statins were not associated with risk of POAG.

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Simvastatin promotes heat shock protein 27 expression and Akt activation in the rat retina and protects axotomized retinal ganglion cells in vivo

Cited by 78 publications

References 54 publications

Redox proteins thioredoxin 1 and thioredoxin 2 support retinal ganglion cell survival in experimental glaucoma

Redox proteins thioredoxin 1 and thioredoxin 2 support retinal ganglion cell survival in experimental glaucoma

Atorvastatin enhances neurite outgrowth in cortical neurons in vitro via up-regulating the Akt/mTOR and Akt/GSK-3β signaling pathways

Association of Statin Use and High Serum Cholesterol Levels With Risk of Primary Open-Angle Glaucoma

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