The neuroprotective actions of FK506 binding protein ligands: neuronal survival is triggered by de novo RNA synthesis, but is independent of inhibition of JNK and calcineurin

Klettner, Alexa; Baumgrass, Ria; Zhang, Y; Fischer, Gunter; Bürger, Erich; Herdegen, Thomas; Mielke, Kirsten

doi:10.1016/s0169-328x(01)00286-8

Cited by 53 publications

(41 citation statements)

References 74 publications

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“…On the other hand, no significant increase of phosphorylated C-JUN protein was observed between 1 and 48 h after ischemia treatment in the CsA administration group, suggesting that calcineurin, a dephosphorylated oxidase, is involved in the expression of phosphorylation of C-JUN protein. Consistent with these results, it has been reported that JNK is activated by calcineurin (33) and that CsA inhibits signal transduction by JNK and p38 (34). In addition, when calcineurin activity was measured with time after cerebral ischemia in the CA1 area of the hippocampus, it increased 3-fold in the early phase after cerebral ischemia (after 1 h), compared to the level before ischemia, and continued to increase (up to 6-fold) for 24 h, following a transient decrease after 6 h, whereas it was repressed through all stages in the CsA administration group (35).…”

Section: +supporting

confidence: 87%

Effect of Cyclosporin A on Immediate Early Gene in Rat Global Ischemia and Its Neuroprotection

Yamaguchi¹,

Miyata²,

Shibasaki³

et al. 2006

J Pharmacol Sci

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Abstract. The expressions of the immediate early genes, c-fos and c-jun, and their product proteins C-FOS, C-JUN, and P-JUN were examined in the hippocampal CA1 subfield after global ischemia and reperfusion in rats treated with cyclosporin A. More than 90% neuronal cell death was seen in hippocampal CA1 7 days after global ischemia in control animals, but only 5% cell death after ischemia was seen in the CsA-treated animals. The expressions of c-fos and c-jun mRNA in the control animals were detected with an increase from 1 to 48 h after ischemia. On the other hand, they showed significant suppression in the CsA-treated animals. Increased expressions of C-FOS were found 1, 24, and 48 h after reperfusion in the control animals. In the CsA-treated animals C-FOS expression was found to increase, but the expression level reduced to a statistically insignificant level within 48 h after the ischemia. C-JUN and P-JUN expressions increased in control animals, but were almost completely suppressed in the CsA-treated animals. The present study demonstrated that the suppressant effects of CsA on IEGs and their products might have causal relationship to the dramatic protecting effect of the drug against delayed neuronal cell death.

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Section: +supporting

confidence: 87%

Effect of Cyclosporin A on Immediate Early Gene in Rat Global Ischemia and Its Neuroprotection

Yamaguchi¹,

Miyata²,

Shibasaki³

et al. 2006

J Pharmacol Sci

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“…26,38 On the basis of our results, PI3K signaling is unlikely to mediate the effects of FKBP39 overexpression on Foxo localization, although it remains possible that FKBP39 may affect Akt independently of PI3K. Therefore, JNK signaling is a promising candidate for mediating at least some of the effects of FKBP39 overexpression, 24 especially considering the strong effect of FKBP39 overexpression on kinases downstream of Ras that are closely related to JNK family kinases. This issue clearly warrants future studies.…”

Section: Discussionmentioning

confidence: 80%

Gene expression profiling identifies FKBP39 as an inhibitor of autophagy in larval Drosophila fat body

et al. 2007

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In Drosophila, the fat body undergoes a massive burst of autophagy at the end of larval development in preparation for the pupal transition. To identify genes involved in this process, we carried out a microarray analysis. We found that mRNA levels of the homologs of Atg8, the coat protein of early autophagic structures, and lysosomal hydrolases were upregulated, consistent with previous results. Genes encoding mitochondrial proteins and many chaperones were downregulated, including the inhibitor of eIF2alpha kinases and the peptidyl-prolyl cis-trans isomerase FK506-binding protein of 39 kDa (FKBP39). Genetic manipulation of FKBP39 expression had a significant effect on autophagy, potentially through modulation of the transcription factor Foxo. Accordingly, we found that Foxo mutants cannot properly undergo autophagy in response to starvation, and that overexpression of Foxo induces autophagy.

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“…Nevertheless, current clinically available immunophilin ligands, including FK506 and cyclosporine A, are immunosuppressive, which limits their chronic use. However, neither calcineurin inhibition nor binding to FKBP-12 were found to be necessary for the neurotrophic effects of immunophilin ligands (Steiner et al, 1997;Costantini et al, 2001;Guo et al, 2001;Klettner et al, 2001;Zhang et al, 2001a;Tanaka et al, 2002b). This fact, together with the neuroprotective effects of immunophilin ligands in models of neurodegenerative disorders (reviewed by Pong and Zaleska, 2003), has led to the design of small ligands that bind to immunophilins, but are not immunosuppressive since they do not interact with calcineurin (e.g.…”

Section: Immunophilin Ligandsmentioning

confidence: 99%

Driving GDNF expression: The green and the red traffic lights

Saavedra

Baltazar

Duarte

2008

Progress in Neurobiology

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The neuroprotective actions of FK506 binding protein ligands: neuronal survival is triggered by de novo RNA synthesis, but is independent of inhibition of JNK and calcineurin

Cited by 53 publications

References 74 publications

Effect of Cyclosporin A on Immediate Early Gene in Rat Global Ischemia and Its Neuroprotection

Effect of Cyclosporin A on Immediate Early Gene in Rat Global Ischemia and Its Neuroprotection

Gene expression profiling identifies FKBP39 as an inhibitor of autophagy in larval Drosophila fat body

Driving GDNF expression: The green and the red traffic lights

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