FK506 potentiates NGF‐induced neurite outgrowth <i>via</i> the Ras/Raf/MAP kinase pathway

Price, Raymond D.; Yamaji, Takayuki; Matsuoka, Naoki

doi:10.1038/sj.bjp.0705522

Cited by 58 publications

(53 citation statements)

References 25 publications

(29 reference statements)

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“…17 The agent FK506 has also been shown to potentiate nerve growth factor-induced neurite outgrowth in SH-SY5Y cells, in PC12 cells, and in sensory neuronal cultures. 11,20,24 Our results indicate that FK506, cyclosporin A, and dexamethasone all can promote neurite outgrowth following thapsigargin-induced calcium challenges, and that they can do so without the presence of neurotrophins. Dexamethasone and cyclosporin A can also lessen the extent of apoptosis after thapsigargin-induced injury.…”

Section: Discussionmentioning

confidence: 83%

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Potentiation of neurite outgrowth and reduction of apoptosis by immunosuppressive agents: implications for neuronal injury and transplantation

Sheehan

Eischeid

Saunders

et al. 2006

FOC

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Object Immunosuppressive agents are believed to play a role in recovery from spinal cord injury, but the underlying mechanisms by which neuronal function is improved by these agents are poorly understood. In this study, the authors evaluate the effect of immunosuppressive medications on neurite outgrowth and cell survival after a pharmacologically induced injury. Methods Differentiated human neuroblastoma SH-SY5Y cells were injured using the calcium agonist thapsigargin. After cellular injury, neurite outgrowth in the presence or absence of immunosuppressive agents was measured. Apoptosis was quantified with the aid of a terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling assay. Neurite outgrowth was severely restricted following thapsigargin injury. Outgrowth was potentiated, however, by the addition of concentrations of 1 and 10 μM cyclosporin A in a dose-dependent fashion. Similarly, addition of 10 nM FK506 increased the percentage of neurites in the 20- to 40-micron range. A low dose (1 μM) of dexamethasone did not have a significant effect on neurite outgrowth, but a higher dose (10 μM) increased the percentage of neurites in the 10- to 45-micron range. These agents also lessened the degree of thapsigargin-induced apoptosis. Conclusions Immunosuppressive agents such as cyclosporin A, FK506, and dexamethasone can potentiate neurite outgrowth and protect against apoptotic cell death in a human postmitotic neuronal cell line. Such effects may have implications for lessening neuronal injury after neurotrauma, stroke, or neurodegeneration.

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Section: Discussionmentioning

confidence: 83%

“…4), although this difference in neurite distribution did not achieve statistical significance. However, addition of 10 M dexamethasone increased the fraction of neurites whose lengths were less than or equal to 10,15,20,25,30,35,40, and 45 microns (Fig. 5) in a statistically significant fashion (p Ͻ 0.05, t-test).…”

Section: Response To Dexamethasonementioning

confidence: 99%

Potentiation of neurite outgrowth and reduction of apoptosis by immunosuppressive agents: implications for neuronal injury and transplantation

Sheehan

Eischeid

Saunders

et al. 2006

FOC

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“…For example, FK506 potentiates NGFinduced neurite outgrowth via the Ras/Raf/MAPK pathway and involves PI3-k signaling (Price et al, 2003(Price et al, , 2005. Gold et al (1999) reported that GA blocked neurotrophic action of FK506, suggesting FK506 interaction with Hsp90 via binding to FKBP52 is important for its neuroregenerative properties.…”

Section: Discussionmentioning

confidence: 99%

An Analog of a Dipeptide-Like Structure of FK506 Increases Glial Cell Line-Derived Neurotrophic Factor Expression through cAMP Response Element-Binding Protein Activated by Heat Shock Protein 90/Akt Signaling Pathway

Cen¹,

Nitta²,

Ohya³

et al. 2006

J. Neurosci.

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Glial cell line-derived neurotrophic factor (GDNF) is an important neurotrophic factor that has therapeutic implications for neurodegenerative disorders. We previously showed that leucine-isoleucine (Leu-Ile), an analog of a dipeptide-like structure of FK506 (tacrolimus), induces GDNF expression both in vivo and in vitro. In this investigation, we sought to clarify the cellular mechanisms underlying the GDNF-inducing effect of this dipeptide. Leu-Ile transport was investigated using fluorescein isothiocyanate-Leu-Ile in cultured neurons, and the results showed the transmembrane mobility of this dipeptide. By liquid chromatography-mass spectrometry and quartz crystal microbalance assay, we identified heat shock cognate protein 70 as a protein binding specifically to Leu-Ile, and molecular modeling showed that the ATPase domain is the predicted binding site. Leu-Ile stimulated Akt phosphorylation, which was attenuated significantly by heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA). Moreover, enhanced interaction between phosphorylated Akt and Hsp90 was detected by immunoprecipitation. Leu-Ile elicited an increase in cAMP response element binding protein (CREB) phosphorylation, which was inhibited by GA, indicating that CREB is a downstream target of Hsp90/Akt signaling. Leu-Ile elevated the levels of GDNF mRNA and protein expression, whereas inhibition of CREB blocked such effects. Leu-Ile promoted the binding activity of phosphorylated CREB with cAMP response element. These findings show that CREB plays a key role in transcriptional regulation of GDNF expression induced by Leu-Ile. In conclusion, Leu-Ile activates Hsp90/Akt/CREB signaling, which contributes to the upregulation of GDNF expression. It may represent a novel lead compound for the treatment of dopaminergic neurons or motoneuron diseases.

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“…Previous studies have shown that immunophilin ligands complement the action of neurotrophic factors and in part by enhancing the MAPK/JNK pathways (Price et al, 2003). On the other hand, earlier study has shown that JNJ460 induces neurogenesis indirectly in a Schwann cell dependent manner, but not when directly administered to PC12 cells (Birge et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

A multiplexed proteomics approach to differentiate neurite outgrowth patterns

Liu

D’Mello

Deng

et al. 2006

Journal of Neuroscience Methods

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We report here a method for proteomics pattern discovery by utilizing a self-organizing map approach to analyze data obtained from a novel multiplex iTRAQ ™ proteomics method. Through the application of this technique, we were able to delineate the early molecular events preceding dorsal root ganglia neurite outgrowth induced by either nerve growth factor (NGF) or an immunophilin ligand, JNJ460. Following pattern analysis we discovered that each neurotrophic agent promoted mostly distinct increases in protein expression with few overlapping patterns. In the NGF-treated group, proteins possessing "biosynthesis function" (p < 0.002) and "ribosome localization" (p < 0.0003) were increased, while proteins promoting "organogenesis" (p < 0.004) and related "signal transduction" (p < 0.008) functions were notably increased in the JNJ460-treated group. This study suggests that the properties of neurite outgrowth triggered by NGF and JNJ460 can be distinguished at the proteome level. Multiplexed proteomics analysis, along with pattern discovery bioinformatics tools, has the capability to differentiate subtle neuroproteomics patterns.

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FK506 potentiates NGF‐induced neurite outgrowth via the Ras/Raf/MAP kinase pathway

Cited by 58 publications

References 25 publications

Potentiation of neurite outgrowth and reduction of apoptosis by immunosuppressive agents: implications for neuronal injury and transplantation

Potentiation of neurite outgrowth and reduction of apoptosis by immunosuppressive agents: implications for neuronal injury and transplantation

An Analog of a Dipeptide-Like Structure of FK506 Increases Glial Cell Line-Derived Neurotrophic Factor Expression through cAMP Response Element-Binding Protein Activated by Heat Shock Protein 90/Akt Signaling Pathway

A multiplexed proteomics approach to differentiate neurite outgrowth patterns

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