A Nonimmunosuppressant FKBP-12 Ligand Increases Nerve Regeneration

Gold, Bruce G.; Zeleny-Pooley, Michelle; Wang, Minsheng; Chaturvedi, Pravin; Armistead, David M.

doi:10.1006/exnr.1997.6630

Cited by 135 publications

(115 citation statements)

References 18 publications

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“…3,16,24 Binding to FKBP-12 and inhibition of calcineurin increases the phosphorylation of several substrate molecules like GAP-43, which is a protein that plays an important role in neural plasticity and is highly expressed in the regenerative growth cones. 16 It has also been reported that nonimmunosuppressant derivatives of FK506 do not inhibit calcineurin but accelerate nerve regeneration.…”

Section: 19mentioning

confidence: 99%

Effects of topically administered FK506 on sciatic nerve regeneration and reinnervation after vein graft repair of short nerve gaps

Azizi

Mohammadi

Amini

et al. 2012

FOC

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Object Despite the development of various nerve coaptation materials and techniques, achievement of desired functional peripheral nerve regeneration is still inadequate, and repair of peripheral nerve injuries is still one of the most challenging tasks and concerns in neurosurgery. The effect of an FK506-loaded vein graft as an in situ delivery system for FK506 in bridging the defects was studied using a rat sciatic nerve regeneration model. Methods A 10-mm sciatic nerve defect was bridged using an inside-out vein graft (IOVG) filled with 10 μl of a carrier-drug dilution (10 ng/ml FK506) in the IOVG/FK506 group. In the IOVG control group, the vein was filled with the same volume of carrier dilution alone. The regenerated fibers were studied 4, 8, and 12 weeks after surgery. Results Functional study confirmed faster recovery of the regenerated axons in the IOVG/FK506 group than in the IOVG group (p < 0.05). There was a statistically significant difference between the mean gastrocnemius muscle weight ratios of the IOVG/FK506 and IOVG control groups (p < 0.05). Morphometric indices of regenerated fibers showed that the number and diameter of the myelinated fibers were significantly higher in the IOVG/FK506 group than in the IOVG control group. Immunohistochemical analysis showed more positive immunoreactivity to S100 protein in the IOVG/FK506 group than in the IOVG control group. Conclusions When loaded in a vein graft, FK506 resulted in improvement of functional recovery and quantitative morphometric indices of sciatic nerve. Topical application of this readily available agent offers the benefit of cost savings as well as avoiding the complications associated with systemic administration.

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Section: 19mentioning

confidence: 99%

Effects of topically administered FK506 on sciatic nerve regeneration and reinnervation after vein graft repair of short nerve gaps

Azizi

Mohammadi

Amini

et al. 2012

FOC

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“…FKBP12 and FKBP52 are up-regulated in regenerating neurons suggesting they may play a protective or regenerative role following injury (15). Additionally, the neuroimmunophilins, FKBP12 and FKBP52, serve as binding proteins for immunosuppressant drugs such as FK506 (16) and derivatives V-10,367 (17), GPI-1046 (18), and JNJ-460 (19) that stimulate neurite outgrowth and promote regeneration. Presently, however, little is known about the mechanisms by which immunophilins regulate cell signaling and neuroprotection.…”

Section: Fkbp52mentioning

confidence: 99%

A Novel Role for the Immunophilin FKBP52 in Copper Transport

Sanokawa-Akakura

Dai

Akakura

et al. 2004

Journal of Biological Chemistry

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FK506-binding protein 52 (FKBP52) is an immunophilin that possesses peptidylprolyl cis/trans-isomerase(PPIase) activity and is a component of a subclass of steroid hormone receptor complexes. Several recent studies indicate that immunophilins can regulate neuronal survival and nerve regeneration although the molecular mechanisms are poorly understood. To investigate the function of FKBP52 in the nervous system, we employed a yeast two-hybrid strategy using the PPIase domain (domain I) as bait to screen a neonatal rat dorsal root ganglia cDNA expression library. We identified an interaction between FKBP52 domain I and Atox1, a copper-binding metallochaperone. Atox1 interacts with Menkes disease protein and Wilson disease protein (WD) and functions in copper efflux. The interaction between FKBP52 and Atox1 was observed in both glutathione S-transferase pull-down experiments and when proteins were ectopically expressed in human embryonic kidney (HEK) 293T cells and was sensitive to FK506. Interestingly, the FKBP52/Atox1 interaction was enhanced when HEK 293T cells were cultured in copper-supplemented medium and decreased in the presence of the copper chelator, bathocuproine disulfate, suggesting that the interaction is regulated in part by intracellular copper. Overexpression of FKBP52 increased rapid copper efflux in 64 Cu-loaded cells, as did the overexpression of WD transporter. Taken together, our present findings suggest that FKBP52 is a component of the copper efflux machinery, and in so, may also promote neuroprotection from copper toxicity. FKBP521 is a high molecular weight FK506-binding immunophilin first identified as a component of steroid hormone receptor heterocomplexes (1). Analysis of mRNA and protein levels has demonstrated that FKBP52 is widely expressed in mammalian tissues but particularly abundant in the nervous system (2, 3). Structurally, FKBP52 contains an N-terminal peptidylprolyl cis-trans-isomerase (PPIase) domain (domain I), a FKBP-like pseudo domain (domain II), three tetratricopeptide repeat (TPR) domains (domain III) that mediate proteinprotein interactions with HSP90, and a C-terminal domain calmodulin-binding site (domain IV) (4, 5).FKBP52 has been shown to play important roles in a diverse number of intracellular processes, but much research has focused on its involvement in steroid hormone regulation. FKBP52 regulates the maturation of steroid hormone receptor complexes through interactions between its TPR domain and HSP90 chaperones, which act as scaffolds for receptor assembly and are thought to enhance the affinity of estrogen receptor and the glucocorticoid receptor toward their ligands (1, 6). The PPIase domain of FKBP52 facilitates translocation of the activated steroid receptors to the nucleus by binding to cytoplasmic dynein (7). FKBP52 serves as a transcriptional regulator by repressing the activity of interferon regulatory factor-4 in immune cells (8) and heat-shock factor-1 in HeLa cells (9). FKBP52 has been implicated in the cardiotrophic effect of cardiotrophin-1 (10...

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“…Recently, neuroregenerative and neuroprotective properties have been assigned to FK506 and related compounds in a number of neurological disease models for Alzheimer's and Parkinson's diseases, as well as in more general neuropathy models (Gold et al, 1997(Gold et al, , 2004Avramut et al, 2001;Guo et al, 2001). At first, the immunosuppressive properties of FK506 were thought to be responsible for these properties.…”

Section: Introductionmentioning

confidence: 99%