A small dose of the immunosuppressive agent FK506 (tacrolimus) protects peripheral nerve from ischemic fiber degeneration

Kihara, Mikihiro; Kamijo, Mikiko; Nakasaka, Yoshikuni; Mitsui, Yosuke; Takahashi, Mitsuo; Schmelzer, James D.

doi:10.1002/mus.1194

Cited by 13 publications

(5 citation statements)

References 105 publications

(108 reference statements)

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“…6 -17 The prototype immunophilin ligand FK506 has been shown to promote regeneration and functional recovery in in vivo animal models of peripheral nerve injury such as crush injury of sciatic and facial nerves. 8,11,13,24 We recently demonstrated that FK506 exerts potent neuroprotective effects on rat penile innervation and preserves erectile function in a cavernous nerve crush injury model. 18 In instances of sciatic and facial crush nerve injury, FKBP 12 localizations and upregulated expression have been confirmed and linked to nerve regeneration.…”

Section: Discussionmentioning

confidence: 99%

FK506 binding protein 12 is expressed in rat penile innervation and upregulated after cavernous nerve injury

et al. 2002

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To evaluate whether FK506 and other immunophilin ligands may have potential therapeutic efficacy for erectile function preservation after penile nerve injury, we demonstrated localizations of the immunophilin FK506 binding protein 12 (FKBP 12) in intact and injured rat penile nerves and correlated these findings with localizations of neuronal nitric oxide synthase (nNOS), which neuronally forms nitric oxide for mediation of penile erection, in response to systemically administered FK506. Adult male Sprague -Dawley rats were subjected to unilateral right cavernous nerve forceps crush injury and administered FK506 (1 mg=kg i.p.) or saline at the same time and daily up to 7 days. At 1, 3 and 7 days after injury, bilateral cavernous nerves and major pelvic ganglia were collected for nNOS immunohistochemistry, FKBP 12 immunohistochemistry, and FKBP 12 in situ hybridisation. Protein expressions of nNOS and FKBP 12 were observed in major pelvic ganglion, cavernous nerve and nerve terminals within the rat penis as well as mRNA expression of FKBP 12 observed in the rat major pelvic ganglion neuronal cell bodies to a minimal extent at baseline conditions. After cavernous nerve injury, nNOS immunoreactivity was observed to be slightly diminished in ipsilateral penile nerve structures at only one day following injury while both FKBP 12 protein and mRNA expressions were observed to be increased at each interval of study. FK506 treatment did not affect staining of intact or injured nerves. Our demonstration that FKBP 12 is localized to penile innervation in the rat and becomes upregulated following cavernous nerve crush injury, independent of FK506 treatment, suggests that this immunophilin mediates a neurotrophic mechanism. Whether FK506 affords neuroprotection that preserves penile erection through FKBP 12 upregulation is unclear.

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Section: Discussionmentioning

confidence: 99%

FK506 binding protein 12 is expressed in rat penile innervation and upregulated after cavernous nerve injury

et al. 2002

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“…In the clinical setting, the ability to manipulate nerve biology at the cellular level provides a significant improvement in nerve recovery [2,5]. In the last decade, some substances such as tacrolimus, an immunosuppressive agent, and alpha-lipoic acid have been shown to protect peripheral nerve from ischemic degeneration [6,7]. However, controversy still exists regarding peripheral nerve injuries with potentially devastating results at the moment.…”

Section: Introductionmentioning

confidence: 99%

Stereological analysis of sciatic nerve in chickens following neonatal pinealectomy: an experimental study

Turğut

Kaplan

Unal

et al. 2014

J Brachial Plex Peripher Nerve Inj

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BackgroundAlthough the injury to the peripheral nervous system is a common clinical problem, understanding of the role of melatonin in nerve degeneration and regeneration is incomplete.MethodsThe current study investigated the effects of neonatal pinealectomy on the sciatic nerve microarchitecture in the chicken. The chickens were divided into two equal groups: unpinealectomized controls and pinealectomized chickens. At the end of the study, biochemical examination of 10 sciatic nerve samples from both groups was performed and a quantitative stereological evaluation of 10 animals in each group was performed. The results were compared using Mann-Whitney test.ResultsIn this study, the results of axon number and thickness of the myelin sheath of a nerve fiber in newly hatched pinealectomy group were higher than those in control group. Similarly, surgical pinealectomy group had significantly larger axonal cross-sectional area than the control group (p < 0.05). In addition, the average hydroxyproline content of the nerve tissue in neonatal pinealectomy group was higher than those found in control group. Our results suggest that melatonin may play a role on the morphologic features of the peripheral nerve tissue and that melatonin deficiency might be a pathophysiological mechanism in some degenerative diseases of peripheral nerves. The changes demonstrated by quantitative morphometric methods and biochemical analysis has been interpreted as a reflection of the effects of melatonin upon nerve tissue.ConclusionIn the light of these results from present animal study, changes in sciatic nerve morphometry may be indicative of neuroprotective feature of melatonin, but this suggestion need to be validated in the human setting.

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“…[ 23 ] Diabetes mellitus, vascular occlusive diseases, compression injuries, entrapments, tourniquet-induced peripheral nerve injuries, necrotizing vasculitis, and trauma are only a few of the pathological conditions that result in neuropathy associated with peripheral nerve ischemia. [ 17 28 ] The extent and type of damage to the nerve fiber depends on the duration of ischemia and blood flow amount. Furthermore, decompression and restoration of an adequate blood supply to peripheral nerves may predispose the nerves to reperfusion injury.…”

Section: Introductionmentioning

confidence: 99%

Effects of α-MSH on ischemia/reperfusion injury in the rat sciatic nerve

Türkoğlu

Serbes²,

Dolgun³

et al. 2012

Surg Neurol Int

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Background:Ischemia/reperfusion (I/R) causes the production of toxic free radicals and leads to pathological changes in nerve tissue. We investigated the effect of alpha-melanocyte stimulating hormone (α-MSH) in a rat model for sciatic nerve I/R and discuss the possible cytoprotective and antioxidant mechanism of α-MSH against ischemic fiber degeneration.Methods:Experiments were performed using 42 adult male Wistar rats. Rats were divided into six experimental groups: control group, ischemia group, I/R groups, and α-MSH treated groups. Ischemia was produced by clamping of the femoral vessels. Immediately after ischemia that lasted 3 h, 75 μg/kg of α-MSH was administered subcutaneously before reperfusion and the tissue malondialdehyde (MDA) level was evaluated as an indicator of lipid peroxidation in groups with different reperfusion periods.Results:The reperfusion injury did not begin in the first hour of reperfusion after 3 h of ischemia, and MDA levels increased on the first day of reperfusion. During the first day, blood MDA levels were decreased in the α-MSH group compared to the control group. The tissue from animals pre-treated with α-MSH showed fewer morphological alterations. Myelin breakdown was significantly diminished after treatment with α-MSH, and the ultrastructural features of axons showed remarkable improvement. Two-way analysis of variance was used for comparing three or more groups. When a significant difference existed, the post-hoc multiple-comparison test was applied to demonstrate the differences.Conclusions:The results confirm that pre-treatment with α-MSH after ischemia protected the peripheral nerves against I/R injury.

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A small dose of the immunosuppressive agent FK506 (tacrolimus) protects peripheral nerve from ischemic fiber degeneration

Cited by 13 publications

References 105 publications

FK506 binding protein 12 is expressed in rat penile innervation and upregulated after cavernous nerve injury

FK506 binding protein 12 is expressed in rat penile innervation and upregulated after cavernous nerve injury

Stereological analysis of sciatic nerve in chickens following neonatal pinealectomy: an experimental study

Effects of α-MSH on ischemia/reperfusion injury in the rat sciatic nerve

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