Neurotrophin‐4/5 is required for the early growth of regenerating axons in peripheral nerves

English, Arthur W.; Meador, William D.; Carrasco, Darío I.

doi:10.1111/j.1460-9568.2005.04124.x

Cited by 96 publications

(103 citation statements)

References 39 publications

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“…As has been shown elsewhere (English et al, 2005a;Groves et al, 2005), the distribution of axon profile lengths measured in nerve allografts is not statistically normal. Some axons grow very little, even during a two week survival period, while others grow considerably, giving rise to a bimodal distribution of lengths.…”

Section: Discussionmentioning

confidence: 70%

“…The growth of regenerating axons is severely compromised if the environment through which they must grow is deficient in either BDNF (Zhang et al, 2000) or neurotrophin 4/5 (NT-4/5) (English et al, 2005a). Application of either of these molecules at the time of surgical repair of cut peripheral nerves results in an enhancement of the growth of these axons (English et al, 2005a). The traditional, targetderived neurotrophin signaling pathway could underlie this augmentation.…”

Section: Introductionmentioning

confidence: 99%

“…If repair of a cut peripheral nerve is delayed, the regeneration of axons is impaired (Fu and Gordon, 1995b;Fu and Gordon, 1995a) and these effects can be reversed by application of moderate amounts of the trkB ligand, brain derived neurotrophic factor (BDNF) (Boyd and Gordon, 2001;Boyd and Gordon, 2002). The growth of regenerating axons is severely compromised if the environment through which they must grow is deficient in either BDNF (Zhang et al, 2000) or neurotrophin 4/5 (NT-4/5) (English et al, 2005a). Application of either of these molecules at the time of surgical repair of cut peripheral nerves results in an enhancement of the growth of these axons (English et al, 2005a).…”

Section: Introductionmentioning

confidence: 99%

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Electrical stimulation promotes peripheral axon regeneration by enhanced neuronal neurotrophin signaling

et al. 2006

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Electrical stimulation of cut peripheral nerves at the time of their surgical repair results in an enhancement of axon regeneration. Regeneration of axons through nerve allografts was used to evaluate whether this effect is due to an augmentation of cell autonomous neurotrophin signaling in the axons or signaling from neurotrophins produced in the surrounding environment. In the thy-1-YFP-H mouse, a single one hour application of electrical stimulation at the time of surgical repair of the cut common fibular nerve results in a significant increase in the proportion of YFP+ dorsal root ganglion neurons that were also immunoreactive for BDNF or trkB as well as an increase in the length of regenerating axons through allografts from wild type litter mates, both one and two weeks later. Axon growth through allografts from neurotrophin-4/5 knockout mice or grafts made acellular by repeated cycles of freezing and thawing is normally very poor, but electrical stimulation results in a growth of axons through these grafts which is similar to that observed through grafts from wild type mice after electrical stimulation. When cut nerves in NT-4/5 knockout mice were electrically stimulated, no enhancement of axon regeneration was found. Electrical stimulation thus produces a potent enhancement of the regeneration of axons in cut peripheral nerves which is independent of neurotrophin production by cells in their surrounding environment but is dependent on stimulation of trkB and its ligands in the regenerating axons themselves.

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Section: Discussionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Electrical stimulation promotes peripheral axon regeneration by enhanced neuronal neurotrophin signaling

et al. 2006

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“…However, in almost all cases of NGC use, regeneration fails if the nerve gap is increased to 15 mm or longer [12,13]. To enhance the performance of NGCs, additional filler materials (such as hydrogels), growth factors, extracellular matrix (ECM) proteins, and fibers have been used [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Differences between the effect of anisotropic and isotropic laminin and nerve growth factor presenting scaffolds on nerve regeneration across long peripheral nerve gaps

2008

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Anisotropic scaffolds of agarose hydrogels containing gradients of laminin-1 (LN-1) and nerve growth factor (NGF) molecules were used to promote sciatic nerve regeneration across a challenging 20 mm nerve gap in rats.Step and continuous gradient anisotropic scaffolds were fabricated and characterized and regeneration was compared to that in isotropic scaffolds with uniform concentrations of LN-1 and NGF and sciatic nerve grafts harvested from syngenic rats. Polysulfone tubular guidance channels were used to present the agarose based scaffolds to the nerve stumps. Fourmonths after implantation, regenerating axons were observed in animals implanted with anisotropic scaffolds with gradients of both LN-1 and NGF molecules and nerve grafts, but not in animals with isotropic scaffold implants. Also, the scaffolds with gradient of either LN-1 or NGF, with the other component being uniformly distributed in the scaffold, did not elicit axonal regeneration. The total number of myelinated axons was similar for the anisotropic scaffold and the nerve graft conditions, with the anisotropic scaffolds having a higher density of axons than the nerve grafts. Axonal diameter distribution was similar for the anisotropic scaffolds and the nerve grafts. The nerve grafts and anisotropic scaffolds resulted in better functional outcome compared to isotropic scaffolds as measured by the relative gastrocnemius muscle weight (RGMW). Additionally the state of neuromuscular junctions as assessed by pre-and post-synaptic staining revealed that both the anistropic scaffolds performed as well as nerve grafts.

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“…Axon regeneration in cut nerves is severely compromised if the availability of BDNF to regenerating axons is reduced, such as by treatments with function-blocking antibodies (10) or by genetic manipulation of BDNF expression in Schwann cells (9). Local treatment of repaired nerves with recombinant human BDNF (rhBDNF) promotes enhanced early regeneration in mice (9,11).…”

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confidence: 99%

Small-molecule trkB agonists promote axon regeneration in cut peripheral nerves

English¹,

Liu²,

Nicolini³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Treatments with two-small molecule tropomyosin receptor kinase B (trkB) ligands, 7,8 dihydroxyflavone (7,8 DHF) and deoxygedunin, were evaluated for their ability to promote the regeneration of cut axons in injured peripheral nerves in mice in which sensory and motor axons are marked by YFP. Peripheral nerves were cut and repaired with grafts from strain-matched, nonfluorescent donors and secured in place with fibrin glue. Lengths of profiles of regenerating YFP + axons were measured 2 wk later from confocal images. Axon regeneration was enhanced when the fibrin glue contained dilutions of 500-nM solution of either small-molecule trkB agonist. In mice in which the neurotrophin receptor trkB is knocked out selectively in neurons, axon regeneration is very weak, and topical treatment with 7,8 DHF had no effect on axon regeneration. Similar treatments with deoxygedunin had only a modest effect. In conditional BDNF knockout mice, topical treatments with either 7,8 DHF or deoxygedunin resulted in a reversal of the poor regeneration found in controls and produced significant enhancement of regeneration. In WT mice treated with 2 wk of daily i.p. injections of either 7,8 DHF or deoxygedunin (5 mg/kg), regenerating axon profiles were nearly twice as long as in controls. Restoration of direct muscle responses evoked by sciatic nerve stimulation to pretransection levels over an 8-wk survival period was found only in the treated mice. Treatments with either small-molecule trkB agonist enhanced axon regeneration and muscle reinnervation after peripheral nerve injuries.

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Neurotrophin‐4/5 is required for the early growth of regenerating axons in peripheral nerves

Cited by 96 publications

References 39 publications

Electrical stimulation promotes peripheral axon regeneration by enhanced neuronal neurotrophin signaling

Electrical stimulation promotes peripheral axon regeneration by enhanced neuronal neurotrophin signaling

Differences between the effect of anisotropic and isotropic laminin and nerve growth factor presenting scaffolds on nerve regeneration across long peripheral nerve gaps

Small-molecule trkB agonists promote axon regeneration in cut peripheral nerves

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