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Thread: Nerve growth success

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    Senior Member Max's Avatar
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    My friend in the hospital suffered lack of oxygen to his optic nerve because of excessive blood loss. In such a situation where the damage was not necessarily localized, does this research give hope that he will get his vision back?

    [This message was edited by Eric Texley on December 09, 2001 at 11:32 AM.]

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    scar tissue?

    And is it really the scar tissue rather than "nogo" that stops nerves from regrowing? I hear so many different things...some people say it's a protein, some people say it's a mechanical and Susan Gould (Science) says that nerves DO regrow, just very very slowly.

    Just how long is the window of opportunity before scar tissue forms ? Is there something additional that can be done in the acute stage to limit scar tissue formation? How many more people will become paralyzed because Drs have to follow cookbook recipes?

    [This message was edited by Eric Texley on December 09, 2001 at 11:32 AM.]

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    Peripheral nerves?

    And whatever happened to the idea of damaging an interconnected peripheral nerve, thus causing the central nerve to "switch gears" ... I remeber an article on this back in 1999... Basically it implied that peripheral nerve grafting is an outdated concept. Yet people are still doing it. Do scientists read each other's publications?

  5. #5
    Eric,

    Let me first comment on this German study that seems to have hit the European media. Many researchers have now reported regeneration in the optic nerve in animals. I posted the abstract of the article from Fischer, et al. (2001)
    in the Research Forum. Please understand that this is not the first time that the optic nerve has been reported to regenerate although these results are possibly the most impressive to date. Miller (2001) recently reviewed much of the published literature on the subject.

    Regeneration of the optic nerve has been known to occur for over a decade. Albert Aguayo summarized many of the early studies which suggest that the environment of the eye and the optic nerve influences the degeneration and regeneration of optic nerves.

    About 6 years ago, Martin Berry and colleagues reported that they were able to stimulate impressive regeneration by transplanting peripheral nerves to the eyes of rats. I remember hearing a presentation by Martin Berry at the time and was very impressed by the river of axons that seemed to be growing across the transection site of optic nerves, crossing the optic chiasm and heading to the brain. These results have been extended by Berry and others recently suggesting that there are functional restoration associated with such regeneration.

    Michal Schwartz's laboratory has shown that activated macrophages and other immune manipulations can also facilitate optic nerve regeneration (see Lazarov, et al. below). Likewise, Lisa McKerracher (who worked with Aguayo) has long used the optic nerve system to test a variety of regenerative therapies. Many of these researchers, as you know, have now turned their attention to the spinal cord.

    Wise.


    • Aguayo AJ, Rasminsky M, Bray GM, Carbonetto S, McKerracher L, Villegas-Perez MP, Vidal-Sanz M and Carter DA (1991). Degenerative and regenerative responses of injured neurons in the central nervous system of adult mammals. Philos Trans R Soc Lond B Biol Sci. 331 (1261): 337-43. Summary: In adult mammals, the severing of the optic nerve near the eye is followed by a loss of retinal ganglion cells (RGCs) and a failure of axons to regrow into the brain. Experimental manipulations of the non-neuronal environment of injured RGCs enhance neuronal survival and make possible a lengthy axonal regeneration that restores functional connections with the superior colliculus. These effects suggest that injured nerve cells in the mature central nervous system (CNS) are strongly influenced by interactions with components of their immediate environment as well as their targets. Under these conditions, injured CNS neurons can express capacities for growth and differentiation that resemble those of normally developing neurons. An understanding of this regeneration in the context of the cellular and molecular events that influence the interactions of axonal growth cones with their non-neuronal substrates and neuronal targets should help in the further elucidation of the capacities of neuronal systems to recover from injury. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&li st_uids=1677478> Centre for Research in Neuroscience, McGill University, Montreal, Quebec, Canada.

    • Berry M, Carlile J and Hunter A (1996). Peripheral nerve explants grafted into the vitreous body of the eye promote the regeneration of retinal ganglion cell axons severed in the optic nerve. J Neurocytol. 25 (2): 147-70. Summary: We have conducted experiments in the adult rat visual system to assess the relative importance of an absence of trophic factors versus the presence of putative growth inhibitory molecules for the failure of regeneration of CNS axons after injury. The experiments comprised three groups of animals in which all optic nerves were crushed intra-orbitally: an optic nerve crush group had a sham implant-operation on the eye; the other two groups had peripheral nerve tissue introduced into the vitreous body; in an acellular peripheral nerve group, a frozen/thawed teased sciatic nerve segment was grafted, and in a cellular peripheral nerve group, a predegenerate teased segment of sciatic nerve was implanted. The rats were left for 20 days and their optic nerves and retinae prepared for immunohistochemical examination of both the reaction to injury of axons and glia in the nerve and also the viability of Schwann cells in the grafts. Anterograde axon tracing with rhodamine-B provided unequivocal qualitative evidence of regeneration in each group, and retrograde HRP tracing gave a measure of the numbers of axons growing across the lesion by counting HRP filled retinal ganglion cells in retinal whole mounts after HRP injection into the optic nerve distal to the lesion. No fibres crossed the lesion in the optic nerve crush group and dense scar tissue was formed in the wound site. GAP-43-positive and rhodamine-B filled axons in the acellular peripheral nerve and cellular peripheral nerve groups traversed the lesion and grew distally. There were greater numbers of regenerating fibres in the cellular peripheral nerve compared to the acellular peripheral nerve group. In the former, 0.6-10% of the retinal ganglion cell population regenerated axons at least 3-4 mm into the distal segment. In both the acellular peripheral nerve and cellular peripheral nerve groups, no basal lamina was deposited in the wound. Thus, although astrocyte processes were stacked around the lesion edge, a glia limitans was not formed. These observations suggest that regenerating fibres may interfere with scarring. Viable Schwann cells were found in the vitreal grafts in the cellular peripheral nerve group only, supporting the proposition that Schwann cell derived trophic molecules secreted into the vitreous stimulated retinal ganglion cell axon growth in the severed optic nerve. The regenerative response of acellular peripheral nerve-transplanted animals was probably promoted by residual amounts of these molecules present in the transplants after freezing and thawing. In the optic nerves of all groups the astrocyte, microglia and macrophage reactions were similar. Moreover, oligodendrocytes and myelin debris were also uniformly distributed throughout all nerves. Our results suggest either that none of the above elements inhibit CNS regeneration after perineuronal neurotrophin delivery, or that the latter, in addition to mobilising and maintaining regeneration, also down regulates the expression of axonal growth cone-located receptors, which normally mediate growth arrest by engaging putative growth inhibitory molecules of the CNS neuropil. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&li st_uids=8699196> Division of Anatomy and Cell Biology, UMDS (Guy's Campus), London, UK.

    • Berry M, Carlile J, Hunter A, Tsang W, Rosustrel P and Sievers J (1999). Optic nerve regeneration after intravitreal peripheral nerve implants: trajectories of axons regrowing through the optic chiasm into the optic tracts. J Neurocytol. 28 (9): 721-41. Summary: We have studied axon regeneration through the optic chiasm of adult rats 30 days after prechiasmatic intracranial optic nerve crush and serial intravitreal sciatic nerve grafting on day 0 and 14 post-lesion. The experiments comprised three groups of treated rats and three groups of controls. All treated animals received intravitreal grafts either into the left eye after both left sided (unilateral) and bilateral optic nerve transection, or into both eyes after bilateral optic nerve transection. Control eyes were all sham grafted on day 0 and 14 post-lesion, and the optic nerves either unlesioned, or crushed unilaterally or bilaterally. No regeneration through the chiasm was seen in any of the lesioned control optic nerves. In all experimental groups, large numbers of axons regenerated across the optic nerve lesions ipsilateral to the grafted eyes, traversed the short distal segment of the optic nerve and invaded the chiasm without deflection. Regeneration was correlated with the absence of the mesodermal components in the scar. In all cases, axon regrowth through the chiasm appeared to establish a major crossed and a minor uncrossed projection into both optic tracts, with some aberrant growth into the contralateral optic nerve. Axons preferentially regenerated within the degenerating trajectories from their own eye, through fragmented myelin and axonal debris, and reactive astrocytes, oligodendrocytes, microglia and macrophages. In bilaterally lesioned animals, no regeneration was detected in the optic nerve of the unimplanted eye. Although astrocytes became reactive and their processes proliferated, the architecture of their intrafascicular processes was little perturbed after optic nerve transection within either the distal optic nerve segment or the chiasm. The re-establishment of a comparatively normal pattern of passage through the chiasm by regenerating axons in the adult might therefore be organised by this relatively immutable scaffold of astrocyte processes. Binocular interactions between regenerating axons from both nerves (after bilateral optic nerve transection and intravitreal grafting), and between regenerating axons and the intact transchiasmatic projections from the unlesioned eye (after unilateral optic nerve lesions and after ipsilateral grafting) may not be important in establishing the divergent trajectories, since regenerating axons behave similarly in the presence and absence of an intact projection from the other eye. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&li st_uids=10859575> Division of Human Anatomy and Cell Biology, GKT School of Biomedical Sciences (Guy's Campus), London SE1 9RT, UK.

    • Inoue T, Sasaki H, Hosokawa M and Fukuda Y (2000). Axonal regeneration of mouse retinal ganglion cells by peripheral nerve transplantation; a quantitative study. Restor Neurol Neurosci. 17 (1): 23-29. Summary: Purpose: Retinal ganglion cells (RGCs) of adult mammals can regenerate their axons along a segment of the peripheral nerve (PN) that is transplanted to the cut optic nerve. There have been many trials of PN transplantation to induce axonal regeneration of RGCs in adult rodents, cats and ferrets. However, because of the technical difficulty in transplant operation, PN transplantation in adult mice has not been carried out in spite of the availability of many kinds of gene-manipulated animals. Here we report the procedures for successful PN transplantation in this species. Methods: We made intraretinal (IR) and retrobulbar (RB) approaches for PN transplantation. Four weeks after PN transplantation, RGCs with regenerated axons were identified by retrograde labeling with rhodamine or horseradish peroxidase applied into the PN segment. Results: A quantitative survey showed that the mean regeneration ratio was 1.0 % (n = 8) in IR transplantation, whereas it was only 0.1 % in RB transplantation (n = 11). As previously shown in other species, the regenerated RGCs were predominantly larger-bodied cells in com-parison to intact cells. Conclusion: Possible reasons for the difference in regeneration ratio between the two transplant approaches and the feature of soma size of regenerated RGCs are discussed. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&li st_uids=11490074> Department of Physiology and Biosignaling, Osaka University Graduate School of Medicine, Osaka, Japan.


    • Negishi H, Dezawa M, Oshitari T and Adachi-Usami E (2001). Optic nerve regeneration within artificial Schwann cell graft in the adult rat. Brain Res Bull. 55 (3): 409-19. Summary: We investigate whether an artificial graft made by cultured Schwann cell, extracellular matrix (ECM) and trophic factors can provide the environment for the regeneration of retinal ganglion cell (RGC) axons in adult rats. Six kinds of artificial grafts were used: ECM (control); ECM and Schwann cells; ECM, Schwann cells and either nerve growth factor, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4); ECM, Schwann cells, BDNF and NT-4, combined with intravitreal injection of BDNF. The grafts were transplanted onto the transected optic nerve. RGC regeneration was evaluated by dil retrograde labeling, immunohistochemistry, and electron microscopy at 3 weeks post-operation. The degree of dil labeled RGC was approximately 2% for ECM alone, and 10% for ECM and Schwann cells (p < 0.01). The labeling increased to approximately 20% by administration of neurotrophins. The addition of intravitreous BDNF injection resulted in highest labeling percentage of 30%. Immunohistochemical study showed that axons were association with GAP-43 and cell adhesion molecules. Neurotrophin receptors [Trk-A and Trk-B) were detected in nerve fibers both in the retina and in the graft. Remyelination was seen by electron microscopic observation. These results demonstrate that the regeneration of RGC axons is induced with the use of cultured Schwann cells and ECM as promoting factors for regrowth. The degree of regeneration was significantly increased by neurotrophins in the grafts and in the vitreous. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&li st_uids=11489349> Department of Ophthalmology and Visual Science (D1), Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan. negishi@ophthalm.m.chiba-u.ac.jp

    • Lazarov-Spiegler O, Solomon AS and Schwartz M (1998). Peripheral nerve-stimulated macrophages simulate a peripheral nerve-like regenerative response in rat transected optic nerve. Glia. 24 (3): 329-37. Summary: We have previously demonstrated that the failure of the mammalian central nervous system (CNS) to regenerate following axonal injury is related to its immunosuppressive nature, which restricts the ability of both recruited blood-borne monocytes and CNS-resident microglia to support a process of repair. In this study we show that transected optic nerve transplanted with macrophages stimulated by spontaneously regenerating nerve tissue, e.g., segments of peripheral nerve (sciatic nerve), exhibit axonal regrowth at least as far as the optic chiasma. Axonal regrowth was confirmed by double retrograde labeling of the injured optic axons, visualized in their cell bodies. Transplanted macrophages exposed to segments of CNS (optic) nerve were significantly less effective in inducing regrowth. Immunocytochemical analysis showed that the induced regrowth was correlated with a wide distribution of macrophages within the transplanted-transected nerves. It was also correlated with an enhanced clearance of myelin, known to be inhibitory for regrowth and poorly eliminated after injury in the CNS. These results suggest that healing of the injured mammalian CNS, like healing of any other injured tissue, requires the partnership of the immune system, which is normally restricted, but that the restriction can be circumvented by transplantation of peripheral nerve-stimulated macrophages. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&li st_uids=9775984> Department of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel.


    • Ellezam B, Selles-Navarro I, Manitt C, Kennedy TE and McKerracher L (2001). Expression of netrin-1 and its receptors DCC and UNC-5H2 after axotomy and during regeneration of adult rat retinal ganglion cells. Exp Neurol. 168 (1): 105-15. Summary: Netrins are a family of chemotropic factors that guide axon outgrowth during development; however, their function in the adult CNS remains to be established. We examined the expression of the netrin receptors DCC and UNC5H2 in adult rat retinal ganglion cells (RGCs) after grafting a peripheral nerve (PN) to the transected optic nerve and following optic nerve transection alone. In situ hybridization revealed that both Dcc and Unc5h2 mRNAs are expressed by normal adult RGCs. In addition, netrin-1 was found to be constitutively expressed by RGCs. Quantitative analysis using in situ hybridization demonstrated that both Dcc and Unc5h2 were down-regulated by RGCs following axotomy. In the presence of an attached PN graft, Dcc and Unc5h2 were similarly down-regulated in surviving RGCs regardless of their success in regenerating an axon. Northern blot analysis demonstrated expression of netrin-1 in both optic and sciatic nerve, and Western blot analysis revealed the presence of netrin protein in both nerves. Immunohistochemical analysis indicated that netrin protein was closely associated with glial cells in the optic nerve. These results suggest that netrin-1, DCC, and UNC5H2 may contribute to regulating the regenerative capacity of adult RGCs. Copyright 2001 Academic Press. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&li st_uids=11170725> Departement de pathologie et biologie cellulaire, Universite de Montreal, Montreal, Quebec, Canada H3C 3J7.

    • Lehmann M, Fournier A, Selles-Navarro I, Dergham P, Sebok A, Leclerc N, Tigyi G and McKerracher L (1999). Inactivation of Rho signaling pathway promotes CNS axon regeneration. J Neurosci. 19 (17): 7537-47. Summary: Regeneration in the CNS is blocked by many different growth inhibitory proteins. To foster regeneration, we have investigated a strategy to block the neuronal response to growth inhibitory signals. Here, we report that injured axons regrow directly on complex inhibitory substrates when Rho GTPase is inactivated. Treatment of PC12 cells with C3 enzyme to inactivate Rho and transfection with dominant negative Rho allowed neurite growth on inhibitory substrates. Primary retinal neurons treated with C3 extended neurites on myelin-associated glycoprotein and myelin substrates. To explore regeneration in vivo, we crushed optic nerves of adult rat. After C3 treatment, numerous cut axons traversed the lesion to regrow in the distal white matter of the optic nerve. These results indicate that targeting signaling mechanisms converging to Rho stimulates axon regeneration on inhibitory CNS substrates. <http://www.jneurosci.org/cgi/content/full/19/17/7537
    http://www.jneurosci.org/cgi/content...act/19/17/7537
    http://www.ncbi.nlm.nih.gov/entrez/q...uids=10460260> Departement de Pathologie et Biologie Cellulaire, Universite de Montreal, Succursale Centreville, Montreal, Quebec H3C 3J7, Canada.

    • Selles-Navarro I, Ellezam B, Fajardo R, Latour M and McKerracher L (2001). Retinal ganglion cell and nonneuronal cell responses to a microcrush lesion of adult rat optic nerve. Exp Neurol. 167 (2): 282-9. Summary: Injury of the optic nerve has served as an important model for the study of cell death and axon regeneration in the CNS. Analysis of axon sprouting and regeneration after injury by anatomical tracing are aided by lesion models that produce a well-defined injury site. We report here the characterization of a microcrush lesion of the optic nerve made with 10-0 sutures to completely transect RGC axons. Following microcrush lesion, 62% of RGCs remained alive 1 week later, and 28% of RGCs, at 2 weeks. Optic nerve sections stained by hematoxylin-based methods showed a thin line of intensely stained cells that invaded the lesion site at 24 h after microcrush lesion. The lesion site became increasingly disorganized by 2 weeks after injury, and both macrophages and blood vessels invaded the lesion site. The microcrush lesion was immunoreactive for chondroitin sulfate proteoglycans (CSPG), and an adjacent GFAP-negative zone developed early after the lesion, disappearing by 1 week. Luxol fast blue staining showed a myelin-free zone at the lesion site, and myelin remained distal to the lesion at 8 weeks. To study the axonal response to microcrush lesion, anterograde tracing was used. Within 6 h after injury all RGC axons retracted back from the site of lesion. By 1 week after injury, axons regrew toward the lesion, but most stopped abruptly at the injury scar. The few axons that were able to cross the injury site did not extend further in the optic nerve white matter by 8 weeks postlesion. Our observations suggest that both the CSPG-positive scar and the myelin-derived growth inhibitory proteins contribute to the failure of RGC regeneration after injury. Copyright 2001 Academic Press. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&li st_uids=11161616> Laboratorio de Oftalmologia Experimental, Facultad de Medicina, Universidad de Murcia, Murcia, Spain.

  6. #6
    Senior Member DA's Avatar
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    i recall seeing in 1992 on science and technology week the supposely first generation of the optic nerve.

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