Restorative Neurology and Neuroscience - Volume 19, issue 1-2

Authors: Müller, Hans W. | Bähr, Mathias

Article Type: Other

Citation: Restorative Neurology and Neuroscience, vol. 19, no. 1-2, pp. 1-1, 2001

Authors: Bosse, Frank | Küry, Patrick | Müller, Hans Werner

Article Type: Research Article

Abstract: Regeneration of the peripheral nervous system after injury depends on a complex sequence of histopathological reactions that comprise a highly reproducible sequence of degenerative reactions, termed Wallerian degeneration. During this period a remodelling of the distal nerve stump prepares a microenvironment that permits successful regrowth of nerve fibers from the proximal nerve fragment. This stereotypical sequence of reactions is reflected by a differential and coordinate expression of genes with specific functions in …the process of regeneration. This review will summarize cellular and molecular reactions that contribute to peripheral nerve regeneration including data of a pilot study in which membrane based cDNA array expression techology was applied. We examined the expression of 588 annotated genes in response to a crush lesion of rat sciatic nerves. Approximately 40 % of the genes spotted onto the array filters showed expression significantly above back-ground and 55 of these detected genes represented differential expression profiles after nerve lesion. This approach revealed to be suitable for systematic screening of regeneration associated genes. Show more

Keywords: Peripheral nervous system (PNS), Schwann cell axon, degeneration, cDNA-array

Citation: Restorative Neurology and Neuroscience, vol. 19, no. 1-2, pp. 5-18, 2001

Authors: Weishaupt, Jochen H. | Bähr, Mathias

Article Type: Research Article

Abstract: Programmed cell death (PCD) or apoptosis is a phenomenon important for proper development and morphological as well as functional fine tuning of the nervous system. In the past two decades it became evident that the same apoptotic machinery, which has crucial functions in dur-ing development, can be reactivated under pathological circumstances in the adult nervous system and contribute to neuronal cell loss due to various neurological disorders like ischemic stroke, neurodegenerative diseases or brain traumata. In …this review, we present the optic nerve transection paradigm as a valuable model for investigation of apoptotic neuronal cell death in the central nervous system (CNS). We review and summarize the most important discoveries regarding molecular pathways and mechanisms of neuronal apoptosis during the past few years, and outline contributions that have been made investigating the death of retinal ganglion cells (RGCs) following transection of the optic nerve. Show more

Citation: Restorative Neurology and Neuroscience, vol. 19, no. 1-2, pp. 19-27, 2001

Authors: Herdegen, Thomas | Waetzig, Vicki

Article Type: Research Article

Abstract: The transection of nerve fibers evokes a characteristic reaction in the injured neurons, the so-called cell body response (CBR), which com-prises aspects of developmental re-differentiation with parallel loss of the transmittory phenotype, efforts or achievement of axonal elongation and re-construction of effective synapses. Neither the signals underlying the onset of CBR nor the programs underlying regeneration are suffi-ciently elucidated. Here we review the putative role of two subfamilies of the MAP kinases, the …JNKs (c-Jun N-terminal kinases) and the p38 kinases in the CBR. Following nerve injury with subsequent CBR, JNKs are rapidly activated and this activation persists for weeks until neu-ronal cell death or successful regeneration. The various functions render JNKs to perfect candidate molecules for the realization of the CBR including axonal transport, activation of c-Jun, modulation of cytoskeletal functions, detection of cytoskeletal alterations, or signal transduc-tion of adhesion molecules in the axon and growth cone. On the other hand, the rapid but transient activation of p38 might interfere with the mitotic arrest, a putative feature of the CBR. Show more

Keywords: cell body response, c-Jun, JNKs, p38, regeneration

Citation: Restorative Neurology and Neuroscience, vol. 19, no. 1-2, pp. 29-39, 2001

Authors: Benowitz, Larry I. | Goldberg, David E. | Irwin, Nina

Article Type: Research Article

Abstract: Axon growth is characterized by a distinctive program of gene expression. We present evidence here that this program is regulated through a purine-sensitive mechanism, and that it can be re-activated in mature CNS neurons to induce extensive axon growth in vitro and in vivo. In dissociated goldfish retinal ganglion cells, the purine nucleoside inosine acts intracellularly to stimulate axon outgrowth by inducing the expression of GAP-43, Tα-1 tubulin, and other growth-associated proteins. The purine …analog 6-thioguanine (6-TG) acts in the opposite fashion, blocking axon growth and the underlying program of molecular changes. Prior studies in PC12 cells have shown that 6-TG selectively inhibits the activity of N-kinase, a 47-49 kDa serine-threonine kinase. Inosine acts as a competitor of 6-TG, suggesting that it acts as an N-kinase agonist, and that this kinase is part of a modular signal transduction pathway controlling axon growth. Following unilateral transections of the corticospinal tract in mature rats, inosine applied to the intact sensorimotor cortex stimulated layer 5 pyramidal cells to upregulate GAP-43 expression and to sprout axon collaterals that crossed the midline and reinnervated regions of the cervical spinal cord which had lost their normal afferents. It will now be important to identify the molecular changes that lie upstream and downstream of N-kinase, and to explore the clinical potential of activating this pathway in patients who have sustained CNS injury. Show more

Citation: Restorative Neurology and Neuroscience , vol. 19, no. 1-2, pp. 41-49, 2001

Authors: Garwood, Jeremy | Rigato, Franck | Heck, Nicolas | Faissner, Andreas

Article Type: Research Article

Abstract: The differentiation and morphogenesis of neural tissues involves a diversity of interactions between neural cells and their environment. Many potentially important interactions occur with the extracellular matrix (ECM), a complex association of extracellular molecules organised into aggregates and polymers. The large modular glycoprotein, Tenascin-C, and the chondroitin sulphate proteoglycan, DSD-1-PG/Phosphacan, have complex and frequently overlapping expression patterns in the developing CNS. Their presence in zones of cell proliferation, migration, and differentiation, as …well as in boundary structures, suggest that they may be involved in the modulation of an extensive range of cellular processes. They are both strongly up-regulated in a range of CNS lesions and pathologies, being components of the glial scar, and expressed by gliomas. Functional roles in many cellular processes are possible through their extensive molecular interaction sites, both with each other, and with many of the same cell surface receptors, adhesion molecules, growth factors and other matrix proteins. These multiple interactions involve sites on both their protein domains and on the heterogeneous carbohydrate groups with which they are post-translationally modified. In vitro assays demonstrate cell-type specific effects on adhesion, migration and the formation and extension of cellular processes, including neurites and axons. Show more

Keywords: RPTP-beta, , chondroitin sulphate proteoglycan, glial scar, glioma, neurite outgrowth, migration, morphogenesis

Citation: Restorative Neurology and Neuroscience, vol. 19, no. 1-2, pp. 51-64, 2001

Authors: Gates, Monte A. | Dunnett, Stephen B.

Article Type: Research Article

Abstract: Over the past few decades astrocytes have emerged from being considered simple packing tissue in the brain to become major players in the development, survival and functioning of central nervous system (CNS) neurons. As the influence that astrocytes (and the various molecules they produce) have on the development of CNS neurons becomes more evident, it will be important to consider how this information can be exploited to bring about better protection, recovery and/or regeneration of circuits …which are destroyed in the adult CNS due to trauma or com-mon neurodegenerative episodes. Although the characterisation of astrocytic responses to brain injuries, neurodegenerative disease, and cell transplantation are becoming more common, we still known little about how astrocytes influence the (re)growth or reconstruction of neural cir-cuitry after the development period is ended, or indeed what is the overall impact of an astrocytic presence on the growth of neurons in the adult CNS. With the major hurdle of recognition of the importance astrocytes in the function and recovery of the adult CNS now cleared, a new chapter in the development of powerful new treatments for CNS disorders and injuries is now open. The following is a brief review of what we know about how astrocytes influence the growth and connectivity of the nigrostriatal circuit during development, and how these cells may affect efforts to reform this circuit after its destruction/degeneration in the adult CNS (as commonly happens in Parkinsons disease). As we obtain more information on the specific influence of these cells in various developmental, traumatic and disease events we can expect to find better ways toward combating major disorders of the human CNS. Show more

Keywords: astrocyte, nigrostriatal circuit, brain injury, neurodegenerative disease, repair, reconstruction, circuitry, transplantation, development

Citation: Restorative Neurology and Neuroscience, vol. 19, no. 1-2, pp. 67-83, 2001

Authors: Rossi, Ferdinando | Buffo, Annalisa | Strata, Piergiorgio

Article Type: Research Article

Abstract: Axon regeneration in the mammalian brain requires that injured neurons upregulate a specific set of growth-associated genes. To investigate the mechanisms that control the intrinsic growth properties of adult central neurons. we have examined the response to injury and regenerative potential of different cerebellar and precerebellar neuron populations. Axotomised neurons in the inferior olive, deep cerebellar nuclei and lateral reticular nucleus upregulate growth-associated molecules and regenerate their neurites into growth-permissive transplants. In contrast, Purkinje cells fail to respond to injury and show extremely poor regenerative capabilities. Targeted overexpression of GAP-43 promotes Purkinje axon plasticity, indicating that the weak regenerative potential …of these neurons is mainly due to the inability to activate growth-associated genes. Application of neutralising antibodies against the myelin-assoeiated protein Nogo-A induces cell body changes and axonal sprouting in intact Purkinje cells. In addition, immature injured Purkinje cells respond to axotomy and regenerate transected neurites, but they progressively lose this ability during postnatal development in parallel with myelin formation and the establishment of intracortical connections. These results indicate that the intrinsic growth potential of Purkinje cells is constitutively inhibited by environmental Signals directed at stabilising the mature connectivity and preventing aberrant neuritic plasticity. Such a strict control eventually leads to restrict the regenerative capabilities of these neurons after injury. Show more

Keywords: axon regeneration, growth-associated genes, Purkinje cells, Nogo-A, myelin, axotomy, cerebellum

Citation: Restorative Neurology and Neuroscience, vol. 19, no. 1-2, pp. 85-94, 2001

Authors: Strata, Piergiorgio | Buffo, Annalisa | Rossi, Ferdinando

Article Type: Research Article

Abstract: Mature neurons display a wide range of regenerative capabilities. As a general rule, peripheral neurons have the highest regenerative abilities both in the form of terminal sprouting and of axonal elongation following axotomy, regardless of the distance of the lesion from the cell body. In contrast, in central neurons reactive sprouting has been demonstrated in a limited number of neuronal populations and this type of growth may be dependent on the constitutive presence of specific growth-associated …proteins. Central axon elongation is critically dependent on the presence of suitable environment and on the intrinsic capabilities of each neuronal population. These capabilities are controlled at least in part by repressive signals that are mainly located along the axons. They are more easily disclosed when a short axon stump is left after axotomy. The adult olivary neurons offer a unique model in the central nervous system for their remarkable plastic properties: i) they undergo extensive remodeling of their terminal arborizations following target manipulations or under the influence of electrical activity; ii) they are capable of axonal regeneration in a suitable environment; iii) their response to injury does not depend on the distance of the axotomy from the cell body. In this respect they are similar to peripheral neurons and likely their target cells are the main source of the repressive signals control-ling growth genes. The demonstration that this pathway is also able to find the proper target cells provides a striking example of how the mature brain may be repaired through appropriate manipulations. Show more

Keywords: cerebellum, regeneration, axotomy, sprouting, reinnervation, growth program

Citation: Restorative Neurology and Neuroscience, vol. 19, no. 1-2, pp. 95-106, 2001

Authors: Chierzi, Sabrina | Fawcett, James W.

Article Type: Research Article

Abstract: Since the first studies on axonal regeneration, the optic nerve (ON) of higher vertebrates has been considered a good experimental system to investigate the failure of mature CNS neurons to re-grow after axotomy. The optic nerve is composed of a single population of fibers the RGC axons and, being separated from the rest of the brain, it is easily accessible to surgical manipulations. All the fibers can be transected without massive damage to the …surrounding tissue, so their reaction to axotomy is not perturbed by extended inflammation processes. Another advantage of the system is the accessibility of RGCs. Being in the more internal retinal layer, RGCs are directly exposed to the humor vitreus, the liquid filling the posterior chamber of the eye. Pharmaceutical treatments are easily injected into the eye and, diffusing in the vitreus, can reach all the RGCs. Last but not least, functional recovery can be easily monitored in the optic nerve; measurement of electrical activity in response to visual stimuli in CNS regions that receive inputs from the retina such as superior colliculus or visual cortex allows evaluation of the re-growth of ON fibers and the restoration of connections. All the experiments carried out so far indicate that the failure of regeneration in the ON, as in the majority of the CNS districts, is a multi-factorial phenomenon, involving three classes of negative events. 1) RGCs die after axotomy: in the adult rat, their number is reduced to a very small percentage in a few weeks after the lesion. 2) The majority of mature axotomised RGCs are not programmed to re-start the process of axonal elongation that they displayed in immature stages. 3) The optic nerve environment contains molecules many of them upregulated after the lesion that are inhibitory for axonal growth. This review, focused on experiments performed in the mammalian optic nerve, traces attempts made to overcome each of these three obstacles, and maps progress towards a combined therapeutic strategy. Show more

Keywords: Optic Nerve, Central Nervous System, Regeneration, Retinal Ganglion Cell, Axonal Growth, Axotomy

Citation: Restorative Neurology and Neuroscience, vol. 19, no. 1-2, pp. 109-118, 2001

Authors: Fricker-Gates, Rosemary A. | Lundberg, Cecilia | Dunnett, Stephen B.

Article Type: Research Article

Abstract: During the last 30 years, the promise of neural transplantation as a therapeutic strategy for neurodegenerative disease has been slowly recognised. Across the world, clinical transplants of embryonic primary dopamine neurones have been shown to ameliorate some of the motor deficits in Parkinsons disease (PD) patients, and more recently, systematic clinical trials have been initiated for the replacement of striatal pro-jection neurones lost in Huntington's disease (HD) . Clinical transplantation as a prospective therapy …for HD poses a particular set of difficulties. The hallmarks of this neurodegenerative disease include extensive loss of medium spiny long-distance projection neurones of the caudate and putamen, affecting downstream target nuclei, the globus pallidus and substantia nigra, leading to dysregulation of motor control. In addition, extensive loss of cortical neurones that form the afferent systems to the basal ganglia leads to widespread cognitive decline. If transplantation therapy is to succeed in replacing degenerating neurones in HD and reinstating controlled function of complex basal gan-glia circuitry, the new neurones must be able to develop specific long-distance projections that can form accurate and functional connections with neurones in precise target regions. Our ongoing studies are aimed at addressing how we can improve the function of striatal transplants, in particular to optimise the reforma-tion of precise long-distance connections and to re-establish normal motor and cognitive function. In particular, we have investigated optimal requirements for embryonic primary tissue to achieve these aims, and also the potential of other cell sources to provide long-distance projection neurones and reconnect complex circuitry. This review describes current progress of experiments to optimise the reconstruction of neu-ronal circuitry using primary embryonic tissue transplants, as well as our current initiatives to use neural stem cells or precursors to replace long distance projection neurones in the degenerating basal ganglia. Show more

Keywords: transplantation, neuronal differentiation, behaviour, function, connectivity, Huntingtons Disease, striatum, neural progenitors

Citation: Restorative Neurology and Neuroscience, vol. 19, no. 1-2, pp. 119-138, 2001

Authors: Hermanns, Susanne | Klapka, Nicole | Müller, Hans Werner

Article Type: Research Article

Abstract: After CNS trauma a sheet-like, collagen type IV (Coll IV) immunopositive basement membrane (BM) develops in the lesion zone as well as at newly formed blood vessels. The basic scaffold of this BM is composed of Coll IV, laminin and nidogen but numerous other proteins some of which are discussed to be inhibitory for axonal regeneration, i.e. chondroitin- and heparansufate-proteoglycans, are associated with BM. This review will focus on the collagenous wound healing scar, discuss its …composition and summarize the experimental results that demonstrate its role in the failure of axonal regeneration in the injured mammalian CNS. Show more

Keywords: basement membrane, glial scar, CNS trauma, collagen IV, extracellular matrix,

Citation: Restorative Neurology and Neuroscience, vol. 19, no. 1-2, pp. 139-148, 2001

Authors: Ramón-Cueto, Almudena | Santos-Benito, Fernando F.

Article Type: Research Article

Abstract: The absence of spontaneous axonal regeneration in the adult mammalian central nervous system cause devastating functional consequences in patients with spinal cord injuries. During the past decades several attempts have been made in order to find a strategy to repair injured spinal cords in experimental animals, that could provide a novel therapeutic approach in humans. Cell transplantation has been broadly used as an intervention to influence neuronal survival and axonal regeneration in the severed neuraxis. Of …the cell types used for transplantation, olfactory ensheathing glia (OEG) promoted a dramatic functional improvement and anatomical repair after complete transection of the adult mammalian spinal cord. These cells can be easily obtained from adult donors opening the possibility of autologous transplantation. Grafting OEG to repair injured spinal cords offers some advantages compared to injections of other cell types. Therefore, OEG have become good candidates to bring about repair in damaged spinal cords. In this article we review OEG transplantation studies, discuss the properties that could account for their axonal growth-promoting ability, and the advantages of using OEG as a repair strategy. Show more

Keywords: axonal regeneration, spinal cord injury, functional recovery, Schwann cells, astrocytes, glial scar, cell migration, demyelination

Citation: Restorative Neurology and Neuroscience, vol. 19, no. 1-2, pp. 149-156, 2001