Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0599766 (functional recovery)
 13,441 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adult mammalian axon regeneration is generally successful in the peripheral nervous system (PNS) but is dismally poor in the central nervous system (CNS). However, many classes of CNS axons can extend for long distances in peripheral nerve grafts. A comparison of myelin from the CNS and the PNS has revealed that CNS white matter is selectively inhibitory for axonal outgrowth. Several components of CNS white matter, NI35, NI250(Nogo) and MAG, that have inhibitory activity for axon extension have been described. The IN-1 antibody, which recognizes NI35 and NI250(Nogo), allows moderate degrees of axonal regeneration and functional recovery after spinal cord injury. Here we identify Nogo as a member of the Reticulon family, Reticulon 4-A. Nogo is expressed by oligodendrocytes but not by Schwann cells, and associates primarily with the endoplasmic reticulum. A 66-residue lumenal/extracellular domain inhibits axonal extension and collapses dorsal root ganglion growth cones. In contrast to Nogo, Reticulon 1 and 3 are not expressed by oligodendrocytes, and the 66-residue lumenal/extracellular domains from Reticulon 1, 2 and 3 do not inhibit axonal regeneration. These data provide a molecular basis to assess the contribution of Nogo to the failure of axonal regeneration in the adult CNS.
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PMID:Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. 1066 97

The lack of regrowth of injured neurons in the adult central nervous system (CNS) of higher vertebrates was accepted as a fact for many decades. In the last few years a very different view emerged; regeneration of lesioned fibre tracts in vivo could be induced experimentally, and molecules that are responsible for inhibition and repulsion of growing neurites have been defined. Mechanisms that link cellular phenomena like growth cone turning or growth cone collapse to intracellular changes in second messenger systems and cytoskeletal dynamics became unveiled. This article reviews recent developments in this field, focusing especially on one of the best characterised neurite out-growth inhibitory molecules found in CNS myelin that was recently cloned: Nogo-A. Nogo-A is a high molecular weight transmembrane protein and an antigen of the monoclonal antibody mAb IN-1 that was shown to promote long-distance regeneration and functional recovery in vivo when applied to spinal cord-injured adult rats. Nogo-A is expressed by oligodendrocytes in white matter of the CNS. With the molecular characterisation of this factor new possibilities open up to achieve structural and functional repair of the injured CNS.
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PMID:Nogo-A, a potent inhibitor of neurite outgrowth and regeneration. 1093 71

Axons in the CNS of higher vertebrates generally fail to regenerate after injury. This lack of regeneration is crucially influenced by neurite growth inhibitory protein constituents of CNS myelin. We have shown previously that a monoclonal antibody (mAb IN-1) capable of binding and neutralizing Nogo-A, a myelin-associated inhibitor of neurite growth, can induce long-distance axonal regeneration and increased structural plasticity with improved functional recovery in rat models of CNS injury. In this paper we demonstrate that a partially humanized, recombinant Fab fragment (rIN-1 Fab) derived from the original mAb IN-1, was able to promote long-distance regeneration of injured axons in the spinal cord of adult rats. When infused into a spinal cord injury site, regrowth of corticospinal fibers in 11 of 18 animals was observed after a survival time of 2 weeks. Regenerating fibers grew for >9 mm beyond the lesion site and arborized profusely in the distal cord. Regenerated fibers formed terminal arbors with varicosities in the spinal cord gray matter, strongly resembling synaptic points of contact to neurons in the spinal cord distal to the lesion. In animals that had received a bovine serum albumin solution or a recombinant IN-1 fragment that had been mutated in the antigen binding site (mutIN-1 Fab), no significant growth beyond normal lesion-induced sprouting was observed. Neutralization of endogenous nerve growth inhibitors represents a novel use of recombinant antibody technology with potential therapeutic applications after traumatic CNS lesions.
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PMID:Regeneration of lesioned corticospinal tract fibers in the adult rat induced by a recombinant, humanized IN-1 antibody fragment. 1105 Jan 27

During the past year, a major advance in the study of axon regeneration was the molecular cloning of Nogo. The expression of Nogo protein by CNS myelin may be a major factor in the failure of CNS axon regeneration. The effect of disrupting Nogo-dependent axon inhibition can now be studied conclusively. In related work, immunization with a Nogo-containing CNS myelin preparation was shown to promote regeneration and dramatic functional recovery after spinal cord trauma.
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PMID:Repulsive factors and axon regeneration in the CNS. 1117 77

The limited plastic and regenerative capabilities of axons in the adult mammalian CNS can be enhanced by the application of a monoclonal antibody (mAb), IN-1, raised against the myelin-associated neurite growth inhibitor Nogo-A. The aim of the present study was to investigate the effects of this treatment on the functional recovery of adult rats with a dorsal over-hemisection of the spinal cord. Directly after injury, half of the animals were implanted with mAb IN-1-secreting hybridoma cells, whereas the others received cells secreting a control antibody (anti-HRP). A broad spectrum of locomotor tests (open field locomotor) score, grid walk, misstep withdrawal response, narrow-beam crossing) was used to characterize locomotor recovery during the 5 weeks after the injury. In all behavioral tests, the recovery in the mAb IN-1-treated group was significantly augmented compared with the control antibody-treated rats. EMG recordings of flexor and extensor muscles during treadmill walking confirmed the improvement of the locomotor pattern in the mAb IN-1-treated rats; step-cycle duration, rhythmicity, and coupling of the hindlimbs were significantly improved. No differences between the two groups with regard to nociception were observed in the tail flick test 5 weeks after the operation. These results indicating improved functional recovery suggest that the increased plastic and regenerative capabilities of the CNS after Nogo-A neutralization result in a functionally meaningful rewiring of the motor systems.
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PMID:Locomotor recovery in spinal cord-injured rats treated with an antibody neutralizing the myelin-associated neurite growth inhibitor Nogo-A. 1133 96

Following injury, axons of the adult mammalian central nervous system (CNS) fail to regenerate. As a result, CNS trauma generally results in severe and persistent functional deficits. The inability of CNS axons to regenerate is largely associated with nonneuronal aspects of the CNS environment that are inhibitory to axonal elongation. This inhibition is mediated by the glial scar, including reactive astrocytes, and by the myelin-associated neurite outgrowth inhibitors chondroitin sulfate proteoglycans, myelin-associated glycoprotein, and Nogo. Nogo is an integral membrane protein that localizes to CNS, but not peripheral nervous system, myelin. In vitro characterization of Nogo has demonstrated its function as a potent inhibitor of axon elongation. In vivo neutralization of Nogo activity results in enhanced axonal regeneration and functional recovery following CNS injury as well as increased plasticity in uninjured CNS fibers. These findings suggest that Nogo may be a major contributor to the nonpermissive nature of the CNS environment.
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PMID:Nogo: a molecular determinant of axonal growth and regeneration. 1159 97

Stroke is a prevalent and devastating disorder, and no treatment is currently available to restore lost neuronal function after stroke occurs. One unique therapy that may improve functional recovery after stroke is blockade of the neurite inhibitory protein Nogo-A with the monoclonal antibody IN-1, through enhancement of neuroanatomical plasticity from uninjured areas of the central nervous system. In the present study, we combined IN-1 treatment with an ischemic lesion (permanent middle cerebral artery occlusion) to determine the effect of Nogo-A neutralization on cortical plasticity and functional recovery. We report here that, following ischemic stroke and treatment with IN-1, adult rats demonstrated functional recovery on a forelimb-reaching task and new cortico-efferent projections from the opposite, unlesioned hemisphere. These results support the efficacy of Nogo-A blockade as a treatment for ischemic stroke and implicate plasticity from the unlesioned hemisphere as a mechanism for recovery.
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PMID:Functional recovery and neuroanatomical plasticity following middle cerebral artery occlusion and IN-1 antibody treatment in the adult rat. 1192 Oct 49

Myelin-derived axon outgrowth inhibitors, such as Nogo, may account for the lack of axonal regeneration in the central nervous system (CNS) after trauma in adult mammals. A 66-residue domain of Nogo (Nogo-66) is expressed on the surface of oligodendrocytes and can inhibit axonal outgrowth through an axonal Nogo-66 receptor (NgR). The IN-1 monoclonal antibody recognizes Nogo-A and promotes corticospinal tract regeneration and locomotor recovery; however, the undefined nature of the IN-1 epitope in Nogo, the limited specificity of IN-1 for Nogo, and nonspecific anti-myelin effects have prevented a firm conclusion about the role of Nogo-66 or NgR. Here, we identify competitive antagonists of NgR derived from amino-terminal peptide fragments of Nogo-66. The Nogo-66(1 40) antagonist peptide (NEP1 40) blocks Nogo-66 or CNS myelin inhibition of axonal outgrowth in vitro, demonstrating that NgR mediates a significant portion of axonal outgrowth inhibition by myelin. Intrathecal administration of NEP1 40 to rats with mid-thoracic spinal cord hemisection results in significant axon growth of the corticospinal tract, and improves functional recovery. Thus, Nogo-66 and NgR have central roles in limiting axonal regeneration after CNS injury, and NEP1-40 provides a potential therapeutic agent.
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PMID:Nogo-66 receptor antagonist peptide promotes axonal regeneration. 1203 67

Three different myelin proteins, Nogo, MAG, and OMgp, inhibit regenerating axons after CNS injury. New work reveals that they all share a common receptor and that blockade of this receptor promotes CNS repair and functional recovery.
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PMID:Nerve regeneration: regrowth stumped by shared receptor. 1236 84

Injured axons in mammalian peripheral nerves often regenerate successfully over long distances, in contrast to axons in the brain and spinal cord (CNS). Neurite growth-inhibitory proteins, including the recently cloned membrane protein Nogo-A, are enriched in the CNS, in particular in myelin. Nogo-A is not detectable in peripheral nerve myelin. Using regulated transgenic expression of Nogo-A in peripheral nerve Schwann cells, we show that axonal regeneration and functional recovery are impaired after a sciatic nerve crush. Nogo-A thus overrides the growth-permissive and -promoting effects of the lesioned peripheral nerve, demonstrating its in vivo potency as an inhibitor of axonal regeneration.
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PMID:Nogo-A expressed in Schwann cells impairs axonal regeneration after peripheral nerve injury. 1237 1


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