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

Currently available therapeutics has been less effective in promoting functional recovery from stroke or other injuries in the central nervous system (CNS). Axonal damage is a characteristic pathology seen in CNS injuries. Previously, it was reported that Nogo-A extracellular peptide residues 1-40 (NEP1-40), a competitive antagonist of Nogo-66 receptor (NgR1), has the ability to promote axonal regrowth and functional recovery after CNS injury. However, delivery of the therapeutic proteins into the brain parenchyma is limited due to its inability to cross the blood-brain barrier (BBB). We first generated a biologically active NEP1-40 fusion protein containing the protein transduction domain (PTD) of the transactivator of transcription (TAT), TAT-NEP1-40, which crosses the BBB in vivo after systemic delivery. The TAT-NEP1-40 can protect PC12 cells against oxygen and glucose deprivation (OGD) and promote neurite outgrowth when added exogenously to culture medium. The TAT-NEP1-40 protein transduced into the brain continued to sustain biological activities and protected the brain against ischemia/reperfusion injury through inhibition of neuronal apoptosis. Collectively, our data suggest that TAT-NEP1-40 may be a novel therapeutic candidate for axonal regeneration and functional recovery from CNS injuries such as cerebral hypoxia-ischemia, cerebral hemorrhage, brain trauma, and also for spinal cord injury.
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PMID:TAT-NEP1-40 as a novel therapeutic candidate for axonal regeneration and functional recovery after stroke. 2036 26

The purpose of this study was to investigate the effects of combination therapy with methylprednisolone (MP) and Nogo-66 antagonistic peptide (NEP1-40) on morphological and functional recovery in adult rats subjected to thoracic compression spinal cord injury (SCI). Animals were randomized into four groups: a trauma control group, an MP group, an NEP1-40 group, and a combined treatment group. The inflammatory reaction, neuronal and oligodendrocyte survival, and ultrastructure were assessed at the injury site. Functional analysis was also performed using Basso, Beattie and Bresnahan (BBB) scoring. Rat behaviour was evaluated regularly up to week 4. NEP1-40 did not alter the beneficial effect of MP on haematogenous inflammatory cell infiltration, while combined treatment resulted in greater neuronal and oligodendrocyte survival compared with monotherapy or control. Combination therapy resulted in better locomotor scores. These results in a clinically-relevant SCI model showed that significant neuroprotection can be obtained by combining an initial acute IV injection of MP with continuously infused NEP1-40.
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PMID:Effect of combined treatment with methylprednisolone and Nogo-A monoclonal antibody after rat spinal cord injury. 2051 70

Small lesions of the adult central nervous system (CNS) often have a good prognosis with extensive functional recovery based in part on spontaneous neuritic sprouting and rearrangements of projections. This is well documented for the cortex, but these changes can also occur in the spinal cord. Nogo-A is a protein present in CNS myelin that inhibits neurite growth. Models of spinal cord injury (SCI) in rats and macaque monkeys demonstrate that treatment with function-blocking antibodies of Nogo-A results in an upregulation of growth-specific proteins, enhanced regenerative and compensatory sprouting of fibers, and the formation of new functional connections in the spinal cord. In animals with unilateral sensorimotor cortex lesions followed by Nogo-A antibody treatment, fibers from the intact corticofugal system crossed the midline, supplying innervation to the denervated brain stem or spinal cord. Behavioral tests showed marked improvements of functional recovery in the Nogo-A antibody treated spinal cord- or brain-injured animals. A Phase I clinical trial applying anti-Nogo-A antibody to subjects with acute SCI has been successfully conducted and a multicentric, multinational Phase II trial is currently in preparation.
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PMID:Anti-Nogo on the go: from animal models to a clinical trial. 2059 May 35

The rewiring of neural networks is a fundamental step in recovering behavioral functions after brain injury. However, there is limited potential for axonal plasticity in the adult CNS. The myelin-associated proteins Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp) are known to inhibit axonal plasticity, and thus targeting the inhibitory pathways they participate in is a potential means of promoting plasticity and functional recovery. Each of Nogo, MAG, and OMgp interacts with both the Nogo receptor (NgR) and paired immunoglobulin-like receptor B (PirB). Here, we determined whether blocking PirB activity enhances axonal reorganization and functional recovery after cortical injury. We found that axons of the contralesional corticospinal tract sprouted into the denervated side of the cervical spinal cord after unilateral injury of the motor cortex. The extent to which this axonal reorganization occurred was far greater in mice lesioned during early postnatal days than in mice lesioned at an age when myelin had begun to form. This suggests that myelin-associated proteins might limit axonal remodeling in vivo. However, the number of sprouting fibers within either the corticospinal or corticorubral tract was not enhanced in PirB(-/-) mice. Blocking PirB signaling also failed to enhance functional recovery with three motor tests. Our results suggest that blocking the function of PirB is not sufficient to promote axonal reorganization or functional recovery after cortical injury.
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PMID:Genetic deletion of paired immunoglobulin-like receptor B does not promote axonal plasticity or functional recovery after traumatic brain injury. 2088 Nov 22

Amblyopia is difficult to cure in adult due to the declination of visual cortical plasticity with age. However, the mechanisms limiting adult cortical plasticity are still unclear. Inhibition factors associated with myelin are suggested to be crucial for the ocular dominance plasticity in the visual cortex. We hypothesize that blocking Nogo-NgR system with NEP1-40 in adult visual cortex will reactivate the structural and functional plasticity. To back up this hypothesis, we subjected postnatal day 21 (P21) rats to monocular deprivation (MD) model until P45. Then the deprived eyes of MD model rats were reopened and followed by NEP1-40 or PBS administration for 7days. Dendritic spine densities, ultrastructral modifications of synaptic junctions and objective visual function were examined at P52 to determine the therapeutic effects of NEP1-40. Our findings suggest a new curative role for NEP1-40 in structural and functional recovery from the deficits of adult MD rats, and offer a potential therapeutic tool for curing amblyopia and other cortically based visual disorders.
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PMID:Reactivation of visual cortical plasticity by NEP1-40 from early monocular deprivation in adult rats. 2139 58

Nogo-A limits axon regeneration and functional recovery after central nervous system injury in adult mammals. Three regions of Nogo-A (Nogo-A-24, Nogo-66, and Nogo-C39) interact with the neuronal Nogo-66 receptor 1 (NgR1). Nogo-66 also interacts with a structurally unrelated cell surface receptor, paired immunoglobulin-like receptor (PirB). We show here that the other two NgR1-interacting domains, Nogo-A-24 and Nogo-C39, also bind to PirB with high affinity. A purified 22-kDa protein containing all three NgR1- and PirB-interacting domains (Nogo-22) is a substantially more potent growth cone-collapsing molecule than Nogo-66 for chick dorsal root ganglion neurons and mature cortical neurons. Moreover, Nogo-22 inhibits axon regeneration of mature cortical neurons in vitro more potently than does Nogo-66. Although all three NgR1-interacting domains of Nogo-A also interact with PirB, expression of PirB in mature cortical cultures is nearly undetectable. Consistent with a relatively minor role for PirB in mature cortical neurons, Nogo-22 inhibition of axon regeneration is abolished by genetic deletion of NgR1. Thus, NgR1 is the predominant receptor for Nogo-22 in regenerating cortical neurons.
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PMID:A multi-domain fragment of Nogo-A protein is a potent inhibitor of cortical axon regeneration via Nogo receptor 1. 2145 5

Following spinal cord injury (SCI) the adult central nervous system (CNS) has a limited but substantial capacity for repair and plastic reorganisation. The degree of reorganisation is determined by a number of factors such as the extent and location of the lesion, the remaining circuit activity within the CNS and the age at injury. However, even in the best cases this spontaneous reorganisation does not lead to full recovery of the affected behaviour but instead often results in a functionally successful but compensatory strategy. Current SCI research focuses on enhancing fibre tract (re-)growth and recovery processes. Two currently promising approaches are the neutralisation of CNS growth inhibitory factors, and rehabilitative training of remaining networks. Independently, both approaches can lead to substantial functional recovery and anatomical reorganisation. In this review we focus on Nogo-A, a neurite growth inhibitory protein present in the adult CNS, and its role in regenerative and plastic growth following SCI. We then discuss the efforts of rehabilitative training and the potential combination of the two therapies.
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PMID:Anti-Nogo-A and training: can one plus one equal three? 2153 May 8

In the adult, both neurologic recovery and anatomical growth after a CNS injury are limited. Two classes of growth inhibitors, myelin associated inhibitors (MAIs) and extracellular matrix associated inhibitors, limit both functional recovery and anatomical rearrangements in animal models of spinal cord injury. Here we focus on how MAIs limit a wide spectrum of growth that includes regeneration, sprouting, and plasticity in both the intact and lesioned CNS. Three classic myelin associated inhibitors, Nogo-A, MAG, and OMgp, signal through their common receptors, Nogo-66 Receptor-1 (NgR1) and Paired-Immunoglobulin-like-Receptor-B (PirB), to regulate cytoskeletal dynamics and inhibit growth. Initially described as inhibitors of axonal regeneration, subsequent work has demonstrated that MAIs also limit activity and experience-dependent plasticity in the intact, adult CNS. MAIs therefore represent a point of convergence for plasticity that limits anatomical rearrangements regardless of the inciting stimulus, blurring the distinction between injury studies and more "basic" plasticity studies.
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PMID:Myelin associated inhibitors: a link between injury-induced and experience-dependent plasticity. 2169 96

Blocking the function of the myelin protein Nogo-A or its signaling pathway is a promising method to overcome an important neurite growth inhibitory factor of the adult central nervous system (CNS), and to enhance axonal regeneration and plasticity after brain or spinal cord injuries. Several studies have shown increased axonal regeneration and enhanced compensatory sprouting, along with substantially improved functional recovery after treatment with anti-Nogo-A antibodies, Nogo-receptor antagonists, or inhibition of the downstream mediator RhoA/ROCK in adult rodents. Proof-of-concept studies in spinal cord-injured macaque monkeys with anti-Nogo-A antibodies have replicated these findings; recently, clinical trials in spinal cord-injured patients have begun. However, the optimal time window for successful Nogo-A function blocking treatments has not yet been determined. We studied the effect of acute as well as 1- or 2-weeks delayed intrathecal anti-Nogo-A antibody infusions on the regeneration of corticospinal tract (CST) axons and the recovery of motor function after large but anatomically incomplete thoracic spinal cord injuries in adult rats. We found that lesioned CST fibers regenerated over several millimeters after acute or 1-week-delayed treatments, but not when the antibody treatment was started with a delay of 2 weeks. Swimming and narrow beam crossing recovered well in rats treated acutely or with a 1-week delay with anti-Nogo-A antibodies, but not in the 2-week-delayed group. These results show that the time frame for treatment of spinal cord lesions with anti-Nogo-A antibodies is restricted to less than 2 weeks in adult rodents.
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PMID:Delayed anti-nogo-a antibody application after spinal cord injury shows progressive loss of responsiveness. 2181 84

Nogo-A, a member of the reticulon family, is one of the most important myelin-associated inhibitors for axonal growth, regeneration, and plasticity in the central nervous system. RhoA has been targeted pharmacologically to promote neurite outgrowth and functional recovery in the brain and spinal cord. However, the underlying mechanism of the inhibition of neurite outgrowth by Nogo-A has not yet been fully defined. Protein kinase B (PKB, also known as Akt) is a protein serine/threonine kinase that plays a key role in intracellular signaling and cellular homeostasis. This study reports the role of PKB signaling on Nogo-A-treated PC12 neuronal cells. An inhibitory fragment of Nogo-A (Nogo-66) activated RhoA and reduced the phosphorylation of PKB at Ser473 in a time-dependent manner. In contrast, pretreatment with Y27632, a specific inhibitor of Rho-A, resulted in an increase of the phosphorylation of PKB. Nogo-66 also inhibited the neurite outgrowth of PC12 cells, whereas pretreatment with LY294002, a specific inhibitor of PKB, ameliorated the neurite outgrowth. These data suggest that PKB is involved in the inhibition of neurite outgrowth by Nogo-A in PC12 cells.
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PMID:Protein kinase B is involved in Nogo-66 inhibiting neurite outgrowth in PC12 cells. 2186 40


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