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)

Secondary injury following traumatic spinal cord injury is induced by the activation of a number of cellular and molecular changes. RhoA, a small GTPase, regulates the organization of the actin cytoskeleton, gene expression, cell proliferation, and has been implicated in the regenerative process. This study was undertaken to investigate the involvement of the RhoA signaling pathway in the secondary injury that follows traumatic spinal cord injury in rats. RhoA mRNA and protein expressions were enhanced significantly in the injured spinal cord 1 week after surgery (P<0.05, ANOVA). C3 exozyme (RhoA inhibitor), Y-27632 (selective Rho kinase inhibitor), and Fasudil (non-selective protein kinase inhibitor) were administered after spinal cord injury, and the subjects were evaluated for 5 weeks as per BBB locomotor score. Poor rat response interrupted the C3 experiment. Y-27632 slightly, but significantly (P<0.05, ANOVA), delayed the recovery. Fasudil significantly improved the BBB score (P<0.05, ANOVA). In conclusion, spinal cord injury activates the RhoA/Rho-kinase alpha, beta associated pathway. However, their role in secondary injury or in the improvement of functional recovery remains unclear. Fasudil might exert a cytoprotective effect by mechanisms other than inhibiting Rho-kinase alpha, beta.
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PMID:A possible role of RhoA/Rho-kinase in experimental spinal cord injury in rat. 1248 Jan 55

CNS myelin inhibits axonal outgrowth in vitro and is one of several obstacles to functional recovery following spinal cord injury. Central to our current understanding of myelin-mediated inhibition are the membrane protein Nogo and the Nogo-66 receptor (NgR). New findings implicate NgR as a point of convergence in signal transduction for several myelin-associated inhibitors. Additional studies have identified a potential coreceptor for NgR as p75(NTR), and a second-messenger pathway involving RhoA that inhibits neurite elongation. Although these findings expand our understanding of the molecular determinants of adult CNS axonal regrowth, the physiological roles of myelin-associated inhibitors in the intact adult CNS remain ill-defined.
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PMID:The Nogo-66 receptor: focusing myelin inhibition of axon regeneration. 1268 70

Inhibition of the small GTPase Rho or of its downstream target Rho-associated kinase (ROCK) has been shown to promote axon regeneration and to improve functional recovery following traumatic CNS lesions in the adult rat. In order to determine the expression pattern of RhoA and RhoB following human traumatic brain injury (TBI) and to assess whether Rho is a possible target for pharmacological intervention in humans, we investigated expression patterns of RhoA and RhoB in brain specimens from 25 patients who died after closed TBI in comparison to brain tissue derived from four neuropathologically unaffected control patients by immunohistochemistry. A highly significant lesional upregulation of both RhoA and RhoB was observed beginning several hours after the traumatic event and continuing for months after TBI. The cellular sources of both molecules included polymorphonuclear granulocytes, monocytes/macrophages, and reactive astrocytes. Additionally, expression of RhoA was also detected in neuronal cells in some of the cases. From our data, we conclude that inhibition of Rho is a promising mechanism for the development of new pharmacological interventions in human TBI. As the observed upregulation of RhoA and RhoB was still detectable months after TBI, we speculate that even delayed treatment with Rho inhibitors might be a therapeutic option.
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PMID:Lesional expression of RhoA and RhoB following traumatic brain injury in humans. 1525 98

Inhibition of the small GTPase RhoA or its downstream target Rho-associated coiled kinase (ROCK) has been shown to promote axon regeneration and to improve functional recovery following spinal cord injury (SCI) in the adult rat. RhoA has also been implicated in delayed secondary injury pathophysiology, such as free radical formation and loss of endothelial integrity leading to edema formation. In the present report, we have analyzed the effect of the central nervous system (CNS) permissive, putatively neuroprotective, anti-inflammatory cyclooxygenase-1/-2 (COX-1/-2) inhibitor indomethacin in CNS effective dosage (2 mg/kg/day) on lesional RhoA expression following subacute spinal cord injury. In control rats receiving vehicle alone, RhoA+ cells accumulate at the lesion site (Th8). At day 3 following SCI, the RhoA+ cellular composition is composed prevailingly of microglia/macrophages and polymononuclear granulocytes, but few reactive astrocytes. In contrast, in the verum group, lesional numbers of RhoA cells were reduced by indomethacin treatment by more than 60% (P < 0.0001). Inflammation-dependent RhoA expression accessible by cyclooxygenase inhibition proposes an immune-related mechanism. Our results identify COX blockers as candidates for a safe, synergistic, adjuvant treatment option in combination with cell-specific approaches to Rho inactivation, effectively minimizing the pool of RhoA+ cells at the lesion site following SCI.
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PMID:Lesional RhoA+ cell numbers are suppressed by anti-inflammatory, cyclooxygenase-inhibiting treatment following subacute spinal cord injury. 1529 35

Inhibition of the small GTPase ras homology protein (Rho) or its downstream target, the Rho-associated kinase (ROCK), has been shown to promote axon regeneration and to improve functional recovery following spinal cord injury (SCI) in the adult rat. Here, we have analyzed the expression of RhoA and RhoB following spinal cord injury in order to assess whether Rho is a possible target for late pharmacological intervention. In control spinal cords, RhoA(+) cells were almost absent, whereas RhoB was localized to some ependymal cells, a few microglia, and some dissociated neurons. In injured spinal cords, RhoA(+) and RhoB(+)cells accumulated at perilesional areas and in the developing necrotic core early after injury at day 1. After reaching their maximum levels (RhoA at day 3; RhoB at day 1), RhoA(+) and RhoB(+) cell numbers remained significantly elevated until day 28. In areas remote from the lesion (> or =0.75 mm), a more discrete accumulation of RhoA(+) and RhoB(+) cells was observed, primarily in areas of ongoing Wallerian degeneration. RhoA and RhoB were predominantly expressed by polymorphonuclear granulocytes, ED1(+) microglia/macrophages, oligodendrocytes, some neurons, and swollen axons/neurites. Furthermore, expression was located to lesional, reactive astrocytes and fibroblastoid cells confined to areas of scar formation. Our experiments have determined that most RhoA(+) and RhoB(+) cells (>70%) are of mononuclear origin. The persistent presence of lesional RhoA(+) and RhoB(+) axon/neurite fibers over a period of 4 weeks after injury suggests that Rho inhibition is a putative therapeutic concept also for delayed intervention after SCI.
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PMID:Prolonged lesional expression of RhoA and RhoB following spinal cord injury. 1588 Apr 94

Repulsive guidance molecule (RGM) is a protein implicated in both axonal guidance and neural tube closure. We report RGMa as a potent inhibitor of axon regeneration in the adult central nervous system (CNS). RGMa inhibits mammalian CNS neurite outgrowth by a mechanism dependent on the activation of the RhoA-Rho kinase pathway. RGMa expression is observed in oligodendrocytes, myelinated fibers, and neurons of the adult rat spinal cord and is induced around the injury site after spinal cord injury. We developed an antibody to RGMa that efficiently blocks the effect of RGMa in vitro. Intrathecal administration of the antibody to rats with thoracic spinal cord hemisection results in significant axonal growth of the corticospinal tract and improves functional recovery. Thus, RGMa plays an important role in limiting axonal regeneration after CNS injury and the RGMa antibody offers a possible therapeutic agent in clinical conditions characterized by a failure of CNS regeneration.
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PMID:RGMa inhibition promotes axonal growth and recovery after spinal cord injury. 1658 68

Axonal regeneration in the central nervous system is blocked by many different growth inhibitory factors. Some of these inhibitors act on neurons by activating RhoA and Rho-kinase, an effector of RhoA. Several studies have shown that Rho-kinase inhibition immediately after spinal cord injury enhances axonal sprouting and functional recovery. In this study, we ask whether delayed treatment with Rho-kinase inhibitor is effective in promoting regeneration and functional recovery. We administered Fasudil, a Rho-kinase inhibitor, locally to the injury site 4 weeks or immediately after contusion of the thoracic spinal cord in rats. Although the immediate treatment significantly stimulated axonal sprouting and recovery of hindlimb function, treatment started 4 weeks after surgery had no effect on fiber sprouting or locomotor recovery. Our findings suggest that RhoA/Rho-kinase alone may not account for the irreversible arrest of axon outgrowth in the chronic stage of injury in the central nervous system.
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PMID:Delayed treatment with Rho-kinase inhibitor does not enhance axonal regeneration or functional recovery after spinal cord injury in rats. 1662 99

LINGO-1 is a CNS-specific protein and a functional component of the NgR1/p75/LINGO-1 and NgR1/TAJ(TROY)/LINGO-1 signaling complexes that mediate inhibition of axonal outgrowth. These receptor complexes mediate the axonal growth inhibitory effects of Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte-myelin glycoprotein (OMgp) via RhoA activation. Soluble LINGO-1 (LINGO-1-Fc), which acts as an antagonist of these pathways by blocking LINGO-1 binding to NgR1, was administered to rats after dorsal or lateral hemisection of the spinal cord. LINGO-1-Fc treatment significantly improved functional recovery, promoted axonal sprouting and decreased RhoA activation and increased oligodendrocyte and neuronal survival after either rubrospinal or corticospinal tract transection. These experiments demonstrate an important role for LINGO-1 in modulating axonal outgrowth in vivo and that treatment with LINGO-1-Fc can significantly enhance recovery after spinal cord injury.
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PMID:LINGO-1 antagonist promotes functional recovery and axonal sprouting after spinal cord injury. 1701 Dec 8

We have previously reported neuroprotection in spinal cord injury (SCI) by Lipitor [atorvastatin (AT)]-pre-treatment. Though informative, pre-treatment studies find only limited clinical application as trauma occurrence is unpredictable. Therefore, this study investigates the efficacy of AT treatment post-SCI. In a rat model of contusion-SCI resulting in complete hindlimb paralysis, AT treatment (5 mg/kg; gavage) was begun 2, 4, or 6 h post-SCI followed by a once daily dose thereafter for 6 weeks. While the placebo vehicle (VHC)-SCI rats showed substantial functional deficit, AT-SCI animals exhibited significant functional recovery. AT diminished injury-induced blood-spinal cord barrier (BSCB) dysfunction with significantly reduced infiltration and tumor necrosis factor-alpha/interleukin-1beta/inducible nitric oxide synthase expression at site of injury. BSCB protection in AT-SCI was attributable to attenuated matrix metalloproteinase-9 (MMP9) expression - a central player in BSCB disruption. Furthermore, endothelial MMP9 expression was found to be RhoA/ROCK pathway-mediated and regulated by AT through an isoprenoid-dependent mechanism. Attenuation of these early inflammatory events reduced secondary damage. Significant reduction in axonal degeneration, myelin degradation, gliosis, and neuronal apoptosis with resultant enhancement in tissue sparing was observed in AT-SCI compared with VHC-SCI. In summary, this novel report presenting the efficacy of post-injury AT treatment might be of critical therapeutic value as effective treatments are currently unavailable for SCI.
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PMID:Post-trauma Lipitor treatment prevents endothelial dysfunction, facilitates neuroprotection, and promotes locomotor recovery following spinal cord injury. 1721 14

After a CNS injury in the adult mammals, axonal regeneration is very limited because of the reduced intrinsic growth capacity and nonpermissive environment for axonal elongation. The growth inhibitions from CNS myelin and astroglial chondroitin sulfate proteoglycans partially account for the lack of CNS repair. Here, we show that the nonsteroidal antiinflammatory drugs (NSAIDs) ibuprofen and indomethacin, the drugs widely used as pain relievers in the clinic, can surmount axon growth restrictions from myelin and proteoglycans by potently inhibiting their downstream pathway RhoA signal. Similar to Rho and Rock inhibitors C3 transferase or Y27632 [(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide], both NSAID drugs stimulate a significant neurite growth in the cultured dorsal root ganglion neurons exposed to the inhibitory substrates. Systemic administration of ibuprofen to spinal cord-lesioned rodents reverses the active RhoA signal around injury area measured via Rho-GTP binding assay. Subcutaneous injections of ibuprofen via minipumps to rats with a thoracic spinal cord transection or contusion injury result in substantial corticospinal and serotonergic axon sprouting in the caudal spinal cord and promote locomotor functional recovery, even delaying the treatment 1 week after trauma. In contrast, the non-RhoA-inhibiting NSAID naproxen does not have the axon growth-promoting effects on cultured or lesioned neurons. These studies demonstrate the therapeutic potential of RhoA-inhibiting NSAIDs in treating CNS injuries characterized by axonal disconnection including spinal cord injury.
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PMID:Nonsteroidal anti-inflammatory drugs promote axon regeneration via RhoA inhibition. 1742 93


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