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)

Our studies indicate that the small GTPase Rho is an important intracellular target for promoting axon regrowth after injury. In tissue culture, inactivation of the Rho signaling pathway is effective in promoting neurite growth on growth inhibitory CNS substrates by two different methods: inactivation of Rho with C3 transferase, and inactivation by dominant negative mutation of Rho. In vivo, we have documented the regeneration of transfected axons after treatment with C3 in two different animals models, microcrush lesion of the adult rat optic nerve, and over-hemisection of adult mouse spinal cord. Mice treated with C3 after SCI showed impressive functional recovery, notwithstanding the fact that mice differ from rats in their response to spinal cord injury, especially in the extent of cavitation at the lesion site (Steward et al., 1999). It remains to be determined to what extent the regeneration of specific descending and ascending spinal axons contribute to the recovery, and whether inactivation of Rho enhances the spontaneous plasticity of axonal and dendritic remodeling after SCI. Inactivation of Rho with C3 to promote regeneration and functional recovery after SCI is simple, and our studies reveal the potential for a new, straightforward technique to promote axon regeneration.
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PMID:Inactivation of intracellular Rho to stimulate axon growth and regeneration. 1244 Mar 79

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

Nogo-A is one of several neurite growth inhibitory components present in oligodendrocytes and CNS myelin membranes. Nogo has a crucial role in restricting axonal regeneration and compensatory fibre growth in the injured adult mammalian CNS. Recent studies have shown that in vivo applications of Nogo neutralizing antibodies, peptides blocking the Nogo receptor subunit NgR, or blockers of the postreceptor components Rho-A and ROCK induce long-distance axonal regeneration and compensatory sprouting, accompanied by an impressive enhancement of functional recovery, in the rat and mouse spinal cord.
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PMID:Nogo and axon regeneration. 1501 47

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

In vitro, cAMP elevation alters neuronal responsiveness to diffusible growth factors and overcomes myelin-associated inhibitory molecules. Significant advances have been made recently in understanding the role of increases in cAMP in promoting axonal growth. Importantly, it has now been shown that cAMP elevation can promote axonal regeneration and functional recovery after central nervous system injury. Elevation of cAMP can be achieved via either direct application of cAMP analogs or an inhibitor of the enzyme phosphodiesterase that degrades cAMP in vivo. Current information points to a number of protein kinase A-mediated pathways (mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase/akt pathway activation and Rho inactivation) underlying cAMP elevation-induced neuronal survival and axonal regeneration.
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PMID:Involvement of cAMP in neuronal survival and axonal regeneration. 1563 59

Rho kinases (ROCKs), the first Rho effectors to be described, are serine/threonine kinases that are important in fundamental processes of cell migration, cell proliferation and cell survival. Abnormal activation of the Rho/ROCK pathway has been observed in various disorders of the central nervous system. Injury to the adult vertebrate brain and spinal cord activates ROCKs, thereby inhibiting neurite growth and sprouting. Inhibition of ROCKs results in accelerated regeneration and enhanced functional recovery after spinal-cord injury in mammals, and inhibition of the Rho/ROCK pathway has also proved to be efficacious in animal models of stroke, inflammatory and demyelinating diseases, Alzheimer's disease and neuropathic pain. ROCK inhibitors therefore have potential for preventing neurodegeneration and stimulating neuroregeneration in various neurological disorders.
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PMID:Rho kinase, a promising drug target for neurological disorders. 1586 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

Rho is an important signaling target to promote repair following spinal cord injury (SCI). Myelin-derived inhibitory proteins, as well as other classes of known growth inhibitory proteins, block regeneration by signaling activation of Rho. Here, we review the molecular mechanisms of Rho activation after SCI and explain known Rho signaling antagonists. We review the data on use of Rho antagonists to promote axon regeneration, neuroprotection, and functional recovery after SCI. We report on efforts to translate the nonclincal studies on rodents to clinical trials in patients with acute SCI.
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PMID:Targeting Rho to stimulate repair after spinal cord injury. 1662 18

Inhibition of Rho-kinase (ROCK) with Y27632 stimulates sprouting by injured corticospinal tract and dorsal column tract axons, and accelerates functional recovery. However, regeneration of these axons across the glial scar was not observed. Here we examined the effects of Y27632 treatment on chondroitin sulfate proteoglycan (CSPG) expression by astrocytes, which are a key component of the reactive gliosis inhibiting axonal regeneration. In vivo, rats underwent a dorsal column transection and were treated with Y27632 via intrathecal pump infusion. Compared with controls, Y27632-treated injury sites displayed exaggerated upregulation of glial fibrillary acid protein and neurocan immunoreactivity along the lesion edge. In vitro, astrocytes assumed a reactive morphology (stellate shape) and increased their expression of CSPGs after Y27632 treatment. Neurite growth by dissociated cortical neurons decreased when cultured on the extracellular matrix (ECM) derived from Y27632-treated astrocytes. This decrease in neurite growth was reversed with chondroitinase-ABC (ChABC) digestion, indicating that the inhibition was due to CSPG depositions within the ECM. Interestingly, conditioned medium (CM) from untreated astrocytes was inhibitory to neurite growth, which was overcome by ChABC digestion. Such inhibitory activity was not found in the CM of Y27632-treated astrocytes. Taken together, these data support a model where ROCK inhibition by Y27632 modifies astrocytic processing of CSPGs, and increases the presence of CSPGs within the ECM while reduces CSPGs in the CM (cerebrospinal fluid in vivo). This increased expression of inhibitory CSPGs in the ECM of the glial scar may counteract the growth promoting effects of ROCK inhibition on axonal growth cones.
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PMID:ROCK inhibition with Y27632 activates astrocytes and increases their expression of neurite growth-inhibitory chondroitin sulfate proteoglycans. 1713 70


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