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)

Despite advances in imaging, understanding the underlying pathways, and clinical translation of animal models of disease there remains an urgent need for therapies that reduce brain damage after stroke and promote functional recovery in patients. Blocking oxidant radicals, reducing matrix metalloproteinase-induced neuronal damage, and use of stem cell therapy have been proposed and tested individually in prior studies. Here we provide a comprehensive integrative management approach to reducing damage and promoting recovery by combining biological therapies targeting these areas. In a rat model of transient cerebral ischemia (middle cerebral artery occlusion) gene delivery vectors were used to overexpress tissue inhibitor of matrix metalloproteinase 1 and 2 (TIMP1 and TIMP2) 3 days before ischemia. After occlusion, autologous bone marrow cells alone or in combination with agents to improve NO bioavailability were administered intraarterially. When infarct size, BrdU incorporation, and motor function recovery were determined in the treatment groups the largest beneficial effect was seen in rats receiving the triple combined therapy, surpassing effects of single or double therapies. Our study highlights the utility of combined drug, gene, and cell therapy in the treatment of stroke.
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PMID:Brain protection using autologous bone marrow cell, metalloproteinase inhibitors, and metabolic treatment in cerebral ischemia. 1736 Jun 88

Investigations into mechanisms that restrict the recovery of functions after an injury to the brain or the spinal cord have led to the discovery of specific neurite growth inhibitory factors in the adult central nervous system (CNS) of mammals. Blocking their growth-suppressive function resulted in disinhibition of axonal growth, i.e. growth of cultured neurons on inhibitory CNS tissue in vitro and regeneration of injured axons in vivo. The enhanced regenerative and compensatory fibre growth was often accompanied by a substantial improvement in the functional recovery after CNS injury. The first clinical studies to assess the therapeutic potential of compounds that neutralize growth inhibitors or interfere with their downstream signalling are currently in progress. This review discusses recent advances in the understanding of how the 'founder molecule' Nogo-A and other glial-derived growth inhibitors restrict the regeneration and repair of disrupted neuronal circuits, thus limiting the functional recovery after CNS injuries.
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PMID:Disinhibition of neurite growth to repair the injured adult CNS: focusing on Nogo. 1797 7

Blocking the neurite growth inhibitor Nogo-A by neutralizing antibodies improves functional recovery after partial spinal cord injury. In parallel, regeneration and sprouting of cortico- and rubrospinal projections are increased and may partially explain the enhanced functional recovery. The serotonergic raphe-spinal tract, which plays a key regulatory role for spinal motor circuits, has not been analysed in detail with regard to its response to Nogo-A function blocking antibody treatment after spinal cord injury. We studied the effect of 2 weeks of intrathecal Nogo-A antibody application after partial thoracic spinal cord injury on the lamina-specific restitution of the serotonergic (5-HT) raphe-spinal projections to the mid-lumbar grey matter. Nine weeks after the lesion, the number of 5-HT fibres in Rexed's laminae 4 and 7 and the number of 5-HT-positive varicosities on motoneurons in lamina 9 returned to their lamina-specific preinjury levels in Nogo-A antibody-treated rats. By contrast, control antibody-treated animals showed only a moderate increase in 5-HT fibre density in the respective laminae, and the number of 5-HT-positive varicosities on motoneurons remained low. Our results suggest that the Nogo-A antibody-induced recovery of descending serotonergic projections to the grey matter is lamina-specific and molecular cues must be present to guide the growing axons to the correct target areas. This appropriate restitution of the serotonergic innervation below the lesion site probably contributes to the impressive recovery of motor function.
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PMID:Lamina-specific restoration of serotonergic projections after Nogo-A antibody treatment of spinal cord injury in rats. 1821 31

Rehabilitation is important for the functional recovery of patients with spinal cord injury. However, neurological events associated with rehabilitation remain unclear. Herein, we investigated neuronal regeneration and exercise following spinal cord injury, and found that assisted stepping exercise of spinal cord injured rats in the inflammatory phase causes allodynia. Sprague-Dawley rats with thoracic spinal cord contusion injury were subjected to assisted stepping exercise 7 days following injury. Exercise promoted microscopic recovery of corticospinal tract neurons, but the paw withdrawal threshold decreased and C-fibers had aberrantly sprouted, suggesting a potential cause of the allodynia. Tropomyosin-related kinase B (TrkB) receptor for brain-derived neurotrophic factor (BDNF) was expressed on aberrantly sprouted C-fibers. Blocking of BDNF-TrkB signaling markedly suppressed aberrant sprouting and decreased the paw withdrawal threshold. Thus, early rehabilitation for spinal cord injury may cause allodynia with aberrant sprouting of C-fibers through BDNF-TrkB signaling.
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PMID:Early exercise in spinal cord injured rats induces allodynia through TrkB signaling. 1922 91

Upregulation of expression of the close homolog of adhesion molecule L1 (CHL1) by reactive astrocytes in the glial scar reduces axonal regeneration and inhibits functional recovery after spinal cord injury (SCI). Here, we investigate the molecular mechanisms underlying upregulation of CHL1 expression by analyzing the signal transduction pathways in vitro. We show that astrogliosis stimulated by bacterial lipopolysaccharide (LPS) upregulates CHL1 expression in primary cultures of mouse cerebral astrocytes, coinciding with elevated protein synthesis and translocation of protein kinase delta (PKCdelta) from cytosol to the membrane fraction. Blocking PKCdelta activity pharmacologically and genetically attenuates LPS-induced elevation of CHL1 protein expression through a phosphatidylinositol 3-kinase (PI3K) dependent pathway. LPS induces extracellular signal-regulated kinases (ERK1/2) phosphorylation through PKCdelta and blockade of ERK1/2 activation abolishes upregulation of CHL1 expression. LPS-triggered upregulation of CHL1 expression mediated through translocation of nuclear factor kappaB (NF-kappaB) to the nucleus is blocked by a specific NF-kappaB inhibitor and by inhibition of PI3K, PKCdelta, and ERK1/2 activities, implicating NF-kappaB as a downstream target for upregulation of CHL1 expression. Furthermore, the LPS-mediated upregulation of CHL1 expression by reactive astrocytes is inhibitory for hippocampal neurite outgrowth in cocultures. Although the LPS-triggered NO-guanylate cyclase-cGMP pathway upregulates glial fibrillary acid protein expression in cultured astrocytes, we did not observe this pathway to mediate LPS-induced upregulation of CHL1 expression. Our results indicate that elevated CHL1 expression by reactive astrocytes requires activation of PI3K/PKCdelta-dependent pathways and suggest that reduction of PI3K/PKCdelta activity represents a therapeutic target to downregulate CHL1 expression and thus benefit axonal regeneration after SCI.
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PMID:Phosphatidylinositol 3-kinase/protein kinase Cdelta activation induces close homolog of adhesion molecule L1 (CHL1) expression in cultured astrocytes. 1967 67

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

Exogenous insulin therapy improves endothelial function in insulin resistant patients, indirectly indicating that nitric oxide synthase activity and NO production may be impaired. Insulin stimulates production of NO by activating a signaling pathway including insulin receptor substrate-1, phosphatidylinositol-3-kinase and protein kinase B (PKB/Akt). Angiotensin II type I (AT1) receptor-evoked oxidative stress is implicated in the inactivation of NO, impairing endothelium-dependent vasodilatation. Blocking the actions of Angiotensin II with an AT1 receptor antagonist (Losartan), has beneficial effects in patients with insulin resistance or type 2 diabetes mellitus. This study investigated whether elevated Angiotensin II influences myocardial insulin resistance, insulin signaling and NO production in a rat model of diet-induced obesity (DIO) by antagonizing the actions of the AT1 receptor with Losartan. Isolated, perfused hearts, Western blotting and flow-cytometric methods were utilized to determine myocardial function, expression and phosphorylation of key proteins and NO production, respectively. Results showed that hearts from DIO rats are insulin resistant (higher serine phosphorylation of IRS-1, lower insulin-stimulated phosphorylation of PKB/Akt and eNOS, lower NO production) and had poorer functional recovery and larger infarct development after ischaemia/reperfusion. Losartan improved the impaired functional recovery, and NO production and enhanced eNOS expression and phosphorylation and reduced infarct size in hearts from the DIO animals. Data obtained from Losartan treatment also revealed that Angiotensin II signaling modulates myocardial PKB/Akt expression. We conclude that Angiotensin II signaling exacerbates inhibition of NO production in insulin resistance and that this can be improved by AT1 antagonism.
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PMID:ANG II type I receptor antagonism improved nitric oxide production and enhanced eNOS and PKB/Akt expression in hearts from a rat model of insulin resistance. 2115 3

Ischemic cell injury leads to cell death. Three main morphologies have been described: apoptosis, cell death with autophagy and necrosis. Their inherent dynamic nature, a point of no return (PONR) and molecular overlap have been stressed. The relationship between a defined cell death type and the severity of injury remains unclear. The functional role of autophagy and its effects on cell death onset is largely unknown. In this study we report a differential induction of cell death, which is dependent on the severity and duration of an ischemic insult. We show that mild ischemia leads to the induction of autophagy and apoptosis, while moderate or severe ischemia induces both apoptotic and necrotic cell death without increased autophagy. The autophagic response during mild injury was associated with an ATP surge. Real-time imaging and Fluorescence Resonance Energy Transfer (FRET) revealed that increased autophagy delays the PONR of both apoptosis and necrosis significantly. Blocking autophagy shifted PONR to an earlier point in time. Our results suggest that autophagic activity directly alters intracellular metabolic parameters, responsible for maintaining mitochondrial membrane potential and cellular membrane integrity. A similar treatment also improved functional recovery in the perfused rat heart. Taken together, we demonstrate a novel finding: autophagy is implicated only in mild injury and positions the PONR in cell death.
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PMID:At the core of survival: autophagy delays the onset of both apoptotic and necrotic cell death in a model of ischemic cell injury. 2142 Apr 1

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

Ischemic stroke is a major cause of mortality and morbidity worldwide but effective treatments are limited. Strategies to enhance neurovascular remodeling following stroke provide promising opportunities to improve tissue repair and functional recovery. We have previously demonstrated that whisker activity promotes central angiogenesis in rodent models of whisker-barrel cortex stroke. However, the mechanisms involved in the regulation of neurovascular plasticity by peripheral stimulation are not well-defined. Here, we report that angiogenesis and neurogenesis occur concurrently after cerebral ischemia and whisker stimulation in mice. We show that neuroblasts expressing vascular endothelial growth factor receptor 2 (VEGFR2) migrate along the vessels. Blocking VEGFR2 with the selective inhibitor SU5416 (semaxinib) attenuates ischemia-induced regenerative responses and completely prevents whisker stimulation-induced neurovascular remodeling. These results suggest that VEGFR2-mediated signaling plays an important role in promoting post-ischemia neurovascular remodeling and provides a link between angiogenesis and neurogenesis.
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PMID:The role of VEGF/VEGFR2 signaling in peripheral stimulation-induced cerebral neurovascular regeneration after ischemic stroke in mice. 2192 79


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