Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that immunotherapy directed against the protein Nogo-A leads to recovery on a skilled forelimb reaching task in rats after sensorimotor cortex stroke, which correlated with axonal and dendritic plasticity. Here we investigated anti-Nogo-A immunotherapy as an intervention to improve performance on a spatial memory task in aged rats after stroke, and whether cognitive recovery was correlated with structural plasticity. Aged rats underwent a unilateral distal permanent middle cerebral artery occlusion and one week later were treated with an anti-Nogo-A or control antibody. Nine weeks post-stroke, treated rats and normal aged rats were tested on the Morris water maze task. Following testing rats were sacrificed and brains processed for the Golgi-Cox method. Hippocampal CA3 and CA1 pyramidal and dentate gyrus granule cells were examined for dendritic length and number of branch segments, and CA3 and CA1 pyramidal cells were examined for spine density and morphology. Anti-Nogo-A immunotherapy given one week following stroke in aged rats improved performance on the reference memory portion of the Morris water maze task. However, this improved performance was not correlated with structural changes in the hippocampal neurons examined. Our finding of improved performance on the Morris water maze in aged rats after stroke and treatment with anti-Nogo-A immunotherapy demonstrates the promising therapeutic potential for anti-Nogo-A immunotherapy to treat cognitive deficits after stroke. The identification of sites of axonal and dendritic plasticity in the aged brain after stroke and treatment with anti-Nogo-A immunotherapy is still under investigation.
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PMID:Cognitive recovery in the aged rat after stroke and anti-Nogo-A immunotherapy. 2003 95

Nogo-A is an oligodendroglial neurite outgrowth inhibitor, the deactivation of which enhances brain plasticity and functional recovery in animal models of stroke. Nogo-A's role in the reperfused brain tissue was still unknown. By using Nogo-A(-/-) mice and mice in which Nogo-A was blocked with a neutralizing antibody (11C7) that was infused into the lateral ventricle or striatum, we show that Nogo-A inhibition goes along with decreased neuronal survival and more protracted neurologic recovery, when deactivation is constitutive or induced 24 h before, but not after focal cerebral ischemia. We show that in the presence of Nogo-A, RhoA is activated and Rac1 and RhoB are deactivated, maintaining stress kinases p38/MAPK, SAPK/JNK1/2 and phosphatase-and-tensin homolog (PTEN) activities low. Nogo-A blockade leads to RhoA deactivation, thus overactivating Rac1 and RhoB, the former of which activates p38/MAPK and SAPK/JNK1/2 via direct interaction. RhoA and its effector Rho-associated coiled-coil protein kinase2 deactivation in turn stimulates PTEN, thus inhibiting Akt and ERK1/2, and initiating p53-dependent cell death. Our data suggest a novel role of Nogo-A in promoting neuronal survival by controlling Rac1/RhoA balance. Clinical trials should be aware of injurious effects of axonal growth-promoting therapies. Thus, Nogo-A antibodies should not be used in the very acute stroke phase.
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PMID:Role of Nogo-A in neuronal survival in the reperfused ischemic brain. 2008 69

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

Functional recovery is markedly restricted following traumatic brain injury (TBI), partly due to myelin-associated inhibitors including Nogo-A, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp), that all bind to the Nogo-66 receptor-1 (NgR1). In previous studies, pharmacological neutralization of both Nogo-A and MAG improved outcome following TBI in the rat, and neutralization of NgR1 improved outcome following spinal cord injury and stroke in rodent models. However, the behavioral and histological effects of NgR1 inhibition have not previously been evaluated in TBI. We hypothesized that NgR1 negatively influences behavioral recovery following TBI, and evaluated NgR1(-/-) mice (NgR1(-/-) study) and, in a separate study, soluble NgR1 infused intracerebroventricularly immediately post-injury to neutralize NgR1 (sNgR1 study) following TBI in mice using a controlled cortical impact (CCI) injury model. In both studies, motor function, TBI-induced loss of tissue, and hippocampal beta-amyloid immunohistochemistry were not altered up to 5 weeks post-injury. Surprisingly, cognitive function (as evaluated with the Morris water maze at 4 weeks post-injury) was significantly impaired both in NgR1(-/-) mice and in mice treated with soluble NgR1. In the sNgR1 study, we evaluated hippocampal mossy fiber sprouting using the Timm stain and found it to be increased at 5 weeks following TBI. Neutralization of NgR1 significantly increased mossy fiber sprouting in sham-injured animals, but not in brain-injured animals. Our data suggest a complex role for myelin-associated inhibitors in the behavioral recovery process following TBI, and urge caution when inhibiting NgR1 in the early post-injury period.
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PMID:Genetic deletion and pharmacological inhibition of Nogo-66 receptor impairs cognitive outcome after traumatic brain injury in mice. 2048

Compensatory neural plasticity occurs in both hemispheres following unilateral cortical damage incurred by seizures, stroke, and focal lesions. Plasticity is thought to play a role in recovery of function, and is important for the utility of rehabilitation strategies. Such effects have not been well described in models of traumatic brain injury (TBI). We examined changes in immunoreactivity for neural structural and plasticity-relevant proteins in the area surrounding a controlled cortical impact (CCI) to the forelimb sensorimotor cortex (FL-SMC), and in the contralateral homotopic cortex over time (3-28 days). CCI resulted in considerable motor deficits in the forelimb contralateral to injury, and increased reliance on the ipsilateral forelimb. The density of dendritic processes, visualized with immunostaining for microtubule-associated protein-2 (MAP-2), were bilaterally decreased at all time points. Synaptophysin (SYN) immunoreactivity increased transiently in the injured hemisphere, but this reflected an atypical labeling pattern, and it was unchanged in the contralateral hemisphere compared to uninjured controls. The lack of compensatory neuronal structural plasticity in the contralateral homotopic cortex, despite behavioral asymmetries, is in contrast to previous findings in stroke models. In the cortex surrounding the injury (but not the contralateral cortex), decreases in dendrites were accompanied by neurodegeneration, as indicated by Fluoro-Jade B (FJB) staining, and increased expression of the growth-inhibitory protein Nogo-A. These studies indicate that, following unilateral CCI, the cortex undergoes neuronal structural degradation in both hemispheres out to 28 days post-injury, which may be indicative of compromised compensatory plasticity. This is likely to be an important consideration in designing therapeutic strategies aimed at enhancing plasticity following TBI.
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PMID:Use-dependent dendritic regrowth is limited after unilateral controlled cortical impact to the forelimb sensorimotor cortex. 2235 53

Axonal damage leads to permanent deficits in the adult central nervous system (CNS) not only because of the weak intrinsic ability of adult neurons to activate their growth program but importantly also because of the presence of specific growth inhibitors in the CNS tissue and the environment of the damaged axons. The well-studied myelin-derived protein Nogo-A is involved in various cellular and molecular events contributing to the failure of CNS axons to regrow and reconnect after transection. Recent studies have shown that, by acting in a negative way on the cytoskeleton and on the growth program of axotomized neurons, Nogo-A exerts fast and chronic inhibitory effects on neurite outgrowth. On the other hand, the blockade of Nogo-A results in a marked enhancement of compensatory and regenerative axonal extension in vivo; this enhancement is often paralleled by significant functional recovery, for example, of locomotion or skilled forelimb reaching after spinal cord or stroke lesions in rats and monkeys. Surprisingly, the blockade of Nogo-A or its receptor NgR in the hippocampus has recently been demonstrated to enhance long-term potentiation. A role of Nogo-A in synaptic plasticity/stability might therefore represent an additional, new and important aspect of CNS circuit remodeling. Function-blocking anti-Nogo-A antibodies are currently being tested in a clinical trial for improved outcome after spinal cord injury.
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PMID:The role of Nogo-A in axonal plasticity, regrowth and repair. 2258 43

Pituitary adenylate cyclase activating peptide (PACAP), a potent neuropeptide which crosses the blood-brain barrier, is known to provide neuroprotection in rat stroke models of middle cerebral artery occlusion (MCAO) by mechanism(s) which deserve clarification. We confirmed that following i.v. injection of 30 ng/kg of PACAP38 in rats exposed to 2 h of MCAO focal cerebral ischemia and 48 h reoxygenation, 50 % neuroprotection was measured by reduced caspase-3 activity and volume of cerebral infarction. Similar neuroprotective effects were measured upon PACAP38 treatment of oxygen-glucose deprivation and reoxygenation of brain cortical neurons. The neuroprotection was temporally associated with increased expression of brain-derived neurotrophic factor, phosphorylation of its receptor-tropomyosin-related kinase receptor type B (trkB), activation of phosphoinositide 3-kinase and Akt, and reduction of extracellular signal-regulated kinases 1/2 phosphorylation. PACAP38 increased expression of neuronal markers beta-tubulin III, microtubule-associated protein-2, and growth-associated protein-43. PACAP38 induced stimulation of Rac and suppression of Rho GTPase activities. PACAP38 downregulated the nerve growth factor receptor (p75(NTR)) and associated Nogo-(Neurite outgrowth-A) receptor. Collectively, these in vitro and in vivo results propose that PACAP exhibits neuroprotective effects in cerebral ischemia by three mechanisms: a direct one, mediated by PACAP receptors, and two indirect, induced by neurotrophin release, activation of the trkB receptors and attenuation of neuronal growth inhibitory signaling molecules p75(NTR) and Nogo receptor.
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PMID:Multimodal neuroprotection induced by PACAP38 in oxygen-glucose deprivation and middle cerebral artery occlusion stroke models. 2267 84

We investigated the association of Nogo-A protein, a myelin-associated inhibitor of axon regeneration, with secondary damage of the ipsilateral substantia nigra pars reticulata (SNr) after distal middle cerebral artery occlusion (dMCAO) in adult stroke-prone, renovascular hypertensive rats. Intracerebroventricular infusion of NEP1-40, a Nogo-66 receptor antagonist peptide, or vehicle was administered starting 24h after dMCAO and continued for 1, 2, or 4 weeks. The expression of Nogo-A in the ipsilateral SNr was assessed by immunohistochemistry. Neuron death and apoptosis were evaluated using Nissl and terminal uridine nick-end labeling (TUNEL) staining. Glial activation was monitored by immunoreactivity of glial fibrillary acidic protein and the oligodendrocyte marker RIP. Axonal damage and regeneration were determined by Bielschowsky's silver staining and immunoreactivity of growth associated protein 43 and microtubule associated protein 2. We found progressive damage in the center of the ipsilateral SNr through 4 weeks after dMCAO. The neuronal loss was topographically related to axonal degeneration that occurred indirectly from the infarcted cortex. Nogo-A protein in oligodendrocytes was persistently increased in the damaged SNr. Administration of NEP1-40 inhibited Nogo-A expression, the loss of neurons, apoptosis, and proliferation of oligodendrocytes and astrocytes. It also boosted the regenerative response of injured axons and encouraged compensatory neurite growth in the ipsilateral SNr. Our data suggest that secondary damage in the ipsilateral SNr may be due to trans-synaptic axonal degeneration that followed the cortical infarct. Further, we showed that Nogo-A is involved in axonal degeneration, and NEP1-40 reduces secondary nigral damage after focal cortical ischemia.
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PMID:Nogo-A is associated with secondary degeneration of substantia nigra in hypertensive rats with focal cortical infarction. 2277 57

Nogo is a member of the reticulon family. Our understanding of the physiological functions of the Nogo-A protein has grown over the last few years, and this molecule is now recognized as one of the most important axonal regrowth inhibitors present in central nervous system (CNS) myelin. Nogo-A plays other important roles in nervous system development, epilepsy, vascular physiology, muscle pathology, stroke, inflammation, and CNS tumors. Since the exact role of Nogo-A protein in human brain development is still poorly understood, we studied its cellular and regional distribution by immunohistochemistry in the frontal lobe of 30 human fetal brains. Nogo-A was expressed in the following cortical zones: ependyma, ventricular zone, subventricular zone, intermediate zone, subplate, cortical plate, and marginal zone. The number of positive cells decreased significantly with increasing gestational age in the subplate and marginal zone. Using different antibodies, changes in isoform expression and dimerization states could be shown between various cortical zones. The results demonstrate a significant change in the expression of Nogo-A during the development of the human brain. The effects of its time- and region-specific regulation have to be further studied in detail.
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PMID:Expression of nogo-a is decreased with increasing gestational age in the human fetal brain. 2314

Neurorestorative therapies for stroke aim to reverse disability by reparative mechanisms (rather than to thrombolyse or to neuroprotect). A substantial and persuasive body of pre-clinical evidence has come from the evaluation of antibodies against Nogo-A (a myelin-associated inhibitor of plasticity) in rat models of stroke. Particularly impressive is the benefit of this therapy in models of permanent middle cerebral artery occlusion (MCAO) when given to elderly animals after a one week delay, in adult rats with co-morbidities, and in adult rats when treatment is delayed by up to 9 weeks after stroke (although antibodies against Nogo-A did not reverse disability in mice after proximal MCAO with reperfusion). We predict that antibodies against Nogo-A will improve outcome further when combined with suitable additional rehabilitation, and also that antibodies against Nogo-A will improve outcome in animal models of haemmorhagic stroke that affect the same brain regions as ischemic stroke caused by MCAO. Antibodies against Nogo-A have been shown to be safe in Phase I clinical trials for acute spinal cord injury, and this may eventually facilitate a trial in stroke.
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PMID:Therapeutics targeting Nogo-A hold promise for stroke restoration. 2339 37


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