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)

Thrombospondins 1 and 2 (TSP-1/2) belong to a family of extracellular glycoproteins with angiostatic and synaptogenic properties. Although TSP-1/2 have been postulated to drive the resolution of postischemic angiogenesis, their role in synaptic and functional recovery is unknown. We investigated whether TSP-1/2 are necessary for synaptic and motor recovery after stroke. Focal ischemia was induced in 8- to 12-week-old wild-type (WT) and TSP-1/2 knockout (KO) mice by unilateral occlusion of the distal middle cerebral artery and the common carotid artery (CCA). Thrombospondins 1 and 2 increased after stroke, with both TSP-1 and TSP-2 colocalizing mostly to astrocytes. Wild-type and TSP-1/2 KO mice were compared in angiogenesis, synaptic density, axonal sprouting, infarct size, and functional recovery at different time points after stroke. Using the tongue protrusion test of motor function, we observed that TSP-1/2 KO mice exhibited significant deficit in their ability to recover function (P<0.05) compared with WT mice. No differences were found in infarct size and blood vessel density between the two groups after stroke. However, TSP-1/2 KO mice exhibited significant synaptic density and axonal sprouting deficits. Deficiency of TSP-1/2 leads to impaired recovery after stroke mainly due to the role of these proteins in synapse formation and axonal outgrowth.
J Cereb Blood Flow Metab 2008 Oct
PMID:Thrombospondins 1 and 2 are necessary for synaptic plasticity and functional recovery after stroke. 1859 57

In a model of glial-specific chemical anoxia, we have examined how astrocytes influence both synaptic transmission and the viability of hippocampal pyramidal neurons. This relationship was assessed using electrophysiological, pharmacological, and biochemical techniques in rat slices and cell cultures, and oxidative metabolism was selectively impaired in glial cells by exposure to the mitochondrial gliotoxin, fluoroacetate. We found that synaptic transmission was blocked shortly after inducing glial metabolic stress and peri-infarct-like spreading depression (SD) waves developed within 1 to 2 h of treatment. Neuronal electrogenesis was not affected until SD waves developed, thereafter decaying irreversibly. The blockage of synaptic transmission was totally reversed by A(1) adenosine receptor antagonists, unlike the development of SD waves, which appeared earlier under these conditions. Such blockage led to a marked reduction in the electrical viability of pyramidal neurons 1 h after gliotoxin treatment. Cell culture experiments confirmed that astrocytes indeed release adenosine. We interpret this early glial response as a novel safety mechanism that allocates metabolic resources to vital processes when the glia itself sense an energy shortage, thereby delaying or preventing entry into massive lethal ischemic-like depolarization. The implication of these results on the functional recovery of the penumbra regions after ischemic insults is discussed.
J Cereb Blood Flow Metab 2008 Nov
PMID:Metabolic challenge to glia activates an adenosine-mediated safety mechanism that promotes neuronal survival by delaying the onset of spreading depression waves. 1861 16

The implicit aim of neuroprotection is to rescue neurons within distressed but still viable tissue, thereby promoting functional recovery upon neuronal salvage. The clinical failure of this approach suggests that previous efforts to develop stroke therapies lacked means to predict success or futility in pre-clinical and early clinical studies. A key translational medicine strategy that can improve predictability relies on imaging methodologies to map the spatiotemporal evolution of the ischemic penumbra. This could serve as a biomarker indicative of neuroprotective potential and could increase likelihood of success in clinical studies by allowing selection of patients who are most likely to respond to therapy.
J Cereb Blood Flow Metab 2009 Jan
PMID:Multimodal magnetic resonance imaging for assessing evolution of ischemic penumbra: a key translational medicine strategy to manage the risk of developing novel therapies for acute ischemic stroke. 1876 99

Functional recovery after cerebral ischemia is mediated by the regeneration of vascular networks and the restoration of synaptic architecture. Netrins have been implicated in neuronal pathfinding and angiogenesis. In this study, we investigated the expression of Netrin-4 and its putative receptors, deleted in colorectal cancer (DCC), Unc5A, and Unc5B after distal middle cerebral artery occlusion in mice. Netrin-4 protein was also administered intracerebroventricularly to examine its effect on angiogenesis and behavioral recovery. Netrin-4 protein was highly upregulated in the ischemic core as soon as 1 day after cerebral ischemia, with subsequent downregulation after 1 week. Its expression was limited to the area of blood-brain barrier damage and was seen on both blood vessels and astrocytic foot processes. Although there was not a significant upregulation of the putative Netrin-4 receptor Unc5A and Unc5B, there was a significant increase in expression of the DCC receptor on neuronal processes in the peri-infarct cortex. Intracerebroventricular administration of Netrin-4 into the ischemic brain increased blood vessel density, endothelial proliferation, and improved behavioral recovery at 1 week after stroke, but did not have an effect on blood-brain barrier permeability or infarct size. These findings suggest that Netrin-4 may improve poststroke functional recovery by enhancing blood vessel proliferation.
J Cereb Blood Flow Metab 2009 Feb
PMID:Netrin-4 enhances angiogenesis and neurologic outcome after cerebral ischemia. 1898 53

Adult neocortex contains dividing satellite glia population even though their characteristics and functions have still remained unknown. Nestin(+)/NG2(+) cells as major fraction of dividing glial cells express bicuculline-sensitive gamma-aminobutyric acid A (GABA(A)) receptors and receive GABAergic inputs. Due to their high [Cl(-)](i), GABAergic activation depolarized the cells and then induced Ca(2+) influx into them. To assess an effect of this GABAergic excitation, we looked for the expression of neurotrophic factors. Among them, we detected the expression of brain-derived neurotrophic factor (BDNF) on the cells. The level of BDNF expression was elevated after cortical ischemia, and this elevation was blocked by bumetanide, an inhibitor for NKCC1 that blocks the GABAergic depolarization. Furthermore, performing a modified adhesive removal test, we observed that the treatment of bumetanide significantly attenuated the recovery in somatosensory dysfunction. Our results may shed a light on satellite glia population in the cortex and imply their roles in the functional recovery after ischemic injuries.
Cereb Cortex 2009 Sep
PMID:Excitatory GABAergic activation of cortical dividing glial cells. 1913 37

Oligodendrocytes are sensitive to ischemic damage. The Sonic hedgehog (Shh) pathway is critical in oligodendrogenesis; Gli1 is the principal effector of Shh signaling. We investigated oligodendrogenesis and Shh/Gli1 pathway activation after bone marrow stromal cell (BMSC) treatment of stroke in rats. Rats were subjected to the middle cerebral artery occlusion (MCAo). BMSCs have been shown to promote functional recovery post stroke. A therapeutic dose of BMSC (3 x 10(6) cells) treatment was initiated 1 day after MCAo. Immunohistochemistry was carried out to measure the oligodendrocyte progenitor cells, oligodendrocytes, myelin, and expressions of Shh and Gli1 at 14 days after MCAo. Gene expression of Shh and Gli1 was tested at 2 days after MCAo. An in vitro study was used to investigate the effects of BMSC on a premature oligodendrocyte cell line (N20.1 cells). BMSC treatment significantly increased O4(+) oligodendrocytes, MBP(+) area, and bromodeoxyuridine (BrdU)(+), NG2(+), BrdU(+)-NG2(+) cells, and mRNA and protein expressions of Shh and Gli1 in the ipsilateral brain of the MCAo rats than that in phosphate buffered saline (PBS)-treated rats. BMSCs promoted N20.1 cell proliferation and Gli1 mRNA expression, and these effects were abolished by the Shh pathway inhibitor cyclopamine. These data indicate that the BMSC treatment stimulates oligodendrogenesis by activation of the Shh/Gli1 pathway post stroke.
J Cereb Blood Flow Metab 2009 Jun
PMID:Bone marrow stromal cells increase oligodendrogenesis after stroke. 1938 36

Males exhibit greater histologic and behavioral impairment after stroke than do age-matched females. However, the contribution of androgens to stroke outcome remains unclear. We compared outcomes from middle cerebral artery occlusion (MCAO) in castrated mice with those in testosterone- or dihydrotestosterone (DHT)-replaced castrated mice. Castrates treated with 1.5 mg testosterone or 0.5 mg DHT before MCAO showed smaller infarct volumes (hemisphere: 27 or 26%) at 24 h after 90 mins MCAO than did untreated castrates (37%), whereas 5 mg testosterone or 1.5 mg DHT exacerbated infarcts (53 or 51%). These outcomes were blocked by the androgen receptor antagonist, flutamide, suggesting that androgen receptors mediate these responses to ischemia. We further evaluated long-term outcomes with a milder 60-min MCAO in castrates treated with the protective 1.5 mg testosterone dose. Consistent with data obtained at 24 h reperfusion, the infarct volume was decreased at 9 days reperfusion. Neurobehavioral analysis showed that motor functional recovery was improved during the first 3 days of reperfusion, but not improved at 7 days. We conclude that testosterone exhibits dose-dependent and time-sensitive effects after ischemia and that testosterone is likely to be an important factor in sex-linked differences in cerebrovascular disease.
J Cereb Blood Flow Metab 2009 Aug
PMID:Dose-dependent effects of androgens on outcome after focal cerebral ischemia in adult male mice. 1943 13

In this study, we examined whether rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, is neuroprotective in focal ischemic brain injury, and whether rosiglitazone can enhance the protective action of tissue plasminogen activator (tPA), an agent used clinically for thrombolytic therapy. Rats were subjected to ischemic brain injury by embolizing preformed clots into the middle cerebral artery (MCA). Treatment with rosiglitazone reduced infarction and improved functional recovery; it also enhanced the neuroprotective action of tPA and lengthened the time window for initiating tPA treatment. Occlusion of MCA resulted in a loss of collagen type IV, a major structural protein of the microvascular basal lamina, and tPA treatment worsened this loss. Rosiglitazone treatment prevented the reduction of collagen type IV in the ischemic injured brain by inhibiting the activation of matrix metallopeptidase-9 (MMP-9). In addition, rosiglitazone treatment reduced inflammatory reactions in the ischemic injured brain. Rosiglitazone either alone or in combination with tPA is an effective agent in the reduction of ischemic brain injury. The reduction of microvascular damage and inflammation contributes to the beneficial actions of rosiglitazone.
J Cereb Blood Flow Metab 2009 Oct
PMID:Rosiglitazone alone or in combination with tissue plasminogen activator improves ischemic brain injury in an embolic model in rats. 1955 6

Experience-dependent plasticity of the adult visual cortex underlies perceptual learning and recovery of function following central nervous system lesions. To reveal the signal transduction cascades involved in adult cortical plasticity, we utilized a model of remapping of cortical topography following binocular retinal lesions. In this model, the lesion projection zone (LPZ) of primary visual cortex (V1) recovers visually driven activity by the sprouting of horizontal axonal connections originating from the cells in the surrounding region. To explore the molecular mechanism underlying this process, we used gene microarrays from an expression library prepared from Macaque V1. By microarray analysis of gene expression levels in the LPZ and the surrounding region, and subsequent confirmation with Quantitative Real-Time polymerase chain reaction and in situ hybridization, the participation of a number of genes was observed, including the Rho GTPase family. Its role in regulation of cytoskeleton assembly provides a possible link between the alteration of neural activity and cortical functional reorganization.
Cereb Cortex 2010 Mar
PMID:Experience-dependent gene expression in adult visual cortex. 1957 Dec 70

Apolipoprotein E (ApoE), a cholesterol transporter and an immunomodulator, is brain protective after experimental stroke and implicated in brain repair. Here, we study the involvement of ApoE in the restoration of brain function after experimental stroke, by using animal housing conditions that differentially improve recovery after occlusion of the middle cerebral artery occlusion (MCAO). We found that after MCAO the ApoE levels increased in the injured hemisphere over a 30 days recovery period. The exception was a proximal narrow peri-infarct rim, in which ApoE was solely localized in S100beta(+)/glial fibrillary acidic protein (GFAP) negative reactive astrocytes at 4 to 7 days of recovery. Enriched housing after MCAO caused a marked decrease in ApoE levels compared with standard housing conditions, particularly in the ApoE/S100beta(+) reactive astrocytes. In addition, the levels of interleukin 1beta were lower in animals housed in an enriched environment. We propose that during the subacute phase after experimental stroke a zone for tissue reorganization with low cellular ApoE levels is formed. We conclude that the strong sensori-motor stimulation provided by enriched housing conditions mitigates the inflammatory response after stroke decreasing the level of ApoE that may contribute to the observed improvement of functional recovery.
J Cereb Blood Flow Metab 2009 Nov
PMID:Enriched environment reduces apolipoprotein E (ApoE) in reactive astrocytes and attenuates inflammation of the peri-infarct tissue after experimental stroke. 1962 95


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