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)

Cyclooxygenase, or prostaglandin G/H synthase, is the rate-limiting step in the production of prostaglandins. A new isoform, cyclooxygenase-2 (COX-2), has been cloned that is induced during inflammation in leukocytes and by synaptic activity in neurons. The objectives of this study are to determine the nature of COX-2 expression in normal and traumatized rat spinal cord, and to determine the effects of selective COX-2 inhibition on functional recovery following spinal cord injury. Using a weight-drop model of spinal cord injury, COX-2 mRNA expression was studied with in situ hybridization. COX-2 protein expression was examined by immunohistochemistry and Western analysis. Finally, using the highly selective COX-2 inhibitor, 1-[(4-methylsufonyl)phenyl]-3-tri-fluro-methyl-5-[(4-flur o)phenyl]prazole (SC58125), the effect of COX-2 inhibition on functional outcome following a spinal cord injury was determined. COX-2 was expressed in the normal adult rat spinal cord. COX-2 mRNA and protein production were increased following injury with increases in COX-2 mRNA production detectable at 2 h following injury. Increased levels of COX-2 protein were detectable for at least 48 h following traumatic spinal cord injury. Selective inhibition of COX-2 activity with SC58125 resulted in improved mean Basso, Beattie, and Bresnahan scores in animals with 12.5- and 25-g/cm spinal cord injuries; however, the effect was significant only for the 12.5g/cm injury group (p=0.0001 vs. p=0.0643 in the 25-g/cm group). These data demonstrate that COX-2 mRNA and protein expression are induced by spinal cord injury, and that selective inhibition of COX-2 improves functional outcome following experimental spinal cord injury.
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PMID:Role of cyclooxygenase 2 in acute spinal cord injury. 987 57

The purpose of this study was to investigate the efficacy of a novel steroid, fluasterone (DHEF, a dehydroepiandrosterone (DHEA) analog), at improving functional recovery in a rat model of traumatic brain injury (TBI). The lateral cortical impact model was utilized in two studies of efficacy and therapeutic window. DHEF was given (25 mg/kg, intraperitoneally) at the initial time point and once a day for 2 more days. Study A included four groups: sham injury, vehicle treated (n = 22); injured, vehicle treated (n = 30); injured, pretreated (5-10 min prior to injury, n = 24); and injured, posttreated (initial dose 30 min postinjury, n = 15). Study B (therapeutic window) included five groups: sham injury, vehicle treated (n = 17); injured, vehicle treated (n = 26); and three posttreatment groups: initial dose at 30 min (n = 18), 2 h (n = 23), or 12 h (n = 16) postinjury. Three criteria were used to grade functional recovery. In study A, DHEF improved beam walk performance both with pretreatment (79%) and 30-min posttreatment group (54%; p < 0.01, Dunnett vs. injured vehicle). In study B, the 12-h posttreatment group showed a 97% improvement in beam walk performance (p < 0.01, Dunnett). The 30-min and 12-h posttreatment groups showed a decreased incidence of falls from the beam, which reached statistical significance (p < 0.05, Dunnett). Tests of memory (Morris water maze) and neurological reflexes both revealed significant improvements in all DHEF treatment groups. In cultured rat mesangial cells, DHEF (and DHEA) potently inhibited interleukin-1beta-induced cyclooxygenase-2 (COX2) mRNA and prostaglandin (PGE2) production. In contrast, DHEF treatment did not alter injury-induced COX2 mRNA levels in the cortex or hippocampus. However, DHEF (and DHEA) relaxed ex vivo bovine middle cerebral artery preparations by about 30%, with an IC(50) approximately 40 microM. This was a direct effect on the vascular smooth muscle, independent of the endothelial cell layer. Fluasterone (DHEF) treatments improved functional recovery in a rat TBI model. Possible mechanisms of action for this novel DHEA analog are discussed. These findings suggest an exciting potential use for this agent in the clinical treatment of traumatic brain injury.
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PMID:A novel dehydroepiandrosterone analog improves functional recovery in a rat traumatic brain injury model. 1280 78

Results from several studies indicate that cyclooxygenase-2 (COX-2) is involved in ischemic brain injury. The purpose of this study was to evaluate the neuroprotective effects of the selective COX-2 inhibitor nimesulide on cerebral infarction and neurological deficits in a standardized model of transient focal cerebral ischemia in rats. Three doses of nimesulide (3, 6 and 12 mg/kg; i.p.) or vehicle were administered immediately after stroke and additional doses were given at 6, 12, 24, 36 and 48 h after ischemia. In other set of experiments, the effect of nimesulide was studied in a situation in which its first administration was delayed for 3-24 h after ischemia. Total, cortical and subcortical infarct volumes and functional outcome (assessed by neurological deficit score and rotarod performance) were determined 3 days after ischemia. The effect of nimesulide on prostaglandin E(2) (PGE(2)) levels in the injured brain was also investigated. Nimesulide dose-dependently reduced infarct volume and improved functional recovery when compared to vehicle. Of interest is the finding that neuroprotection conferred by nimesulide (reduction of infarct size and neurological deficits and improvement of rotarod performance) was also observed when treatment was delayed until 24 h after ischemia. Further, administration of nimesulide in a delayed treatment paradigm completely abolished PGE(2) accumulation in the postischemic brain, suggesting that COX-2 inhibition is a promising therapeutic strategy for cerebral ischemia to target the late-occurring inflammatory events which amplify initial damage.
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PMID:Wide therapeutic time window for nimesulide neuroprotection in a model of transient focal cerebral ischemia in the rat. 1506 40

The selective cyclooxygenase-2 (COX-2) inhibitor has been reported to have antiinflammatory, neuroprotective, and antioxidant effects in ischemia models. In this study, the authors examined whether a selective COX-2 inhibitor (celecoxib) reduces cerebral inflammation and edema after intracerebral hemorrhage (ICH), and whether functional recovery is sustained with longer treatment. ICH was induced using collagenase in adult rats. Celecoxib (10 or 20 mg/kg) was administered intraperitoneally 20 minutes, 6 hours, and 24 hours after ICH and then daily thereafter. Seventy-two hours after ICH induction, the rats were killed for histologic assessment and measurement of brain edema and prostaglandin E2. Behavioral tests were performed before and 1, 7, 14, 21, and 28 days after ICH. The brain water content of celecoxib-treated rats decreased both in lesioned and nonlesioned hemispheres in a dose-dependent manner. Compared with the ICH-only group, the number of TUNEL-positive, myeloperoxidase-positive, or OX42-positive cells was decreased in the periphery of hematoma and brain prostaglandin E2 level was reduced in the celecoxib-treated group. Celecoxib-treated rats recovered better by the behavioral tests at 7 days after ICH throughout the 28-day period, and the earlier the drug was administered, the better the functional recovery. Evidence of similar effects in an autologous blood-injected model showed that direct collagenase toxicity was not the major cause of inflammation or cell death. These data suggest that celecoxib treatment after ICH reduces prostaglandin E2 production, brain edema, inflammation, and perihematomal cell death in the perihematomal zone and induces better functional recovery.
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PMID:Celecoxib induces functional recovery after intracerebral hemorrhage with reduction of brain edema and perihematomal cell death. 1536 23

BACKGROUND: Previous studies suggest that the cyclooxygenase-2 (COX-2) inhibitor nimesulide has a remarkable protective effect against different types of brain injury including ischemia. Since there are no reports on the effects of nimesulide on permanent ischemic stroke and because most cases of human stroke are caused by permanent occlusion of cerebral arteries, the present study was conducted to assess the neuroprotective efficacy of nimesulide on the cerebral infarction and neurological deficits induced by permanent middle cerebral artery occlusion (pMCAO) in the rat. METHODS: Ischemia was induced by permanent occlusion of the middle cerebral artery in rats, via surgical insertion of a nylon filament into the internal carotid artery. Infarct volumes (cortical, subcortical and total) and functional recovery, assessed by neurological score evaluation and rotarod performance test, were performed 24 h after pMCAO. In initial experiments, different doses of nimesulide (3, 6 and 12 mg/kg; i.p) or vehicle were administered 30 min before pMCAO and again at 6, 12 and 18 h after stroke. In later experiments we investigated the therapeutic time window of protection of nimesulide by delaying its first administration 0.5-4 h after the ischemic insult. RESULTS: Repeated treatments with nimesulide dose-dependently reduced cortical, subcortical and total infarct volumes as well as the neurological deficits and motor impairment resulting from permanent ischemic stroke, but only the administration of the highest dose (12 mg/kg) was able to significantly (P < 0.01) diminish infarct volume. The lower doses failed to significantly reduce infarction but showed a beneficial effect on neurological function. Nimesulide (12 mg/kg) not only reduced infarct volume but also enhanced functional recovery when the first treatment was given up to 2 h after stroke. CONCLUSIONS: These data show that nimesulide protects against permanent focal cerebral ischemia, even with a 2 h post-treatment delay. These findings have important implications for the therapeutic potential of using COX-2 inhibitors in the treatment of stroke.
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PMID:Effects of the cyclooxygenase-2 inhibitor nimesulide on cerebral infarction and neurological deficits induced by permanent middle cerebral artery occlusion in the rat. 1565 9

Memantine, a N-methyl-D-aspartate (NMDA) receptor antagonist, inhibits hematoma expansion and celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, reduces perihematomal inflammation in intracerebral hemorrhage. We examined whether the combination treatment has additive effects in experimental intracerebral hemorrhage (ICH). ICH was induced using stereotaxic infusion of collagenase into brains of adult rats. After the induction of ICH, rats were treated with intraperitoneal injection of memantine (20 mg/kg), celecoxib (20 mg/kg) or both agents. Only vehicles were administrated in rats of the control group. Results showed that the combination treatment of memantine and celecoxib reduced both hematoma volume and brain edema. Combination treatment also induced the better functional recovery with further attenuation of cerebral inflammation and apoptosis compared to the control group. When compared to the single agent groups, the combination treatment showed better effects in neuroprotection and anti-inflammation. These results suggest the feasible combined application of memantine and celecoxib in ICH treatment.
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PMID:Combined neuroprotective effects of celecoxib and memantine in experimental intracerebral hemorrhage. 1712 15

Angiotensin II exerts its central nervous system effects primarily via its receptors AT1 and AT2, and it participates in the pathogenesis of ischemia via AT1. The selective AT1 receptor blocker (ARB) is used in the hypertension treatment, and it exerts a variety of pleiotropic effects, including antioxidative, antiapoptotic, and anti-inflammatory effects. In this study, we investigated the therapeutic effect of the ARB telmisartan in experimental intracerebral hemorrhage (ICH) in normotensive rats. ICH was induced via the collagenase infusion or autologous blood injection. Either telmisartan at 30 mg/kg/dose or phosphate-buffered saline was orally administered 2 h after ICH induction. We evaluated hemorrhage volume, brain water content, and functional recovery, and we performed the histological analysis for terminal deoxynucleotidyl transferase dUTP nick-end labeling, leukocyte infiltration, and microglia activation. A variety of intracellular signals, in terms of oxidative stress, apoptotic molecules, and inflammatory mediators, were also measured. Telmisartan reduced hemorrhage volume, brain edema, and inflammatory or apoptotic cells in the perihematomal area. Telmisartan was noted to induce the expression of endothelial nitric-oxide synthase and peroxisome proliferator-activated receptor gamma and decrease oxidative stress, apoptotic signal, tumor necrosis factor-alpha, and cyclooxygenase-2 expression. The telmisartan-treated rats exhibited less pronounced neurological deficits and recovered better. Thus, telmisartan seems to offer neural protection, including antiapoptosis, anti-inflammatory, and antioxidant benefits in the intracerebral hemorrhage rat model.
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PMID:Blockade of AT1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage. 1753 8

The Edmonton protocol for islet transplantation utilizes fresh islet grafts but other protocols increasingly transplant short-term cultured grafts mainly for practical reasons. To improve our understanding of the impact of culture pretreatment of human islets, we assessed post-transplant function by nude mouse bioassay, islet ATP, activity of stress-activated MAP kinases, and expression of stress-related genes by focused cDNA array in freshly isolated and cultured islets. Mean blood glucose levels over 4 weeks after transplantation (2000 IE) of (i) freshly isolated, (ii) cultured and preculture counted (recovery rate; 78 +/- 6%), and (iii) cultured and postculture counted islets in diabetic mice were 330 +/- 40, 277 +/- 65, and 256 +/- 52 mg/dl (i versus ii, P = 0.004; i versus iii, P = 0.002). During culture, islet ATP/DNA and ATP/ADP increased; JNK and p38 MAPK activities decreased. Among 96 genes studied, mRNA expression of heat shock protein 70 genes decreased >twofold during culture in all four pairs; expression of cyclooxygenase-2, superoxide dismutase-2, interleukin-6 and cytochromes P450 1A1 genes increased. Our results show that culturing human islets before transplantation is not disadvantageous in regard of functional recovery from changes induced by nonphysiologic stimuli during islet isolation. The increase in expression of several stress-related genes during culture also shows that improving culture conditions may further enhance post-transplant islet function.
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PMID:Effect of short-term culture on functional and stress-related parameters in isolated human islets. 1945 31

The inflammatory response appears to be essential in the modulation of the degeneration and regeneration process after peripheral nerve injury. In injured nerves, cyclooxygenase-2 (COX-2) is strongly upregulated around the injury site, possibly playing a role in the regulation of the inflammatory response. In this study we investigated the effect of celecoxib, a COX-2 inhibitor, on functional recovery after sciatic nerve crush in rats. Unilateral sciatic nerve crush injury was performed on 10 male Wistar rats. Animals on the experimental group (n = 5) received celecoxib (10 mg/kg ip) immediately before the crush injury and daily for 7 days after the injury. Control group (n = 5) received normal saline at equal regimen. A sham group (n = 5), where sciatic nerve was exposed but not crushed, was also evaluated. Functional recovery was then assessed by calculating the sciatic functional index (SFI) on days 0,1,7,14 and 21 in all groups, and registering the day of motor and walking onset. In comparison with control group, celecoxib treatment (experimental group) had significant beneficial effects on SFI, with a significantly better score on day 7. Anti-inflammatory drug celecoxib should be considered in the treatment of peripheral nerve injuries, but further studies are needed to explain the mechanism of its neuroprotective effects.
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PMID:Celecoxib accelerates functional recovery after sciatic nerve crush in the rat. 1903 61

Inflammation has been known to play an important role in the pathogenesis after spinal cord injury (SCI). Microglia are activated after injury and produce a variety of proinflammatory factors such as tumor necrosis factor-alpha, interleukin-1beta, cyclooxygenase-2, and reactive oxygen species leading to apoptosis of neurons and oligodendrocytes. In this study, we examined the neuroprotective effects of total ethanol extract of Scutellaria baicalensis (EESB), after SCI. Using primary microglial cultures, EESB treatment significantly inhibited lipopolysaccharide-induced expression of such inflammatory mediators as tumor necrosis factor-alpha, IL-1beta, IL-6, cyclooxygenase-2, and inducible nitric oxide synthase. Furthermore, reactive oxygen species and nitric oxide production were significantly attenuated by EESB treatment. For in vivo study, rats that had received a moderate spinal cord contusion injury at T9 received EESB orally at a dose of 100 mg/kg. EESB inhibited expression of proinflammatory factors and protein carbonylation and nitration after SCI. EESB also inhibited microglial activation at 4 h after injury. Furthermore, EESB significantly inhibited apoptotic cell death of neurons and oligodendrocytes and improved functional recovery after SCI. Lesion cavity and myelin loss were also reduced following EESB treatment. Thus, our data suggest that EESB significantly improve functional recovery by inhibiting inflammation and oxidative stress after injury.
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PMID:Neuroprotective effect of Scutellaria baicalensis on spinal cord injury in rats. 1951 65


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