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)

The cellular isoform of prion protein, PrPc, may confer neuroprotection in the brain, according to recent studies. To elucidate the role of PrPc in stroke pathology, we subjected PrPc-knockout (Prnp(0/0)), wild-type and PrPc-transgenic (tga20) mice to 30 min of intraluminal middle cerebral artery occlusion, followed by 3, 24 or 72 h reperfusion, and examined how PrPc levels influence brain injury and cell signaling. In immunohistochemical experiments and Western blots, we show that PrPc expression is absent in the brains of Prnp(0/0) mice, detectable in wild-type controls and approximately 4.0-fold elevated in tga20 mice. We provide evidence that PrPc deficiency increases infarct size by approximately 200%, while transgenic PrPc restores tissue viability, albeit not above levels in wild-type animals. To elucidate the mechanisms underlying Prnp(0/0)-induced injury, we performed Western blots, which revealed increased activities of ERK-1/-2, STAT-1 and caspase-3 in ischemic brains of Prnp(0/0)mice. Our data suggest a role of cytosolic signaling pathways in Prnp(0/0)-induced cell death.
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PMID:Aggravation of ischemic brain injury by prion protein deficiency: role of ERK-1/-2 and STAT-1. 1589 68

The biosynthesis of oxygenated arachidonic acid messengers triggered by cerebral ischemia-reperfusion is preceded by an early and rapid phospholipase A2 activation reflected in free arachidonic and docosahexaenoic acid (DHA) accumulation. These fatty acids are released from membrane phospholipids. Both fatty acids are derived from dietary essential fatty acids; however, only DHA, the omega-3 polyunsaturated fatty acyl chain, is concentrated in phospholipids of various cells of brain and retina. Synaptic membranes and photoreceptors share the highest content of DHA of all cell membranes. DHA is involved in memory formation, excitable membrane function, photoreceptor cell biogenesis and function, and neuronal signaling, and has been implicated in neuroprotection. In addition, this fatty acid is required for retinal pigment epithelium cell (RPE) functional integrity. Here we provide an overview of the recent elucidation of a specific mediator generated from DHA that contributes at least in part to its biological significance. In oxidative stress-challenged human RPE cells and rat brain undergoing ischemia-reperfusion, 10,17S-docosatriene (neuroprotectin D1, NPD1) synthesis evolves. In addition, calcium ionophore A23187, IL-1beta, or the supply of DHA enhances NPD1 synthesis. A time-dependent release of endogenous free DHA followed by NPD1 formation occurs, suggesting that a phospholipase A2 releases the mediator's precursor. When NPD1 is infused during ischemia-reperfusion or added to RPE cells during oxidative stress, apoptotic DNA damage is down-regulated. NPD1 also up-regulates the anti-apoptotic Bcl-2 proteins Bcl-2 and BclxL and decreases pro-apoptotic Bax and Bad expression. Moreover, NPD1 inhibits oxidative stress-induced caspase-3 activation. NPD1 also inhibits IL-1beta-stimulated expression of COX-2. Overall, NPD1 protects cells from oxidative stress-induced apoptosis. Because photoreceptors are progressively impaired after RPE cell damage in retinal degenerative diseases, understanding of how these signals contribute to retinal cell survival may lead to the development of new therapeutic strategies. Moreover, NPD1 bioactivity demonstrates that DHA is not only a target of lipid peroxidation, but rather is the precursor to a neuroprotective signaling response to ischemia-reperfusion, thus opening newer avenues of therapeutic exploration in stroke, neurotrauma, spinal cord injury, and neurodegenerative diseases, such as Alzheimer disease, aiming to up-regulate this novel cell-survival signaling.
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PMID:Neuroprotectin D1 (NPD1): a DHA-derived mediator that protects brain and retina against cell injury-induced oxidative stress. 1591 89

The incidence of perinatal stroke is approximately 0.025%. About two thirds of these patients develop long-lasting neurological deficits. Preconditioning-induced neuroprotection, a phenomenon in which application of a stimulus induces brain ischemic tolerance, is investigated to improve outcome after a perinatal stroke. We applied prenatal hypoxia to fetuses by exposing 22-day pregnant mother rats to 15% oxygen for 30 min and subjected newborns with or without this prenatal hypoxia to brain ischemia 48 h later. Newborns with the prenatal hypoxia had a lower mortality rate, less brain tissue and neuronal loss and fewer active caspase 3 (an indicator for cell apoptosis) positive brain cells than newborns with the brain ischemia only. This neuroprotection was abolished by an inhibitor of inducible nitric oxide synthase (iNOS). The expression of iNOS proteins but not endothelial and neuronal NOS proteins was increased by the prenatal hypoxia. Thus, the prenatal hypoxia-induced neuroprotection may be iNOS-dependent.
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PMID:Prenatal hypoxia-induced adaptation and neuroprotection that is inducible nitric oxide synthase-dependent. 1599 93

After recent clinical trials, statins have gained increasing significance in secondary stroke prevention. From experimental studies, it is well established that statins have beneficial action when delivered prophylactically prior to a stroke. Conversely, much less is known about the effects of statins on injury development when delivered after ischemia. We here examined the effects of a post-ischemic delivery of rosuvastatin (0.5, 5 or 20 mg/kg, administered i.p. immediately after reperfusion onset), a potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on brain injury and cell signaling after focal cerebral ischemia, induced by 90 min of intraluminal middle cerebral artery occlusion in mice. In animals receiving normal saline, 0.5 or 5 mg/kg rosuvastatin, middle cerebral artery occlusions resulted in reproducible brain infarcts at 24 h after reperfusion onset, which did not differ in size. However, rosuvastatin, administered at higher doses (20 mg/kg), reduced infarct volume at 24 and 48 h after ischemia (by 34+/-16% and 18+/-3%, respectively, P<0.05). Western blots revealed that rosuvastatin decreased phosphorylated extracellular-regulated kinase-1/-2 and reduced activated caspase-3 levels in ischemic brain areas, while endothelial NO synthase expression, p38 and Jun kinase phosphorylation were not influenced by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Rosuvastatin also significantly diminished expression levels of inducible NO synthase in the ischemic brain. Our results indicate that rosuvastatin may have utility not only as stroke prophylaxis but also as acute therapy inhibiting executive cell death pathways.
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PMID:Post-ischemic delivery of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor rosuvastatin protects against focal cerebral ischemia in mice via inhibition of extracellular-regulated kinase-1/-2. 1600 98

Active anti-stroke fraction of Cerebral preparation (extract of water-soluble molecules from brain tissue of animals with hemorrhagic stroke) decreased caspase-3 expression and improved survival of experimental animals in the acute period after hemorrhagic stroke.
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PMID:Effect of active fraction of cerebral on expression of caspase-3 and beta-amyloid precursor protein during therapy of hemorrhagic stroke in the acute and delayed periods. 1602 8

Stroke is the third leading cause of death and disability, and the risk for ischemic stroke is greater in diabetics. Previous studies have demonstrated both structural and functional nervous system changes in diabetes, and these changes may be enhanced by apoptosis. In the present study, we evaluated several indexes of both necrosis and apoptosis in the CNS of normals and two different models of diabetes (insulinopenic and insulin-resistant). Studies were conducted following middle cerebral artery occlusion (MCAO) with or without reperfusion. The sensory motor cortex (layer-5 and -6) and the CA1 and CA3 sectors of the hippocampus were analyzed following MCAO. We observed that both insulinopenic and insulin-resistant diabetic rats have increased basal level of apoptosis that is uniformly and bilaterally distributed as indicated by both caspase-3 activity and TUNEL staining. Twenty-four hours after MCAO, apoptosis was further increased in both diabetic models. Reperfusion after a 2 h MCAO compared to 24 h MCAO was associated with a decrease in TUNEL staining and caspase-3 activity in the control animal but exacerbated apoptosis, especially in the hippocampus of insulin-resistant diabetic rats. MCAO-induced lesion volumes were greater in insulinopenic rats compared to insulin-resistant and control rats. We conclude that both insulinopenic and insulin-resistant diabetic animals have increased apoptosis in the CNS in response to MCAO, and restoration of blood flow especially in the insulinopenic diabetic animals paradoxically exacerbates this process. Furthermore, restoration of blood flow did not decrease lesion volume in insulinopenic diabetic animals.
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PMID:Cerebral ischemia induced apoptosis and necrosis in normal and diabetic rats. 1603 84

Systemic injections of the neurosteroid progesterone improve cognitive recovery after traumatic brain injury (TBI) and stroke, and decrease molecular indicators of neuronal damage. Suddenly withdrawing progesterone after repeated dosing (PW) exacerbates ischemia and causes increased anxiety, seizure susceptibility, and excitotoxicity. Adult male Sprague-Dawley rats received either bilateral medial frontal cortex contusions or sham surgery. Injections were administered at 1 and 6 h post-injury, then every 24 h for 7 days. Vehicle-treated rats received 2-hydroxypropyl-beta-cyclodextrin (HBC). Acute PW (AW) rats received a full 16 mg/ml of progesterone for 7 days, and tapered PW (TW) rats received 5 days at full dosage, then 2 days with progressively halved dosages. Anxiety behaviors were observed pre- and post-surgery, and compared to levels at the peak of withdrawal. AW rats with lesions exhibited significantly more anxiety than any other treatment group, while both lesion- and sham-operated TW rats were indistinguishable from vehicle-treated intact animals. After behavioral tests were complete, the brains were extracted and prepared for Western blotting. TNFalpha, cFos, Caspase-3, and NFkappaB, among others, were investigated. While all progesterone treatments resulted in improved molecular recovery, TW animals had significantly fewer active markers for apoptosis and inflammation than AW animals. In conclusion, although progesterone treatment decreases inflammation and apoptosis, acute withdrawal increases activity in some apoptotic and inflammatory pathways and increases anxiety behavior during the acute healing phase. A tapered withdrawal of the hormone further enhances short-term recovery after TBI.
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PMID:Tapered progesterone withdrawal enhances behavioral and molecular recovery after traumatic brain injury. 1603 52

The present study was undertaken to evaluate whether in a neonatal model of stroke a prophylactic neuroprotective treatment with simvastatin modulates hypoxia-ischemia-induced inflammatory and apoptotic signaling. Procaspase-3 and cleaved caspase-3 expression showed a peak at 24 h and returned to control values after 5 days. Caspase-3 activity followed the same pattern of caspase-3 proteolytic cleavage. In simvastatin-treated ischemic animals, the expression of these proteins and caspase-3 activity were significantly lower when compared to that of ischemic animals. alpha-Spectrin and protein kinase C-alpha (PKCalpha) cleavages were not affected by the treatment. Poly (ADP-ribose) polymerase fragmentation, caspase-1 activation, and IL-1beta and ICAM-1 mRNA expression were increased by hypoxia-ischemia and significantly reduced in simvastatin-treated animals. The results indicate that simvastatin-induced attenuation of hypoxia-ischemia brain injury in the newborn rat occurs through reduction of the inflammatory response, caspase-3 activation, and apoptotic cell death.
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PMID:Simvastatin reduces caspase-3 activation and inflammatory markers induced by hypoxia-ischemia in the newborn rat. 1605 75

Two primary drugs used to treat bipolar mood disorder are lithium and valproate. Emerging evidence supports the notion that both mood stabilizers have neuroprotective effects. In primary cultures of rat cerebellar granule cells and cortical neurons, lithium and valproate robustly and potently protect against glutamate-induced, N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity. The neuroprotective mechanisms involve inactivation of NMDA receptors through inhibition of NR2B tyrosine phosphorylation, activation of cell survival factors such as the PI 3-kinase/Akt signaling pathway, and induction of neurotrophic/neuroprotective proteins, including brain-derived neurotrophic factor, heat-shock protein (HSP), and Bcl-2. Both drugs are also effective against other forms of insults such as ER stress in neurally related cell types. The molecular targets likely involve glycogen synthase kinase-3 (GSK-3) and histone deacetylase (HDAC) for lithium and valproate, respectively. In a rat cerebral artery occlusion model of stroke, postinsult treatment with lithium or valproate reduces ischemia-induced brain infarction, caspase-3 activation, and neurological deficits, and these neuroprotective effects are associated with HSP70 upregulation and, in the case of valproate, HDAC inhibition. In a rat excitotoxic model of Huntington's disease in which an excitotoxin is infused into the striatum to activate NMDA receptors, short-term lithium pretreatment is sufficient to protect against DNA damage, caspase activation, and apoptosis of striatal neurons, and this neuroprotection is concurrent with Bcl-2 induction. Moreover, lithium treatment increases cell proliferation near the site of striatal injury, and some newborn cells have phenotypes of neurons and astroglia. Thus, lithium and valproate are potential drugs for treating some forms of neurodegenerative diseases.
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PMID:The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials. 1617 24

Heat stroke-induced death is a major killer worldwide. Mice were subjected to acute heat stress by exposing them to whole-body hyperthermia (WBH) treatment and were used as a model to study heat stroke. Administration of L-arginine (L-arg, 120 mg/kg, i.p) 2 h after the cessation of WBH rescued the mice from heat-induced death and reduced the hypothermia. Heat shock protein 70 levels in the liver were increased significantly in heat-stressed mice administered L-arg compared with the heat-stressed group. WBH induced apoptosis, as indicated by DNA fragmentation, and increased levels of p53 and caspase-3 activity, which were significantly reduced by the administration of L-arg. The levels of inducible nitric oxide synthase in the liver, nitrite, and inflammatory cytokines like interleukin 1beta and tumor necrosis factor-alpha in the serum increased in WBH-treated mice. The levels of the above markers of heat stress significantly decreased in L-arg-treated mice. Kinin-B1 receptor (kinin-B1R) in cardiac tissue that is upregulated in heat stressed mice was significantly lower in L-arg-administered mice. These data suggest the potential use of L-arg, a nonessential amino acid that is used as an enteral diet supplement, to treat heat stroke-related injury when administered at the appropriate dose and time.
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PMID:Therapeutic treatment with L-arginine rescues mice from heat stroke-induced death: physiological and molecular mechanisms. 1620 19


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