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)

Poly(ADP-ribosyl) ation is a reversible post-translational protein modification implicated in the regulation of a number of biological functions. Whereas an 18 member superfamily of poly(ADP-ribose) polymerase (PARP) enzymes synthesize poly(ADP-ribose) (PAR), a single protein, PAR glycohydrolase (PARG) is responsible for the catabolism of the polymer. PARP-1 accounts for more than 90% of the poly(ADP-ribosyl)ating capacity of the cells. PARP-1 activated by DNA breaks cleaves NAD(+) into nicotinamide and ADP-ribose and uses the latter to synthesize long branching PAR polymers covalently attached to acceptor proteins including histones, DNA repair enzymes, transcription factors and PARP-1. Whereas activation of PARP-1 by mild genotoxic stimuli may facilitate DNA repair and cell survival, irreparable DNA damage triggers apoptotic or necrotic cell death. In apoptosis, early PARP activation may assist the apoptotic cascade [e.g. by stabilizing p53, by mediating the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus or by inhibiting early activation of DNases]. In most severe oxidative stress situations, excessive DNA damage causes over activation of PARP-1, which incapacitates the apoptotic machinery and switches the mode of cell death from apoptosis to necrosis. Besides serving as a cytotoxic mediator, PARP-1 is also involved in transcriptional regulation, most notably in the NF kappaB and AP-1 driven expression of inflammatory mediators. Pharmacological inhibition or genetic ablation of PARP-1 provided remarkable protection from tissue injury in various oxidative stress-related disease models ranging from stroke, diabetes, diabetic endothelial dysfunction, myocardial ischemia-reperfusion, shock, Parkinson's disease, arthritis, colitis to dermatitis and uveitis. These beneficial effects are attributed to inhibition of the PARP-1 mediated suicidal pathway and to reduced expression of inflammatory cytokines and other mediators (e.g. inducible nitric oxide synthase).
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PMID:Structure and function of poly(ADP-ribose) polymerase-1: role in oxidative stress-related pathologies. 1602 17

We demonstrate that the spontaneously hypertensive rat stroke-prone rat (SHRsp) undergoes premature aging of the CNS compared to the related normotensive Wistar Kyoto rat (WKY) as demonstrated by presence of activated microglia/macrophages, increased expression of inducible nitric oxide synthase and increased astrogliosis. We tested the hypothesis that dietary intake of phase 2 protein inducers would decrease these aging-associated degenerative changes. The source of dietary phase 2 protein inducers was dried broccoli sprouts of a cultivar containing high amounts of glucoraphanin that gives rise to phase 2 protein-inducing isothiocyanate sulforaphane. This diet significantly decreased the aging-related degenerative changes in the SHRsp CNS. We conclude that modest changes in diet may have profound effects on the aging CNS.
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PMID:Dietary approach to decrease aging-related CNS inflammation. 1605 42

An increase in reactive oxygen species has been shown to play a role in perpetuating hypertension and cerebral injury in stroke-prone spontaneously hypertensive rats (SHRsp). Lipid peroxidation in the cerebral cortex is much more intense in SHRsp after establishment of severe hypertension as compared to that in normotensive Wistar-Kyoto rats (WKY). Cortical neurons from SHRsp are more vulnerable to hypoxia and hyponutritional conditions. We sought to investigate whether long-term administration of seleno-glutathione peroxidase mimic ebselen (PZ51) would have a protective effect on cortical neurons in SHRsp, and, if so, the possible mechanisms of this effect. Twenty-two 8-week-old SHRsp were randomized into a PZ51 group and control group. Age-matched WKY were used as normal controls. We examined the levels of malonaldehyde (MDA) and nitric oxide (NO) in the cerebral cortex (CC) homogenate, detected the three isoforms of nitric oxide synthase (NOS) by Western blotting, and examined cortical neurons by transmission electron microscopy. The results showed that PZ51 treatment significantly decreased both MDA and NO in the CC, inhibited inducible nitric oxide synthase (iNOS) protein expression, and alleviated the damage to cortical neurons compared to the findings for the control group. In conclusion, the present study showed that PZ51 administration suppressed lipid peroxidation and inhibited iNOS protein expression in CC homogenate, and it was suggested that these mechanisms may play a role in the protective effects of PZ51 on cortical neurons of SHRsp.
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PMID:Protective effect of antioxidant ebselen (PZ51) on the cerebral cortex of stroke-prone spontaneously hypertensive rats. 1609 69

1. There is evidence that the induction of inducible nitric oxide synthase (iNOS) and peroxynitrite by ischaemia/reperfusion may lead to renal cell injury. Herein, we investigated whether Sheng mai san (SMS), a Chinese herbal medicine, protects against renal ischaemic injury during heat stroke by reducing iNOS-dependent nitric oxide (NO) and peroxynitrite formation. 2. Urethane-anaesthetized rats were exposed to heat stress (ambient temperature 43 degrees C) to induce heat stroke. Control rats were exposed to 24 degrees C. Mean arterial pressure and renal blood flow after the onset of heat stroke were significantly lower in heat stroke rats than in control rats. However, both colonic temperature and renal damage score were greater in heat stroke rats compared with control rats. Similarly, plasma NO, creatinine and blood urea nitrogen (BUN), as well as the renal immunoreactivity of iNOS and peroxynitrite, were significantly higher in heat stroke rats compared with their normothermic controls. 3. Pretreatment with SMS (1.2 g/day per rat for 7 consecutive days before the initiation of heat stress) significantly attenuated the heat stroke-induced arterial hypotension, hyperthermia, renal ischaemia and damage, the increased renal immunoreactivity of iNOS and peroxynitrite and the increased plasma levels of NO, creatinine and BUN. Pretreatment with SMS resulted in a prolongation of survival time in heat stroke. 4. The results of the present study suggest that SMS protects against renal ischaemic damage by reducing iNOS-dependent NO and peroxynitrite production during heat stroke.
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PMID:Sheng mai san, a Chinese herbal medicine, protects against renal ischaemic injury during heat stroke in the rat. 1617 31

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

In the present study, the underlying protective mechanism of melatonin on kainic acid (KA)-induced excitotoxicity was examined in the hippocampus of mice. KA, administered intracerebroventricularly (i.c.v.), induced marked neuronal cell death with concurrent microglial activation and subsequent induction of inducible nitric oxide synthase (iNOS) in the hippocampus. Histopathological analysis demonstrated that melatonin (10 mg/kg), administered 1 hr prior to KA, attenuated KA-induced death of pyramidal neurons in the CA3 region. Melatonin obviously suppressed KA-induced microglial activation and consequent iNOS expression that were determined by increased immunoreactivities of microglial marker OX-6 and iNOS, respectively. Increased phosphorylation of Akt in pyramidal neurons was observed as early as 2 hr after administration of melatonin. Further, melatonin resulted in increased expression of astroglial glial cell line-derived neurotrophic factor (GDNF), which started to appear approximately 6 hr after administration of melatonin. The results of the present study demonstrate that melatonin exerts its neuroprotective action against KA-induced excitotoxicity both through the activation of neuronal Akt and via the direct action on hippocampal neurons and through the increased expression of astroglial GDNF, which subsequently activates neuronal PI3K/Akt pathway. Therefore, the present study suggests that melatonin, pineal secretory product, is potentially useful in the treatment of acute brain pathologies associated with excitotoxic neuronal damage such as epilepsy, stroke, and traumatic brain injury.
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PMID:Sustained activation of Akt by melatonin contributes to the protection against kainic acid-induced neuronal death in hippocampus. 1631 2

An age- and blood pressure-associated increase in methylglyoxal (MG) and MG-induced advanced glycation endproducts (AGEs), including N(epsilon)-carboxyethyl-lysine (CEL) and N(epsilon)-carboxymethyl-lysine (CML), in the kidney of spontaneously hypertensive rats (SHR) has been shown. In the present study, gender-related changes in AGEs and nitric oxide synthase were investigated in Sprague-Dawley (SD) and stroke-prone SHR (SHRsp) rats. Immunohistochemical analyses were conducted on kidneys from 24-week-old male and female SD rats as well as SHRsp. The systolic blood pressure of SHRsp was significantly higher than that of SD rats. Male SD rats had more intense kidney staining for CEL than female SD rats. Both male and female SHRsp had more marked CEL and CML staining localized to kidney tubules, as opposed to SD rats. Female rats showed more staining in glomerular vessels than male rats in both SD and SHRsp. Nuclei containing nuclear factor-kappaB (NF-kappaB) p65 and activated macrophages were seen in the kidney from SHRsp, not so much in SD rats, localized to renal tubules in male and glomerular vessels in female SHRsp. A higher protein level of NF-kappaB p65 was found in SHRsp than in SD rats. SD rats had more intense kidney neuronal nitric oxide synthase staining than SHRsp. The intensity of inducible nitric oxide synthase staining was significantly higher in SHRsp than in SD rats, with no gender differences in either strain. SHRsp and male rats exhibited higher AGEs and oxidative stress than SD and female rats, respectively. These differences might partly account for the development of hypertension in SHRsp and the higher vulnerability of male animals to renal pathology.
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PMID:Gender-related differences in advanced glycation endproducts, oxidative stress markers and nitric oxide synthases in rats. 1640 17

Strokes due to transmural vasculitis associated with coccidioidal meningitis result in significant morbidity and mortality. The immunological and inflammatory processes responsible are poorly understood. To determine the inflammatory mediators, i.e. cytokines, chemokines, iNOS, matrix metalloproteinase-9 (MMP-9), that possibly contribute to vasculitis, temporal mRNA expression in brain basilar artery samples and MMP-9 protein in the CSF of male NZW rabbits infected intracisternally with 6.5 x 10(4) arthroconidia of Coccidioides immitis were assessed. Five infected and 3 sham-injected rabbits at each time point were euthanized 4, 9, 14 and 20 days post infection. All infected rabbits had neurological abnormalities and severe vasculitis in the basilar arteries on days 9-20. In basilar arteries of infected animals versus controls, mRNAs encoding for IL-6, iNOS, IFN-gamma, IL-2, MCP-1, IL-1beta, IL-10, TNF-alpha, CCR-1, MMP-9, TGF-beta, as well as MMP-9 protein in CSF, were found to be significantly up-regulated. Thus, this study identified inflammatory mediators associated with CNS vasculitis and meningitis due to C. immitis infection. Assessment of the individual contribution of each mediator to vasculitis may offer novel approaches to the treatment of coccidioidal CNS infection. This study also provides unique methodology for immunology studies in a rabbit model.
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PMID:Temporal expression of inflammatory mediators in brain basilar artery vasculitis and cerebrospinal fluid of rabbits with coccidioidal meningitis. 1648 45

The involvement of plasma nitric oxide metabolites (NO(x)) in hypertension was examined in stroke-resistant spontaneously hypertensive rats during the development of hypertension. Continuous application of a static magnetic field (SMF; a maximum magnetic flux density of 180 millitesla, a peak magnetic gradient of 133 millitesla/mm) to the left carotid sinus baroreceptors of rats was carried out for 6 weeks using a disc-shaped magnetic implant (4.4 mm in diameter, 2.2 mm in height). An L-type voltage-gated Ca2+ channel blocker, nicardipine (2 mg/kg) was administered intraperitoneally three times a week for 6 weeks, and then 15 min after each injection, mean arterial blood pressure (MAP), heart rate (HR), skin blood flow (SBF), skin blood velocity (SBV) and plasma NO(x) were monitored. The nicardipine significantly decreased MAP, and increased HR, SBF and SBV in the nicardipine-treated rats compared with the control rats (p<0.001) without changing plasma NO(x) levels. The SMF exposure alone significantly suppressed or retarded the development of hypertension in SMF-exposed rats compared with the control rats (p<0.05). The SMF significantly promoted the nicardipine-induced MAP decrease (p<0.001) and induced a significant increase in plasma NO(x) levels (p<0.01) in SMF-exposed, nicardipine-treated rats compared with the unexposed, nicardipine-treated rats. The SMF did not significantly induce any changes in the SBF and SBV in nicardipine-treated nor untreated rats. These results suggest that the SMF may enhance nicardipine-induced hypotension by more effectively antagonizing the Ca2+ influx through the Ca2+ channels compared with the nicardipine treatment alone. In addition, the enhanced antihypertensive effects of the SMF on the nicardipine-treated rats might be, at least in part, related to the increased NO(x), primarily due to the upregulation of inducible nitric oxide synthase.
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PMID:Elevated plasma nitric oxide metabolites in hypertension: synergistic vasodepressor effects of a static magnetic field and nicardipine in spontaneously hypertensive rats. 1654 50

Edaravone, a potent antioxidant, is currently being used in the management of acute ischemic stroke in relatively high-aged populations. Mitogen activated protein kinase (MAPK) pathways have been shown to play important roles in neuronal cell death. We examined the role of MAPK pathways and the effect of treatment with edaravone in the brain after cerebral ischemia-reperfusion (I/R) injury in a bilateral carotid artery occlusion (BCAO) model with ischemia for 85 min followed by reperfusion for 45 min in aged rats. Western immunoblotting, immunostaining, enzyme-linked immunosorbent assay (ELISA), spectrophotometry, terminal deoxynucleotidyl transferase nick end labeling (TUNEL) and triphenyl tetrazolium chloride (TTC) staining were performed to evaluate various proteins in the homogenate, c-Jun NH2-terminal kinase (JNK) in the tissue sections, protein carbonyl, glutathione peroxidase (GSHPx), apoptosis and infarct size, respectively. Our results showed that I/R injury resulted in a reduction of GSHPx, but protein carbonyl content and inducible nitric oxide synthase were increased. The activation of JNK and its downstream molecule c-Jun was significantly increased after injury, whereas the activities of p38 MAPK and extracellular-regulated kinase 1/2 were slightly but not significantly increased. Edaravone (3 mg/kg, i.v.) treatment significantly reduced all of these changes. Our findings suggest that the JNK pathway differentially mediates neuronal injury in aged rats after BCAO, and edaravone treatment significantly reduces the neuronal damage after I/R injury by inhibiting oxidative stress and the JNK-c-Jun pathway with concomitant inhibition of overall MAPK activity in the brains of aged rats.
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PMID:Edaravone inhibits JNK-c-Jun pathway and restores anti-oxidative defense after ischemia-reperfusion injury in aged rats. 1659 5


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