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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The original neuroprotective hypothesis of estrogen was based on the gender difference in brain response to the ischemia-reperfusion injury. Additional clinical reports also suggest that estrogen may improve cognition in patients with Alzheimer disease. 17beta-Estradiol is the most potent endogenous ligand of estrogen, which protects against neurodegeneration in both cell and animal models. Estrogen-mediated neuroprotection is probably mediated by both receptor-dependent and -independent mechanisms. Binding of estrogen such as 17beta-estradiol to estrogen receptors (ERs) activates the homodimers of ER-DNA and its binding to estrogen response elements in the promoter region of genes such as neuronal nitric oxide synthase (NOS1) for regulating gene expression in target brain cells. In addition to the induction of NOS1, estrogen increases the expression of antiapoptotic protein such as bcl-2. Furthermore, our recent observations provide new molecular biologic and pharmacologic evidence suggesting that physiologic concentrations of 17beta-estradiol (<10 nM) activate ERs (ERbeta > ERalpha) and upregulate a cyclic guanosine 5'- monophosphate (cGMP)-dependent thioredoxin (Trx) and MnSOD expression following the induction of NOS1 in human brain-derived SH-SY5Y cells. We thus proposed that the estrogen-mediated gene induction of Trx plays a pivotal role in the promotion of neuroprotection because Trx is a multifunctional antioxidative and antiapoptotic protein. For managing progressive neurodegeneration such as Alzheimer dementia, our estrogen proposal of the signaling pathway of cGMP-dependent protein kinase (PKG) in mediating estrogen-induced cytoprotective genes thus fosters research and development of the new estrogen ligands devoid of female hormonal side effects such as carcinogenesis.
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PMID:Induction of antioxidative and antiapoptotic thioredoxin supports neuroprotective hypothesis of estrogen. 1277

The expression and cellular localization of neuronal nitric oxide (NO) synthase (nNOS) were studied in the rabbit spinal cord following ischemic injury induced by clamping the descending aorta. In the normal spinal cord, nNOS immunoreactivity was localized to certain motor neurons located in the margin of the ventral horn. Following transient ischemia, immunoreactive spinal neurons increased in number, peaking five days after reperfusion. Quantitative evaluation by western blotting showed that nNOS peaked at 180% of control levels five days after reperfusion and decreased to 120% of controls by 14 days. These findings suggest that overproduced NO may act as a neurotoxic agent in the ischemic spinal cord.
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PMID:Regulation and localization of neuronal nitric oxide synthase in the ischemic rabbit spinal cord. 1287

Nitric oxide (NO.) generated from nitric oxide synthase (NOS) isoforms bound to cellular membranes may serve to modulate oxidative stresses in cardiac muscle and thereby regulate the function of key membrane-associated enzymes. Ischemia is known to inhibit the function of sarcolemmal enzymes, including the (Na+ + K+)-ATPase, but it is unknown whether concomitant injury to sarcolemma (SL)-associated NOS isoforms may contribute to this process by reducing the availability of locally generated NO. Here we report that nNOS, as well as eNOS (SL NOSs), are tightly associated with cardiac SL membranes in several different species. In isolated perfused rat hearts, global ischemia caused a time-dependent irreversible injury to cardiac SL NOSs and a disruption of SL NO. generation. Pretreatment with low concentrations of the NO. donor 1-hydroxy-2-oxo-3-(N-3-methyl-aminopropyl)-3-methyl-1-triazene (NOC-7) markedly protected both SL NOS and (Na+ + K+)-ATPase functions against ischemia-induced inactivation. Moreover, ischemia impaired SL Na+/K+ binding, and NOC-7 significantly prevented ischemic injury to the ion binding sites on (Na+ + K+)-ATPase. These novel findings indicate that NO. can protect cardiac SL NOSs and (Na+ + K+)-ATPase against ischemia-induced inactivation and suggest that locally generated NO. may serve to regulate SL Na+/K+ ion active transport in the heart.
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PMID:Nitric oxide protects cardiac sarcolemmal membrane enzyme function and ion active transport against ischemia-induced inactivation. 1290 95

Chronic brain hypoperfusion (CBH) using permanent occlusion of both common carotid arteries in an aging rat model, has been shown to mimic human mild cognitive impairment (MCI), an acknowledged high risk condition that often converts to Alzheimer's disease. An aging rat model was used to determine whether hippocampal nitric oxide (NO) is abnormally expressed following CBH for two or eight weeks. At each time point, spatial memory was measured with the Morris water maze and hippocampal A beta 1-40/1-42 concentrations were obtained using sandwich ELISA. Real-time amperometric measures of NO representing the constitutive isoforms of neuronal nitric oxide synthase (nNOS) and endothelial (e)NOS were also taken at each time point to ascertain whether NO levels changed as a result of CBH, and if so, whether such NO changes preceded or followed any memory or amyloid-beta pathology. We found that two weeks after CBH, NO hippocampal levels were upregulated nearly four-fold when compared to nonoccluded rats but no alteration in spatial memory of A beta products were observed at this time point. By contrast, NO concentration had declined to control levels by eight weeks but spatial memory was found significantly impaired and A beta 1-40 (but not A beta 1-42) had increased in the CBH group when compared to control rats. Since changes in shear stress are known to upregulate eNOS but generally not nNOS, these results suggest that shear stress induced by CBH hyperactivated vascular NO derived from eNOS in the first two weeks as a reaction by the capillary endothelium to maintain homeostasis of local cerebral blood flow. The return of vascular NO to basal levels after eight weeks of CBH may have triggered metabolic changes within hippocampal cells resulting in hippocampal dysfunction as reflected by spatial memory impairment and by accumulation of A beta 1-40 peptide. In conclusion, our study shows that CBH initiates spatial memory loss in aging rats thus mimicking human MCI and also increases A beta 1-40 in the hippocampus. The memory and amyloid changes are preceded by NO upregulation in the hippocampus. These preliminary findings may be important in understanding, at least in part, the molecular mechanisms that precede memory impairment during chronic brain ischemia and as such, the pre-clinical stage leading to Alzheimer's disease.
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PMID:Hippocampal nitric oxide upregulation precedes memory loss and A beta 1-40 accumulation after chronic brain hypoperfusion in rats. 1450 18

Glial-derived monocarboxylate lactate is thought to be an important energy source for neurons during brain activation or in hypoxia-ischemia. Treatment with alpha-cyano-4-hydroxycinnamate (4-CIN), a monocarboxylate transporter inhibitor, has been recently reported to exacerbate delayed neuronal damage in a rat model of cerebral ischemia, an effect ascribed to inhibition of lactate/pyruvate transport. Since monocarboxylate transporters are abundant in the retina, we examined the effect of 4-CIN administration on the outcome of high intraocular pressure-induced retinal ischemia in rats. Retinal ischemic damage was assessed by changes in the electroretinogram (ERG), the retinal localization of choline acetyltransferase (ChAT) and neuronal nitric oxide synthase (nNOS) immunoreactivities, and the loss of retinal mRNA for Thy-1. Intraperitoneal or intravitreal administration of 4-CIN had no effect on the ERG or the localization of ChAT and nNOS immunoreactivities in either the control retina or a retina subjected to ischemia/reperfusion. In addition, intravitreal injection of 4-CIN had no effect on ischemia-induced reduction of retinal mRNA levels for Thy-1. These results provide no evidence to support the view that blockade of lactate uptake and/or pyruvate entry into mitochondria for oxidative metabolism has an influence on the outcome of retinal ischemia/reperfusion.
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PMID:The monocarboxylate transport inhibitor, alpha-cyano-4-hydroxycinnamate, has no effect on retinal ischemia. 1451 20

We report the effects of a newly developed NOS inhibitor on the neurotoxicity induced by NMDA on cultured fetal rat cortical neurons. To date, three different isoforms of NOS have been characterized. It has been considered that both neuronal NOS and inducible NOS activities are detrimental to the ischemic brain, whereas endothelial NOS plays a prominent role in maintaining cerebral blood flow and prevents neuronal injury during ischemia. ONO-1714 is a newly developed competitive NOS inhibitor that has selective inhibitory potency for iNOS than eNOS. However, its effect on nNOS has not been investigated yet. In this study, we investigated the neuroprotective effect of ONO-1714 on NMDA-induced neurotoxicity in our established model of primary cultured cortical neurons of rat foetus. Cortical neurons (prepared from E16 rat foetuses) were used after 13-14 days in culture. The cells were exposed to 30 muM NMDA for 24 h in the culture. To evaluate the neuroprotective effects of NOS inhibitors, ONO-1714 and L-NAME, neurons were exposed to various concentrations of an NOS inhibitor with 30 muM NMDA. The NMDA induced neurotoxicity was significantly attenuated by ONO-1714 in all concentrations, but not in low to moderate concentrations of L-NAME. These findings demonstrate that the neuroprotective effect of ONO-1714 was more potent than L-NAME. Moreover, ONO-1714 has a strong inhibitory effect on nNOS and would be a powerful tool for the protection of neurons against cerebral ischemia.
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PMID:The neuroprotective effect of ONO-1714 on NMDA-mediated cytotoxicity in vitro. 1456 25

This article is a review of our experimental results regarding the physiological statuses and roles of chemical mediators in tourniquet shock, and a novel phenomenon, modulation reflex, that is commonly observed in this shock model is discussed. In a rabbit with a tourniquet applied to a hind limb for 24 hrs, blood pressure (BP) gradually falls after release of the tourniquet, but the decline in BP stops when a tourniquet is again applied to the hind limb, indicating that shock mediators are attributed to the hind limb. The levels of dipeptides (anserine and carnosine) and lysosomes in blood samples as well as the levels of leukotrienes (LTD4 and LTE4) in blood and muscle samples from rabbits in tourniquet shock were elevated. However, injection of a large amount of a dipeptide into an ear vein of a rabbit did not reduce BP, suggesting that both peptides may not be directly related with reduction in BP of rabbits in tourniquet shock. Injection of a platelet-activating factor (PAF) antagonist into an ear vein resulted in slight elevation of BP and the elevated level was maintained for about 1 to 4 hrs during the period of decline in BP in tourniquet shock. As for interleukin-6 (IL-6), IL-6-deficient mice at young ages have a significantly greater blood volume than do wild-type mice without concomitant changes in body composition. Therefore, the role for IL-6 in the regulation of peripheral circulation may be to elevate, not reduce BP. In mice in tourniquet shock, superoxide (O2-) production is observed in skeletal muscle cells and these cells correspond to mitochondria-rich cells. However, RT-PCR of muscle samples showed no significant nitric oxide synthase (NOS) mRNA expression after tourniquet release. Pretreatment with NOS inhibitors before tourniquet release reduced O2- production in the skeletal muscle. These results indicate that O2- produced in muscle subjected to ischemia/repefusion may be involved in shock. As for changes in mRNA expression patterns of pro-inflammatory cytokines and nerve growth factors in blood samples from rats in tourniquet shock, up-regulation of M-CSF mRNA began at 2 h after tourniquet application and was short-lived. The level of ATF-3 mRNA had increased at 1 h and NGF mRNA gradually increased and reached a significantly high level at 4 h after tourniquet application. These results indicate that the transient mRNA expressions probably trigger secondary events that may be beneficial to wound repair and regeneration. In the early stage of tourniquet shock, the levels of IL-6 mRNA in the liver and kidneys of rats increased progressively and significantly, and the levels of iNOS mRNA in the kidneys increased. These findings suggest that that humoral and/or cellular mediators produced locally in the hind limb are responsible for remote organ injuries. Thus, these mediators, interacting each other, may contribute to the progress of shock. We have also found a novel phenomenon in tourniquet shock using rabbits. When a tourniquet is applied to the upper hind limb of a rabbit for 24 hrs, and pressure is applied to the femoral medial area immediately after tourniquet release, a reflex of decrease in blood pressure and decrease in heart rate, which last for a short period, is usually observed. This reflex is mediated through the ipsilateral femoral nerves, central nervous system and vagal nerves. Since the modulation reflex may be due to peripheral nerve injury, we investigated morphological and molecular changes in sciatic nerves and dorsal root ganglion (DRG) neurons in rats after tourniquet application. At 4 hr after tourniquet application, light microscopic examination showed only degeneration of the tourniquet segment in the sciatic nerve but no morphological changes in the DRG, while electron microscopic examination revealed mitochondrial swelling in some DRG neurons on the tourniquet-applied side and calcium deposition in these swollen mitochondria. These findings suggest that peripheral nerve injury induced a large amount of calcium influx into neuronal cell somas and that excess amounts of calcium-influx into neurons resulted in mitochondial swelling. Results of mRNA level analyses showed NGF mRNA expression followed by NGF protein expression in Schwann cells of the ipsilateral DRGs at 4 h after tourniquet application but not in the contralateral or control DRGs. Similarly, significantly high nNOS and iNOS mRNA levels were observed in the ipsilateral DRGs at 4 h, and expressions of nNOS and iNOS proteins were detected in the ganglion of the ipsilateral DRG. In addition, the TNF-alpha mRNA levels were significantly increased in the ipsilateral DRGs at 1 h after tourniquet application, indicating that TNF-alpha was activated in the early stage of nerve injury and then induced iNOS mRNA expression. Large amounts of nitric oxide (NO) produced by iNOS might result in damage to the host cells, and an overdose of NO might induce apoptosis and eliminate damaged cells during the early stage of nerve injury.
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PMID:[Novel findings from an animal tourniquet shock model]. 1457 64

Cortical spreading depression (CSD) is characterized by slowly propagating waves of neuronal/astrocytic depolarization and metabolic changes, followed by a period of quiescent neuronal and electroencephalographic activity. CSD acts as a preconditioning stimulus in brain, reducing cell death when elicited up to several days prior to an ischemic insult. Precise mechanisms associated with this neuroprotection are not known, although CSD increases the expression of a number of potentially neuroprotective genes/proteins. The nitric oxide (NO) system may be of particular importance, as it is acutely activated and chronically up-regulated in cerebral cortex by CSD, and NO can ameliorate and exacerbate cell death under different conditions. Several molecules have recently been identified that modulate the production and/or cellular actions of NO, but it is not known whether their expression is altered by CSD. Therefore, the present study examined the effect of CSD on the spatiotemporal expression of PIN, CAPON, PSD-95, Mn-SOD and Cu/Zn-SOD mRNA in the rat brain. In situ hybridization using specific [35S]-labelled oligonucleotides revealed that levels of PIN mRNA were significantly increased in the cortex and claustrum ( approximately 30-180%; p </= 0.01) after 6 h and 1 and 2 days, but were again equivalent to contralateral (control) cortical values at 7, 14 and 28 days. CAPON mRNA levels were increased ( approximately 30-180%; p </= 0.05) in the ipsilateral cortical hemisphere at 6 h and 2 days post treatment, but not at the other times examined. In contrast, levels of PSD-95, Mn- and Cu/Zn-SOD mRNA were not altered at any time after CSD. These results suggest that following CSD, nNOS activity and NO levels may be tightly regulated by both transcriptional and translational alterations in a range of nNOS adaptor proteins, which may contribute to CSD-induced neuroprotection against subsequent ischemia.
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PMID:Neuronal-NOS adaptor protein expression after spreading depression: implications for NO production and ischemic tolerance. 1471 93

Recent study has indicated that postsynaptic density protein 95 (PSD95) promotes Ca2+/calmodulin-dependent protein kinase II (CaMKII)-mediated serine phosphorylation of neuronal nitric oxide synthase (nNOS). To investigate whether PSD95 is involved in the brain ischemia-induced enhancement of serine phosphorylation of nNOS by CaMKII in rat hippocampus, we examined the interactions among CaMKIIalpha, PSD95 and nNOS, and the effects of suppression of PSD95 expression on both the increased serine phosphorylation of nNOS and the interactions mentioned above by immunoprecipitation and immunoblotting. The following results were observed: (1) brain ischemia increased markedly the interactions of CaMKIIalpha and nNOS with PSD95. (2) Intracerebroventricular infusion of PSD95 antisense oligodeoxynucleotides, but not missense oligodeoxynucleotides or vehicle, not only significantly decreased the protein level of PSD95 but also attenuated the elevated serine phosphorylation of nNOS and the interactions among CaMKIIalpha, PSD95 and nNOS induced by 15 min ischemia. These data suggested that PSD95 is important for facilitating nNOS serine phosphorylation by CaMKII.
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PMID:Postsynaptic density protein 95 mediates Ca2+/calmodulin-dependent protein kinase II-activated serine phosphorylation of neuronal nitric oxide synthase during brain ischemia in rat hippocampus. 1473 65

Recent studies have shown that (-)-epigallocatechin gallate (EGCG), one of the green tea polyphenols, has a potent antioxidant property. Nitric oxide (NO) plays an important role in the neuropathogenesis induced by brain ischemia/reperfusion and hypoxia. This study aimed to explore the potential neuroprotective effect of EGCG on the ganglionic neurons of the nodose ganglion (NG) in acute hypoxic rats. Thus, the young adult rats were pretreated with EGCG (10, 25, or 50 mg/kg, i.p.) 30 min before they were exposed to the altitude chamber at 10,000 m with the partial pressure of oxygen set at the level of 0.27 atm (pO2=43 Torr) for 4 h. All the animals examined were allowed to survive for 3, 7, and 14 successive days, respectively, except for those animals sacrificed immediately following hypoxic exposure. Nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry and neuronal nitric oxide synthase (nNOS) immunohistochemistry were carried out to detect the neuronal NADPH-d/nNOS expression in the NG. The present results show a significant increase in the expression of NADPH-d/nNOS reactivity in neurons of the NG at various time intervals following hypoxia. However, the hypoxia-induced increase in NADPH-d/nNOS expression was significantly depressed only in the hypoxic rats treated with high dosages of EGCG (25 or 50 mg/kg). These data suggest that EGCG may attenuate the oxidative stress following acute hypoxia.
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PMID:Green tea polyphenol (-)-epigallocatechin gallate attenuates the neuronal NADPH-d/nNOS expression in the nodose ganglion of acute hypoxic rats. 1474 23


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