Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Policosanol, a defined mixture of high molecular weight aliphatic alcohol isolated and purified from sugar cane (Saccharum officinarum, L) wax is a new cholesterol-lowering agent effective in experimental models, healthy volunteers, and patients with type II hypercholesterolemia. Also, policosanol prevents the onset of spontaneously- and experimentally-induced atherosclerotic lesions and cerebral ischemia in Mongolian gerbils. Free radicals are linked to many diseases including atherosclerosis and ischemia/ reoxidation cellular injury. Therefore, in this study the authors evaluate the antioxidant activity of policosanol on rat liver microsomes. The extent of lipid peroxidation was measured by thiobarbituric acid reactive substances (TBARS). When policosanol was administered orally (100 and 250 mg/kg) for up to 4 weeks, a partial prevention of rat in vitro microsomal lipid peroxidation was noted. The formation of TBARS in microsomes isolated from treated rats was significantly decreased by about 50%, when peroxidation was initiated by Fe3+/ADP/ NADPH, Fe2+/ascorbate and CCl4/NADPH-generating system. Also, oral administration of policosanol in rats provides a partial inhibition of lipid peroxidation, but the mechanism supporting such effect remains to be elucidated. This beneficial effect of policosanol on membrane lipid peroxidation may be useful in protecting to some extent against free radical-associated diseases.
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PMID:Effect of policosanol on in vitro and in vivo rat liver microsomal lipid peroxidation. 929 30

Recirculation following 2 h of focal ischemia due to transient middle cerebral artery (MCA) occlusion has previously been found to be accompanied by an initial, partial recovery of the cellular bioenergetic state and of mitochondrial respiratory functions, with secondary deterioration during the first 2-4 h of reflow. Both the free radical spin trap alpha-phenyl-N-tert-butyl nitrone (PBN) and the immunosuppressant drug FK506 ameliorate the damage incurred by the 2-h period of focal ischemia, even when given 1-3 h after the start of the recirculation. The primary objective of this study was to find out if FK506, like PBN, prevents the secondary deterioration of mitochondrial function, as this can be studied in vitro. Since this proved to be the case, we addressed the question of whether the secondary mitochondrial dysfunction and bioenergetic failure were related to a secondary compromise of microcirculation and cellular oxygen delivery. Six groups of male Wistar rats were studied for measurement of mitochondrial respiratory activity (total, n = 36). One group was used as control (n = 6). In the other groups of animals, MCA occlusion of 2 h duration was induced by an intraluminal filament technique, Neocortical focal and perifocal ("penumbra") tissues were sampled after 2 h of ischemia (n = 6) and after 1 h (n = 6), 2 h (n = 6 with vehicle), and 4 h (n = 6 with vehicle; n = 6 with FK506) of recirculation. The vehicle or 1.0 mg.kg-1 of FK506 was injected intravenously after 1 h of recirculation. Homogenates were prepared, and stimulated (+ADP), nonstimulated (-ADP), and uncoupled respiratory rates were measured polarographically. The uncoupling agent used was carbonyl cyanide m-chlorophenylhydrazone. Local CBF and tissue oxygen tension were evaluated by laser-Doppler flowmetry and PO2 microelectrodes, respectively, throughout the whole periods of 2 h of ischemia and 4 h of recirculation, using a remote MCA occlusion technique. After 2 h of ischemia, the penumbra showed a moderate decrease and the focus a marked decrease in ADP-stimulated and uncoupled respiratory rates, with a marked fall in the respiratory control ratio, defined as ADP-stimulated divided by nonstimulated respiration. Recirculation (1 h) brought about partial recovery, but continued reflow (2 and 4 h) was associated with a secondary deterioration of respiratory functions. The secondary deterioration was prevented by FK506. The results thus confirm previous findings showing that secondary mitochondrial dysfunction occurs following transient focal cerebral ischemia and demonstrate that FK506, like PBN, improves the in vitro performance of mitochondria in focal and penumbral areas. Following MCA occlusion, local CBF in a penumbral area and tissue PO2 in a focal area decreased to about 30 and 5% of control, respectively. However, recirculation brought about rapid recovery of blood flow and oxygen delivery. During the whole 4-h period of recirculation, local CBF and tissue PO2 were maintained close to 100% and at about 160% of the preischemic level, respectively. The results make it highly unlikely that the secondary bioenergetic failure during recirculation is due to a compromised microcirculation. It follows that oxygen delivery is not rate-limiting for recovery events. Very likely, FK506 (and PBN) acts at the cellular level to improve mitochondrial energy functions.
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PMID:The immunosuppressant drug FK506 ameliorates secondary mitochondrial dysfunction following transient focal cerebral ischemia in the rat. 936 6

The present study investigates the interrelation between cerebral energy metabolism and memory capacities after acute and permanent occlusions of carotid and vertebral arteries in adult Wistar rats (n=60). Tissue ATP, phosphocreatine, ADP, AMP and adenosine concentrations were determined in rat brain by high-pressure liquid chromatography (HPLC) analysis. Lactate and pyruvate were measured spectrophotometrically. Rats underwent psychometric testing by means of a holeboard test, closed field activity, and passive avoidance behaviour. Acute cerebral ischaemia was associated with a substantial deficit in energy load (-50%). Cortical adenosine and lactate exhibited a 7- and a 10-fold increase, respectively, in concentration. After 2 weeks of four-vessel occlusion, cortical ATP and phosphocreatine showed a partial enhancement in their concentrations if compared with acute ischaemia. Consequently, energy load (micromol/g) increased from 0.59 to 1.42 in cerebral cortex and from 0.58 to 1.14 in hippocampus under conditions of acute and permanent ischaemia, respectively. While lactate was normalized, adenosine showed a 2-fold increase in its cortical concentration. All animals improved their abilities in learning, memory and cognition after a 7-day training period. Acute vessel occlusion severely decreased working memory (WM), reference memory (RM) and locomotor activity. Simultaneously, the passive avoidance test showed a significant reduction in latency time from 247+/-85 s (sham) to 145+/-132 s. The partial improvement in brain energy state was accompanied by a relative improvement in WM and RM, although both memory capacities remained significantly lower than in controls. The data of the present study demonstrate a linear relationship between cerebral energy metabolism and brain memory capacities after acute and permanent vessel occlusions in rats.
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PMID:Interrelation between cerebral energy metabolism and behaviour in a rat model of permanent brain vessel occlusion. 1036 89

1. Nitric oxide (NO), peroxynitrite, formed from NO and superoxide anion, poly (ADP-ribole) synthetase have been implicated as mediators of neuronal damage following focal ischaemia. Here we have investigated the effects of n-acetylcysteine (NAC) treatment in Mongolian gerbils subjected to cerebral ischaemia. 2. Treatment of gerbils with NAC (20 mg kg(-1) 30 min before reperfusion and 1, 2 and 6 h after reperfusion) reduced the formation of post-ischaemic brain oedema, evaluated by water content. 3. NAC also attenuated the increase in the brain levels of malondialdehyde (MDA) and the increase in the hippocampus of myeloperoxidase (MPO) caused by cerebral ischaemia. 4. Positive staining for nitrotyrosine was found in the hippocampus in Mongolian gerbils subjected to cerebral ischaemia. Hippocampus tissue sections from Mongolian gerbils subjected to cerebral ischaemia also showed positive staining for poly (ADP-ribose) synthetase (PARS). The degree of staining for nitrotyrosine and for PARS were markedly reduced in tissue sections obtained from animals that received NAC. 5. NAC treatment increased survival and reduced hyperactivity linked to neurodegeneration induced by cerebral ischaemia and reperfusion. 6. Histological observations of the pyramidal layer of CA1 showed a reduction of neuronal loss in animals that received NAC. 7. These results show that NAC improves brain injury induced by transient cerebral ischaemia.
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PMID:Beneficial effects of n-acetylcysteine on ischaemic brain injury. 1090 58

Recent studies have demonstrated that melatonin is a scavenger of oxyradicals and peroxynitrite and an inhibitor of nitric oxide (NO) production. NO, peroxynitrite (formed from NO and superoxide anion), and poly (ADP-Ribose) synthetase (PARS) have been implicated as mediators of neuronal damage following focal ischemia. In the present study, we have investigated the effects of melatonin treatment in Mongolian gerbils subjected to cerebral ischemia. Treatment of gerbils with melatonin (10 mg kg(-1), 30 min before reperfusion and 1, 2, and 6 hr after reperfusion) reduced the formation of post-ischemic brain edema, evaluated by water content. Melatonin also attenuated the increase in the brain levels malondialdehyde (MDA) and the increase in the hippocampus of myeloperoxidase (MPO) caused by cerebral ischemia. Positive staining for nitrotyrosine was found in the hippocampus of Mongolian gerbils subjected to cerebral ischemia. Hippocampus tissue sections, from Mongolian gerbils subjected to cerebral ischemia, also showed positive staining for PARS. The degrees of staining for nitrotyrosine and for PARS were markedly reduced in tissue sections obtained from animals that received melatonin. Melatonin treatment increased survival and reduced hyperactivity linked to neurodegeneration induced by cerebral ischemia and reperfusion. Histological observations of the pyramidal layer of CA-1 showed a reduction of neuronal loss in animals that received melatonin. These results show that melatonin improves brain injury induced by transient cerebral ischemia.
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PMID:Protective effects of melatonin in ischemic brain injury. 1106 44

The potential benefits of SM-20302, (2S)-3-(3-(4-amidinobenzoylamino)propanoylamino)-2-(4-ethyl)benzensulfonylaminopropionic acid hydrochloride, a nonpeptide GPIIb/IIIa receptor antagonist, were compared with those of aspirin and ticlopidine in a transient cerebral ischemia model in guinea pigs. Transient cerebral ischemia was induced in guinea pigs by an infusion of ADP/epinephrine into the left internal carotid artery. Each compound was orally administered 1 h (SM-20302 and aspirin) or 3 h (ticlopidine) before the ADP/epinephrine infusion. The ischemic area in coronal brain slices was assessed 1 min after the cessation of ADP/epinephrine infusion by a carbon black perfusion method. In a separate experiment, neurological deficits and lactate contents of ipsilateral hemispheres were evaluated 60 min after the cessation of ADP/epinephrine infusion by neurological scores and the standard enzymatic method, respectively. SM-20302 (0.3 and 1 mg/kg p.o.) significantly reduced the ischemic area, neurological deficits and lactate contents in comparison with the vehicle control. Aspirin (100 mg/kg po) had no significant effect on either parameter. Ticlopidine (300 mg/kg p.o.) reduced the lactate content. Although a combination of aspirin (100 mg/kg p.o.) and ticlopidine (300 mg/kg po) also reduced the lactate content, no additive effect was observed. These results suggest that SM-20302 is of potential clinical benefit in the treatment of thromboembolic diseases.
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PMID:Protective effects of SM-20302, an orally active GPIIb/IIIa antagonist, in an ADP/epinephrine-induced guinea pig model of transient cerebral ischemia. 1122 35

Atherosclerosis involves structural change to the intima and media of medium- and large-sized arteries. Although an atherosclerotic plaque may remain clinically silent, it is prone to disruption, leading to local platelet activation and aggregation. Therefore, the major complication of atherosclerosis is thrombosis, with local occlusion or distal embolism - a generalized disease process known as atherothrombosis. The three main clinical manifestations of atherothrombosis are coronary heart disease (myocardial infarction and angina), peripheral arterial disease and cerebral ischaemia. Atherothrombosis is a leading cause of mortality, and stroke is the leading cause of disability in adults, the second most important cause of dementia and the third most common cause of death in Western countries. Ischaemic stroke accounts for 80% of strokes and atherothrombosis accounts for approximately 20% of all strokes. Criteria for atherothrombotic stroke are evidence of a 50% (or greater) stenosis of a cervical artery and exclusion of other potential causes. The incidence of cerebrovascular events is 2,900 per million inhabitants per year, consisting of 500 transient ischaemic attacks and 2,400 strokes, of which 75% are first-ever stroke. The prevalence of stroke in the same population is 12,000, of which 800 patients (7%) per year have recurrences. The risk of ipsilateral stroke is 5% per year and the risk of a cardiac event is higher at 7%. Besides optimal management of risk factors for atherothrombosis and carotid surgery, antiplatelet therapy is the cornerstone of vascular prevention. In secondary prevention, antiplatelet agents are effective in reducing the risk of further ischaemic events in patients with atherothrombosis. Clopidogrel, a newly licensed ADP receptor antagonist, is the only antiplatelet agent to have demonstrated its superiority versus aspirin for the reduction of major ischaemic events (myocardial infarction, ischaemic stroke, vascular death) in patients whose initial manifestation of atherothrombosis was one of the three main clinical manifestations of the disease (recent ischaemic stroke, myocardial infarction, established peripheral arterial disease).
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PMID:Atherothrombosis: a major health burden. 1131 15

Abnormal platelet reactivity has been linked to unstable angina, myocardial infarction, post angioplasty stenosis, cerebral ischemia, thrombotic stroke and a variety of inflammatory vascular disorders associated with transplantation. Drugs that inhibit blood coagulation, promote fibrinolysis or block platelet activation are important therapeutic agents in cardiovascular medicine. However, many of the current antiplatelet modalities are nonspecific, ineffective or associated with severe side effects that limit their usefulness. In this article, we discuss some basic aspects of platelet pathophysiology to illustrate the importance of ADP stimulation and signaling in platelet activation. CD39, the ATP diphosphohydrolase (ATPDase) expressed on quiescent vascular endothelium, modulates platelet purinoreceptor activity by the sequential hydrolysis of extracellular ATP or ADP directly to AMP. This thromboregulatory potential of CD39 has been recently demonstrated by the generation of mutant mice with disruption of the gene, and by a series of experiments where high level ATPDase expression has been attained by adenoviral vectors in the injured vasculature. Systemic administration of soluble derivatives of CD39 or targeted expression of the native protein to sites of vascular injury may have future therapeutic application.
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PMID:New developments in anti-platelet therapies: potential use of CD39/vascular ATP diphosphohydrolase in thrombotic disorders. 1146 20

Poly(ADP-ribose) polymerase (PARP) can initiate an energy-consuming and inefficient repair cycle following cerebral ischemia/reperfusion by transferring ADP ribose units to nuclear proteins eventually leading to cellular dysfunction and neuronal death. 3-Aminobenzamide (3-AB) is a selective inhibitor of PARP that can significantly reduce brain damage after focal ischemia in rats and displays a low toxicity in vivo. The goals of this study were to determine if inhibiting PARP with 3-AB has a long-term neuroprotective effect and if functional outcome improves in rats following focal ischemia and treatment with 3-AB. Focal ischemia was induced by a 2-h occlusion of the middle cerebral artery (MCA), using an intraluminal filament. Motor functions were evaluated from 5 to 28 days after reperfusion in four groups of rats: stroke without treatment; stroke treated with 3-AB at doses of 15 mg/kg, stroke treated with 3-AB at doses of 55 mg/kg; and the non-ischemic control rats. Functional behaviors were tested by a series of motor function tasks (foot placing, parallel bar crossing, rope and ladder climbing), as well as a neurological examination. Infarct volume of stroke brain in the same rat was determined by Nissl staining 28 days after surgery. Comparison of the untreated stroke group (n=11) and the treated stroke groups indicates that impairment of motor function was significantly (P<0.001) reduced by administration of 3-AB at doses of 15 mg/kg (n=9) or 55 mg/kg (n=10). Neurological outcome was also improved significantly (P<0.001). Infarct volume was significantly (P<0.01) reduced in both treated groups. Long-term neuroprotection following ischemia/reperfusion injury to the brain can be obtained by administration of a PARP inhibitor. The motor tests employed in this study can be used as sensitive, objective and reproducible measurements of functional impairment in rats following an ischemic stroke.
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PMID:Long-term neuroprotective effect of inhibiting poly(ADP-ribose) polymerase in rats with middle cerebral artery occlusion using a behavioral assessment. 1159 10

The aim of the study was to assess the sensitivity of brain synaptosomes and their mitochondria to the effects of global cerebral ischaemia caused by temporary cardiac arrest and the early and late consequences. The effects of 10 min of global ischaemia were measured immediately and after 1 h, 24 h and 7 days post-resuscitation. Ischaemia caused a reduction in oxygen consumption by synaptosomes of about 20%, a drop in ATP/ADP ratio of about 40%, a decrease in CrP/Cr ratio at about 45% and a reduction of synaptic vesicles and disturbances in the mitochondrial structure in isolated synaptosomes and in nerve endings of brain specimens. Morphometric analysis showed that ischaemic conditions caused a decrease in synaptic vesicles by about 61% and an increase of mitochondrial damage to 58 and 50% after 1 and 24 h postreperfusion time, respectively. Seven days postresuscitation, all the observed changes returned to normal but small numbers (about 2%) of neurones which were destroyed neurons appeared at that time. It is concluded that global ischaemia with early resuscitation after cardiac arrest may lead to damage of synaptosomes and synaptic mitochondria. This, in turn, modifies substrate oxidation, synthesis of energy variables and affects neurotransmitter function. The observed disturbances return to normal later after resuscitation but the ischaemic events and reoxygenation caused selective morphological injury of certain neurones and this may form the basis for irreversible brain damage.
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PMID:Synaptosomal susceptibility on global ischaemia caused by cardiac arrest correlated with early and late times after recirculation in rats. 1184 89


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