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Query: UMLS:C0038454 (stroke)
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Trace metal contents of cerebral vessels in age-matched and sex-matched subjects from three population groups were estimated. The trace metals included calcium, manganese, zinc, magnesium, copper and iron. The American blacks in Washington, D.C., who are ethnologically related to Nigerian Africans, have different patterns of trace metal contents in their cerebral vessels and the observed levels also differed in some respects from Minnesota Caucasians living in a similar environment. The greatest amounts of calcium, zinc, and copper were found in the vessels of American blacks while the greatest amount of magnesium was found in vessels of Minnesota Caucasians. There was no statistically significant difference in the manganese content of the cerebral vessels in three population groups. Nigerian Africans had the least amounts of copper and magnesium but had the highest iron content. A similar high level of iron was observed in the vessels of American blacks. Since it has been shown that American blacks have the most extensive and severe degree of atherosclerosis among the three population groups, it would appear that iron, calcium and manganese in the cerebral vessels may not directly relate to the severity of cerebral atherosclerosis. Relatively high levels of copper and magnesium, which were observed in the cerebral vessels of American blacks and Caucasians, may be of significance in the pathogenesis of cerebral atherosclerosis. The low levels of the trace metals in Nigerians may be protective. The possible role of zinc requires further studies.
Stroke
PMID:Trace metal content of cerebral vessels in American Blacks, Caucasians and Nigerian Africans. 119 34

White matter of the mammalian brain is susceptible to anoxic injury, but little is known about the pathophysiology of this process. We studied the mechanisms of anoxic injury in white matter using the isolated rat optic nerve, a typical central nervous system white-matter tract. Optic nerve function, measured as the area under the compound action potential, rapidly failed when exposed to anoxia. Postanoxic recovery was variable, depending on duration of the anoxic insult; after a standard 60-minute period of anoxia, the compound action potential recovered to 28.5% of control. Irreversible anoxic injury was critically dependent on extracellular Ca2+; maintaining the tissue in zero [Ca2+] solution throughout the anoxic period resulted in 100% compound action potential recovery. Increasing perfusate [Ca2+] during anoxia from zero to 4 mM resulted in progressively less recovery. Anoxic damage to the optic nerve appears to depend on the gradual accumulation (over tens of minutes) of Ca2+ in a cytoplasmic compartment. The inorganic Ca2+ channel blockers Mn2+ (1 mM), Co2+ (1 mM), or La3+ (0.1 mM) had no effect on recovery of the compound action potential after anoxia; only Mg2+ (10 mM) significantly improved recovery. Treatment with the dihydropyridine Ca2+ channel blockers nifedipine (1-10 microM) or nimodipine (1-40 microM) also had no effect on recovery from anoxia. Thus, Ca2+ influx during anoxia does not occur via conventional Ca2+ channels. Preliminary evidence suggests that this Ca2+ influx may occur via other cation channels that are imperfectly selective for Ca2+ or via the Na(+)-Ca2+ exchanger.(ABSTRACT TRUNCATED AT 250 WORDS)
Stroke 1990 Nov
PMID:The pathophysiology of anoxic injury in central nervous system white matter. 223 86

The activity of three forms of ATPase were examined in fractions of the brain of the gerbil treated with ethylene glycol-N-N-tetra-acetic acid (EGTA) under a variety of conditions of primary and secondary (reflow) ischemia. In animals which were unilateral ischemic (ligation of the right common carotid), damage to Na+, K+-ATPase alone was observed only after at least 6 hr of ischemia had elapsed. The phenomenon occurred in only symptomatic gerbils and was absent in animals which were either asymptomatic or only displayed partial neurological symptoms. Under conditions of bilateral cerebral ischemia, in which both carotid arteries were clamped, only irreversible ischemia (60 min) followed by reflow, was associated with highly significant damage to cerebral Na+, K+-ATPase. In regional studies of the forebrain involving ischemia for 60 min plus 30 min reflow, damage to Na+, K+-ATPase was evident in the cerebrum, hippocampus, striatum and thalamus, while the hypothalamus and olfactory bulb were spared. Pretreatment of gerbils with allopurinol, clonazepam or combinations of thiopental plus either indomethacin or methylprednisolone offered protection to cerebral Na+, K+-ATPase subsequent to secondary ischemia. With only minor exceptions (striatum) neither Ca2+, Mg2+- nor Mn2+-ATPase were altered by stroke or treatment with drugs.
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PMID:Classification of ischemic-induced damage to Na+, K+-ATPase in gerbil forebrain. Modification by therapeutic agents. 299 3

It has been previously established that prolonged bilateral carotid occlusion followed by recirculation produces damage to the synaptic enzyme adenylate cyclase in the frontal cortex of the gerbil. Since calcium entrance into the brain may account in part for the deleterious consequences of stroke, the present study examined whether pretreatment with calcium channel blockers would modify the effects of 60 min of bilateral ischemia plus 40 min of reflow on various parameters of cortical adenylate cyclase activation. In this context activation of cerebral homogenates by norepinephrine with or without 5'-guanylyl imidodiphosphate was preserved by pretreatment of ischemic gerbils with verapamil but worsened by flunarizine. In contrast, in particulate fractions (treated with EGTA to reduce metallic ion levels) the damage to the Mn2+-sensitive catalytic site of adenylate cyclase was prevented only by flunarizine. Pretreatment with the two calcium channel blockers resulted in an elevated basal activity of the enzyme, thereby reducing the response in the homogenate preparation to forskolin. Gerbils pretreated with verapamil tended to have an increased ability for survival resulting from the ischemic episode. Under in vitro conditions the enzyme preparations were not markedly influenced by either drug.
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PMID:Modulation of ischemic-induced damage to cerebral adenylate cyclase in gerbils by calcium channel blockers. 350 45

A rapid increase in the need to explore the molecular basis of cellular function and injury in the central nervous system has led neuroscientists to employ transgenic mouse technology. The successful making of transgenic mice (Tg) overexpressing human CuZn-superoxide dismutase (SOD-1) activity has made it possible to investigate the role of oxygen free radicals in ischemic and traumatic brain injury in a molecular fashion. It has been demonstrated that the 3-fold increase in SOD-1 transgene activity in SOD-1 Tg mice offers protection against cerebral ischemia and reperfusion in two different models of focal cerebral ischemia, as compared to nontransgenic wild-type littermates. Studies involving traumatic brain injury have also demonstrated that acute injuries, including brain edema and blood-brain barrier permeability, are significantly reduced in SOD-1 Tg mice. Furthermore, chronic neurological deficits, such as beam walking, beam balance, and body weight, are significantly improved in these transgenic animals following traumatic brain injury. In addition to the SOD-1 Tg mice being a useful tool for the study of CNS injury, targeted disruption of the mouse gene for mitochondrial manganese SOD (SOD-2) has been successful. These SOD-2 knockout mutant mice, in addition to the recently developed knockout mutants of neuronal nitric oxide synthase (NOS), are believed to offer a unique opportunity to elucidate the oxidative mechanisms in brain injury following stroke and trauma.
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PMID:Transgenic mice and knockout mutants in the study of oxidative stress in brain injury. 859 9

The hemodynamic actions and left ventricular mechanical effects of two new superoxide dismutase mimetics, SC-55858 [Manganese (II) dichloro (2R,3R,8R,9R-bis-cyclohexano-1,4,7,10,13-pentaazacyclopentadeca ne)] (n = 10) and SC-55417 [Manganese (II) dichloro (trans-2,3-cyclohexano-1,4,7,10,13-pentaazacyclopentadecane) ] (n = 8), were studied in chronically instrumented dogs in the conscious state and after 30 min equilibration at 0.033, 0.067, 0.233, and 0.667 microM.kg-1.min-1 SC-55858 or SC-54417 (total doses of 1, 2, 7, and 20 microM.kg-1). SC-55858 and SC-54417 increased heart rate and decreased mean arterial pressure and left ventricular systolic and end-diastolic pressures. SC-55858 decreased preload recruitable stroke work slope and +dP/dtmax and increased the time constant of isovolumic relaxation, consistent with a direct negative inotropic and lusitropic effect. In contrast, SC-54417 did not depress left ventricular systolic and diastolic function. Decreases in mean arterial pressure caused by SC-55858 may be secondary to negative inotropic effects and reduction in cardiac preload. In contrast, SC-54417 does not depress myocardial contractility but also reduces arterial pressure via venodilation.
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PMID:Comparison of the cardiovascular effects of two novel superoxide dismutase mimetics, SC-55858 and SC-54417, in conscious dogs. 881 87

1. Enzyme activities and contents of manganese and copper-zinc superoxide dismutase (Mn-, Cu/Zn-SOD) and oxygen free-radical scavengers were determined in the myocardium (right, left ventricle) and brain (cerebral cortex, hippocampus) of 15 and 31 week old stroke-prone spontaneously hypertensive rats (SHRSP). 2. In 15 week old SHRSP myocardium, both Mn- and Cu/Zn-SOD activities were higher but in 31 week old SHRSP, these were lower than that in Wistar-Kyoto (WKY) rats. Further, correlation between Mn-SOD content and activity in 31 week old SHRSP myocardium showed that specific activity was lower than that in WKY. 3. In 15 and 31 week old SHRSP cerebral cortex and hippocampus, SOD content and activity showed a tendency to be lower than that in WKY. 4. These results indicate that enzymatically inactive or low-active Mn-SOD protein exists in SHRSP myocardium, and that the alteration of SOD may be one of the causative factors for the vulnerability of the myocardium and brain against O2-radicals.
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PMID:Regional distribution of superoxide dismutase in the brain and myocardium of the stroke-prone spontaneously hypertensive rat. 907 37

The interaction of myosin with actin, coupled with hydrolysis of ATP, is the molecular basis of muscle contraction. The head segment of myosin, called S1, contains the distinct binding sites for ATP and actin and is responsible for the ATPase activity. The myosin-catalyzed ATP hydrolysis consists of several intermediate steps and each step is accompanied by conformational changes in the S1 segment. The rate-limiting step of the ATP hydrolysis is the dissociation of the S1 x ADP x Pi complex which is accelerated by actin. The substitution of Pi with phosphate analogs (PA), such as vanadate, beryllium fluoride (BeFx) or aluminum fluoride (AlF4-), yields stable complexes which mimic the intermediates of the ATP hydrolysis. In this work, tertiary structure changes in S1 in the vicinity of aromatic residues was studied by comparing near-UV circular dichroism (CD) spectra from S1-nucleotide-phosphate analog complexes in the presence of Mg2+ and other cations. A significant difference between the MgATP and MgADP spectra indicated notable tertiary structural changes accompanying the M**ADP x Pi --> M*ADP transition. The spectra of the S1 x MgADP x BeFx and S1 x MgADP x AlF4- complexes resemble to those obtained upon addition of MgATPgammaS and MgATP to S1, and correspond to the M* x ATP and M** x ADP x Pi intermediates, respectively. We have found recently that the presence of divalent metal cations (Me2+) is essential for the formation of stable S1 x MeADP x PA complexes. Moreover, the nature of the metal cations strongly influences the stability of these complexes [Peyser, Y. M., et al. (1996) Biochemistry 35, 4409-4416]. In the present work we studied the effect of Mg2+, Mn2+, Ca2+, Ni2+, Co2+, and Fe2+ on the near-UV CD spectrum of the ATP, ADP, ADP x BeFx, and ADP x AlF4- containing S complexes. The CD spectra obtained with ADP, ATP ADP x BeFx and ADP x AlF4- were essentially identical in the presence of Co2+ and rather similar in the case of Ca2+, while they were partially different in other cases. An interesting correlation was found between actin activation and ATP versus ADP difference spectra in the presence of various metal ions. The distribution of the fractional concentration of the intermediates of ATP hydrolysis was estimated in the presence of each cation from the CD spectra with phosphate analogs. In the presence of Mg2+ the predominant intermediate is the M** x ADP x Pi state, which is in accordance with the kinetic studies. On the other hand with non-native cations the predominant intermediate is the M* x ADP state and the release of ADP is the rate limiting step in the myosin-catalyzed ATP hydrolysis. According to the results, the near-UV CD spectrum originating from aromatic residues in S1 not only can distinguish identifiable states in the ATP hydrolysis cycle but can also pinpoint to changes in the tertiary structure caused by complex formation with nucleotide or nucleotide analog and various divalent metal cations. These findings, that are correlative with actin activation, and thus with the power stroke, suggest new strategies for perturbing S1 structure in the continuous efforts directed toward the elucidation of the mechanism of muscle contraction.
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PMID:Effect of metal cations on the conformation of myosin subfragment-1-ADP-phosphate analog complexes: a near-UV circular dichroism study. 913 78

The biosynthesis of cholesterol is regulated mainly by HMG-CoA reductase, however, recent studies indicated the pivotal role of another enzyme in cholesterol homeostasis. A previous report showed a marked decrease in the activity of mevalonate pyrophosphate decarboxylase (MPD) in stroke-prone spontaneously hypertensive rats and its possible involvement in the pathogenesis of the disorder. In this study, we purified liver MPD from rats fed a diet containing cholestyramine and pravastatin (CP diet) using conventional chromatographic techniques. We obtained two electrophoretically homogeneous enzyme preparations; 45 and 37 kDa proteins with specific activities of 8.0 and 7.4 micromol/min/mg, respectively. The enzymes showed similar molecular weights of 90 kDa, as judged on gel permeation chromatography. A kinetic study indicated apparent Km values for mevalonate pyrophosphate and ATP of 22.7 microM and 0.71 mM, respectively, for the 45 kDa MPD, and 20.0 microM and 0.80 mM, respectively, for the 37 kDa MPD. Half maximum activities were observed at 1.5 mM and 1.1 mM Mg2+ for the 45 and 37 kDa MPDs, respectively. Both enzymes required ATP as a phosphate acceptor, and in addition Mg2+, Mn2+, and Co2+ were effective as divalent cations. The optimum pH for both enzymes was 7.0. The isoelectric points for the 45 and 37 kDa MPDs were 5.6 and 5.4, respectively. Polyclonal antiserum raised against the 45 kDa enzyme detected both the 45 and 37 kDa bands on immunoblots with CP diet-induced liver crude extract as an antigen. However, non-induced liver contained the 45 kDa protein but not the 37 kDa protein. These results indicated that the CP diet induced a new species, 37 kDa, of MPD which is characteristically and immunologically very similar to the well-known 45 kDa MPD.
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PMID:Purification and characterization of two mevalonate pyrophosphate decarboxylases from rat liver: a novel molecular species of 37 kDa. 934 97

Stroke is a severe and prevalent syndrome for which there is a great need for treatment, including agents to block the cascade of brain injury that occurs in the hours after the onset of ischemia. Reactive oxygen species (ROS) have been implicated in this destructive process, but antioxidant enzymes such as superoxide dismutase (SOD) have been unsatisfactory in experimental stroke models. This study is an evaluation of the effectiveness of salen-manganese complexes, a class of synthetic SOD/catalase mimetics, in a rat focal ischemia model involving middle cerebral artery occlusion. We focus on EUK-134, a newly reported salen-manganese complex demonstrated here to have greater catalase and cytoprotective activities and equivalent SOD activity compared with the previously described prototype EUK-8. The administration of EUK-134 at 3 hr after middle cerebral artery occlusion significantly reduced brain infarct size, with the highest dose apparently preventing further infarct growth. EUK-8 was also protective but substantially less effective. These findings support a key role for ROS in the cascade of brain injury after stroke, even well after the onset of ischemia. The enhanced activity of EUK-134 suggests that, in particular, hydrogen peroxide contributes significantly to this injury. Overall, this study suggests that synthetic SOD/catalase mimetics might serve as novel, multifunctional therapeutic agents for stroke.
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PMID:Synthetic combined superoxide dismutase/catalase mimetics are protective as a delayed treatment in a rat stroke model: a key role for reactive oxygen species in ischemic brain injury. 943 81


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