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Metformin exerts its effect via AMP-activated protein kinase (AMPK), which is a key sensor for energy homeostasis that regulates different intracellular pathways. Metformin attenuates oxidative stress and cognitive impairment. In our experiment, rats were divided into 8 groups; some were pretreated with metformin (Met, 200 mg/kg) and (or) the AMPK inhibitor Compound C (CC) for 14 days. On day 14, rats underwent transient forebrain global ischemia. Data indicated that pretreatment of ischemic rats with metformin reduced working memory deficits in a novel object recognition test compared to group with ischemiareperfusion (I-R) (P < 0.01). Pretreatment of the I-R animals with metformin increased phosphorylated cyclic-AMP response element-binding protein (pCREB) and c-fos levels compared to the I-R group (P < 0.001 for both). The level of CREB and c-fos was significantly lower in ischemic rats pretreated with Met + CC compared to the Met + I-R group. Field excitatory postsynaptic potential (fEPSP) amplitude and slope was significantly lower in the I-R group compared to the sham operation group (P < 0.001). Data showed that fEPSP amplitude and slope was significantly higher in the Met + I-R group compared to the I-R group (P < 0.001). Treatment of ischemic animals with Met + CC increased fEPSP amplitude and slope compared to the Met + I-R group (P < 0.01). We unravelled new aspects of the protective role of AMPK activation by metformin, further emphasizing the potency of metformin pretreatment against cerebral ischemia. Key words: global cerebral ischemia, metformin, AMPK, memory and learning, CREB. La metformine agit par l'intermediaire de la proteine kinase activee par l'AMP (AMPK pour <>), un detecteur de l'homeostasie energetique qui assure la regulation de differentes voies de signalisation intracellulaires. La metformine attenue le stress oxydatif et l'affaiblissement des fonctions cognitives. Dans nos experiences, nous avons reparti des rats dans 8 groupes; certains avaient ete exposes au prealable a de la metformine (Met, 200 mg/kg) et (ou) a un inhibiteur de l'AMPK, le compose C (CC) pendant 14 jours. Au jour 14, les rats ont subi une ischemie transitoire globale du cerveau anterieur. Les resultats d'un test de reconnaissance de nouveaux objets ont montre que chez des rats soumis a l'ischemie, l'exposition prealable a de la metformine permettait d'attenuer les deficits mnesiques dans une plus grande mesure que dans le groupe ayant subi une ischemie-reperfusion (I-R) (P < 0,01). L'exposition prealable des animaux I-R a de la metformine a entraine une augmentation plus importante des taux de proteines de liaison a l'element de reponse de l'AMP cyclique phosphorylees (pCREB pour <>) et de c-fos que dans le groupe I-R (P < 0,001 pour les deux substances). Chez les rats ischemiques, l'exposition prealable a l'association Met + CC a entraine une diminution nettement plus importante des taux de CREB et de c-fos que dans le groupe Met + I-R. L'amplitude et la pente du potentiel postsynaptique excitateur (PPSE) de champ etaient nettement moins eleveee dans le groupe I-R que chez les animaux ayant subi une intervention chirurgicale factice (P < 0,001). Les donnees ont montre que l'amplitude et la pente du PPSE de champ etaient nettement plus elevees dans le groupe Met + I-R que dans le groupe I-R (P < 0,001). L'exposition des animaux ischemiques a l'association Met + CC entrainait une augmentation plus importante de l'amplitude et de la pente du PPSE de champ que dans le groupe Met + I-R (P < 0,01). Nous avons eclairci de nouveaux aspects du role protecteur de l'activation de l'AMPK par la metformine, ce qui met encore plus d'emphase sur le pouvoir de l'exposition prealable a la metformine contre l'ischemie cerebrale. [Traduit par la Redaction] Mots-cles : ischemie cerebrale globale, metformine, AMPK, memoire et apprentissage, CREB., Introduction Decreased cerebral blood flow following cardiac arrest is a known etiology for some neurodegenerative disorders, such as Alzheimer disease (AD), Parkinson disease (PD), and cerebral ischemia with memory impairment [...]

This study investigates the modulatory effect of tadalafil, a selective phosphodiesterase (PDE-5) inhibitor, on the neuroprotective effects of ischemic postconditioning (iPoCo) in mice. Bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 h was employed to produce ischemia and reperfusion induced cerebral injury. Cerebral infarct size was measured using TTC staining. Memory was assessed using the Morris water maze test. Degree of motor incoordination was evaluated using inclined beam-walking, rota-rod, and lateral push tests. Brain nitrite/nitrate, acetylcholinesterase activity, TBARS, and glutathione levels were also estimated. BCAO followed by reperfusion produced a significant increase in cerebral infarct size, brain nitrite/nitrate and TBARS levels, and acetylcholinesterase activity along with a reduction in glutathione. Marked impairment of memory and motor coordination was also noted. iPoCo consisting of 3 episodes of 10 s carotid artery occlusion and reperfusion instituted immediately after BCAO significantly decreased infarct size, memory impairment, motor incoordination, and altered biochemistry. Pretreatment with tadalafil mimicked the neuroprotective effects of iPoCo. The tadalafil-induced neuroprotective effects were significantly attenuated by l-NAME, a nonselective NOS inhibitor. We concluded that tadalafil mimics the neuroprotective effects of iPoCo, probably through a nitric oxide dependent pathway, and PDE-5 could be a target of interest with respect to the neuroprotective mechanism of iPoCo. Key words: cerebral ischemia, ischemic postconditioning, neuroprotection, tadalafil, l-NAME. Cette etude examine l'effet modulateur du tadalafil, un inhibiteur selectif de phosphodiesterases (PDE5), sur l'effet neuro-protecteur du post-conditionnement ischemique (iPoCo) chez la souris. Une occlusion bilaterale de l'artere carotide (OBAC) de 12 min suivie d'une reperfusion de 24 h a ete utilisee pour produire un dommage cerebral induit par l'ischemie et la reperfusion. La taille de l'infarctus cerebral a ete mesuree par coloration au CTT. La memoire a ete evaluee par le test de la piscine de Morris. Le degre d'incoordination motrice a ete evalue par un test de marche sur plan incline, un test sur un Rotarod et un test de poussee laterale. Le rapport nitrite/nitrate du cerveau, l'activite de l'acetylcholinesterase et les niveaux de TBARS et de glutathion ont aussi ete estimes. L'OBAC suivie d'une reperfusion produisait une augmentation significative de la taille de l'infarctus cerebral, du rapport nitrite/nitrate du cerveau, des niveaux de TBARS et de l'activite de l'acetycholinesterase, parallelement aun abaissement du niveau de glutathion. Un deficit marque de la memoire et de la coordination motrice avait aussi ete note. L'iPoCo, consistant en 3 episodes d'occlusion de l'artere carotide et de reperfusion de 10 s, realises immediatement apres l'OBAC, diminuait significativement la taille de l'infarctus, ameliorait le deficit de la memoire et l'incoordination motrice, et contrait la modification des parametres biochimiques. Le pretraitement au tadalafil mimait l'effet neuro-protecteur de l'iPoCo. L'effet neuro-protecteur induit par le tadalafil etait significativement attenue par le l-NAME, un inhibiteur non-selectif de NOS. En conclusion, le tadalafil mime les effets neuro-protecteurs de l'iPoCo probablement a travers une voie dependante de l'oxyde nitrique, et la PDE5 pourrait constituer une cible d'interet du mecanisme neuro-protecteur de l'iPoCo. [Traduit par la Redaction] Mots-cles: ischemie cerebrale, post-conditionnement ischemique, neuro-protection, tadalafil, l-NAME., Introduction Injury due to cerebral ischemia and ischemia-reperfusion is an important contributor to acute cerebral stroke (Ryou et al. 2012; Gulati et al. 2013). Ischemic stroke remains the second leading [...]

Theanine and caffeine, 2 naturally occurring components in tea, have repeatedly been shown to deliver unique cognitive benefits when consumed in combination. In this study, we assessed the beneficial synergistic effects of concurrent treatment with theanine and caffeine against cerebral damage in rats. Theanine and caffeine had no effect on physiological variables, including pH, partial pressures of oxygen (Pa[O.sub.2]) and carbon dioxide (PaC[O.sub.2]), mean arterial blood pressure, plasma glucose, or regional cerebral blood flow. Treatment with theanine (1 mg/kg body mass, intraperitoneal injection) alone significantly reduced cerebral infarction induced by cerebral ischemia-reperfusion, but caffeine (10 mg/kg, intravenous administration) alone only had a marginal effect. However, the combination of theanine plus caffeine resulted in a significant reduction of cerebral infarction and brain edema compared with theanine monotherapy. Meanwhile, increased malondialdehyde levels as well as decreased superoxide dismutase activity, glutathione peroxidase activity, and glutathione levels observed in the cerebral cortex after cerebral ischemia-reperfusion were significantly ameliorated by the combination therapy. Furthermore, the elevated inflammatory response levels observed in the cortex after cerebral ischemia-reperfusion were markedly attenuated by the combined treatment. Thus, it is suggested that the neuroprotective potential of a combination therapy with theanine and caffeine against cerebral ischemia-reperfusion is partly ascribed to their antioxidant and antiinflammatory properties. Key words: theanine, caffeine, cerebral ischemia-reperfusion, synergism, neuroprotection. La theanine et la cafeine, deux composes naturellement presents dans le the, se sont montrees conferer de facon repetee des effets cognitifs benefiques s'ils sont consommes conjointement. Dans l'etude presente, nous avons evalue les effets synergiques benefiques d'un traitement simultane a la theanine et a la cafeine sur le dommage cerebral chez les rats. La theanine et la cafeine n'exercaient pas d'effets sur les variables physiologiques dont le pH, la pression d'oxygene (Pa[O.sub.2]) et de dioxyde de carbone (PaC[O.sub.2]), la pression arterielle moyenne, le glucose plasmatique ou le flux sanguin cerebral regional. Un traitement a la theanine seule (1 mg/kg de masse corporelle, injection intraperitoneale) reduisait signiicativement l'infarctus cerebral induit par l'ischemie-reperfusion, mais la cafeine seule (10 mg/kg, injection intraveineuse) n'exercait qu'un effet marginal. Toutefois, la combinaison de theanine et de cafeine reduisait significativement l'infarctus cerebral et l'oedeme cerebral comparativement a la monotherapie a la theanine. Parallelement, les niveaux eleves de malondialdehyde (MDA) et la diminution de l'activite de la superoxyde dismutase (SOD) et de la glutathion peroxydase (GSH-Px), de meme que la reduction du niveau de glutathion (GSH), observes dans le cortex cerebral apres une ischemie-reperfusion, etaient signiicativement ameliores par la therapie combinee. De plus, les niveaux eleves de reponse inflammatoire observes dans le cortex apres une ischemie-reperfusion cerebrale etaient attenues de facon marquee par le traitement combine. Dans l'ensemble, il est suggere que le potentiel neuroprotecteur de la therapie combinee a la theanine et a la cafeine envers le dommage d'ischemie-reperfusion cerebral est partiellement imputable aux activites anti-oxydantes et anti-inflammatoires. [Traduit par la Redaction] Mots-cles: theanine, cafeine, ischemie-reperfusion cerebrale, synergie, neuroprotection., Introduction For several decades, ischemic cerebral stroke has become one of the leading causes of human death and disability across the world. As the methods of treatment are not satisfactory [...]

The Stroke Prevention by Aggressive Reduction in Cholesterol Levels trail is designed to determine whether a daily dose of 80 mg of atorvastatin would reduce the risk of stroke in patients with no known coronary heart disease, who have had a stroke or transient Ischemic attack (TIA). In such patients 80 mg of atrvastatin per day reduced the overall incidence of strokes and of cardiovascular events, despite a small increase in the incidence of hemorrhagic stroke.

Patients treated with intravenous t-PA within three hours of the onset of acute ischemic stroke appear to have beneficial outcomes. Researchers tested tissue plasminogen activator (t-PA) for clinical activity 24 hours after stroke onset in 291 patients in part 1 of the trial, and evaluated 333 patients given t-PA within three hours of ischemic stroke for clinical outcome at three months in part 2. Patients treated with t-PA were 30% more likely to have little or no disability on assessment scales after three months compared to the patients given placebo. No specific differences were noted in patients given t-PA and placebo in the first 24 hours. A negative effect of t-PA was the increased incidence of symptomatic intracranial hemorrhage among patients given the drug, although the patients affected had more serious neurological problems at initial evaluation. Three-month mortality was 21% in a placebo group and 17% in the t-PA group.

The neurological damage associated with acute ischemic stroke may be reduced through the administration of intravenous thrombolysis for a limited number of patients, but complications from thrombolysis can occur in other groups. Patients aged 18 to 80 years showing symptoms of acute ischemic hemispheric stroke and at least moderate neurological deficit confirmed with computed tomography, the target population, and others with less severe neurological deficit were given either 1.1 mg per kilogram of body weight of recombinant tissue plasminogen activator (rt-PA) or a placebo within 6 hours of the onset of a stroke. Patients from the target population who received rt-PA showed better Rankin Scale scores, as well as faster and more complete neurological recovery than those in the placebo group. While the target population of stroke patients, those with moderate or greater neurological deficit and no extended infarct signs when first examined, appeared to benefit from the rt-PA, those who did not meet these criteria showed a high incidence of brain hemorrhages when treated with rt-PA., Objective.--To evaluate the efficacy and safety of intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) in patients with acute ischemic stroke. Design.--Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial. Setting.--A total of 75 hospitals in 14 European countries. Patients.--A total of 620 patients with acute ischemic hemispheric stroke and moderate to severe neurologic deficit and without major early infarct signs on initial computed tomography (CT). Intervention.--Patients were randomized to treatment with 1.1 mg per kilogram of body weight of rt-PA (alteplase) or placebo within 6 hours from the onset of symptoms. Outcome Measures.--Primary end points included Barthel Index (BI) and modified Rankin Scale (RS) at 90 days. Secondary end points included combined BI and RS, Scandinavian Stroke Scale (SSS) at 90 days, and 30-day mortality. Tertiary end points included early neurologic recovery (SSS) and duration of in-hospital stay. Safety parameters included mortality and incidence of intracranial or extracranial hemorrhage. Results.--The distribution of demographic variables was similar among patients in the rt-PA and placebo treatment arms in both the intention-to-treat (ITT) analysis and the explanatory analysis for the target population (TP). A total of 109 patients (17.4%) were included in the trial despite major protocol violations but excluded from the TP. There was no difference in the primary end points in the ITT analysis, while the TP analysis revealed a significant difference in the RS in favor of rt-PA--treated patients (P=.035). Of the secondary end points, the combined BI and RS showed a difference in favor of rt-PA--treated patients in both analyses (P

The best dosage of anticlotting drugs for atrial fibrillation patients who have recently experienced a cerebral ischemic event may be one that produces an international normalized ratio (INR) of coagulation between 2.0 and 3.9. A cerebral ischemic event, such as a stroke, is a lack of blood supply to brain tissue, caused by blockage of a blood vessel. For an average of 2.1 years, researchers monitored 214 nonrheumatic atrial fibrillation patients receiving anticlotting drugs, such as acenocoumarol. Too low of a dosage is ineffective in preventing further events, while too high of a dosage causes bleeding. Patients with INRs above 5.0 had the highest rates of hemorrhages, at 60 per 100 patient-years. Patients with INRs below 2.0 had the highest rates of blood vessel blockage, at 18 per 100 patient-years. An INR between 2.0 and 2.9 reduced the rate of events by 80%. An INR of 3.0 may be the best target in administering anticlotting drugs.

Resuscitation is necessary, but not sufficient, to save a heart attack victim. More than half of resuscitated patients die during hospitalization. In many cases, the cause of death is injury sustained by the brain because of lack of adequate blood flow, a condition called ischemia. There is some reason to believe that the flow of calcium ions into brain cells might play a role in the cell death which follows ischemia in the brain. Calcium flow clearly precedes cell death in the brain, and experiments in laboratory animals have shown that drugs which decrease the influx of calcium also reduce the extent of the resulting brain damage. However, as convincing as some of the laboratory data might be, it has not yet been shown that similar calcium-blocking treatments might be of value to human heart attack victims at risk for ischemic brain damage. Lidoflazine, an experimental drug which blocks calcium channels in the cell membrane, was used in the treatment of patients who remained comatose after resuscitation for cardiac arrest. A total of 520 patients were included in the study; they were randomly assigned to receive either lidoflazine or placebo. No statistically significant differences were found between the lidoflazine group and the control group. Eighty-two and 83 percent of the lidoflazine and placebo group, respectively, died during six months of follow-up. Fifteen and 13 percent of the lidoflazine and placebo group, respectively, recovered good cerebral function, and 1.2 and 1.9 percent, respectively, suffered severe neurological damage. Other calcium-channel blocking drugs may yet be shown to provide benefit. However, the present data indicate that lidoflazine is of no benefit in the treatment of comatose survivors of cardiac arrest. (Consumer Summary produced by Reliance Medical Information, Inc.)

Brain cells require oxygen for normal function, and inadequate supply of oxygen from the blood (ischemia) adversely affects brain function. The chain of events that begins with the disruption of oxygen supply and ends with irreversible damage to nerve cells is quite complex, and it appears to be possible to intervene to reduce the toll exacted by ischemia. In a stroke, for example, the blood flow to a portion of the brain is disrupted. If the ischemia is more than very brief, infarction, or tissue damage, may result. In an experimental model of this process in laboratory rats, it has been shown that early intervention with insulin or diazepam can reduce the extent of ischemic damage to the brain. Researchers clamped the carotid arteries for 10.5 minutes, a period which had been shown to result in extensive damage to many parts of the brain. Immediately after the arteries were unclamped, the experimental rats received either insulin, diazepam, or both. The control rats received no drug therapy. All three treatments reduced the number of necrotic (dead) cells which were visible upon pathological examination. The greatest protection was obtained with a combination of the two drugs. The mechanisms by which these drugs might protect the brain is not certain, but the authors speculate it may be due to effects upon the release of glutamate. Ischemia induces the release of glutamate, which seems to be a key step in the excessive stimulation of some receptors and a damaging increase in the calcium uptake into some cells. Both insulin and diazepam have inhibitory effects within the brain; it may be that these inhibitory effects also inhibit the damaging processes occurring after ischemia. While the mechanisms of the effect of these drugs remain unknown, the authors point out that both drugs are approved for human use, and there appears to be no reason why such treatment should not be considered for human patients suffering the effects of acute cerebral ischemia. (Consumer Summary produced by Reliance Medical Information, Inc.)

Strokes result when ischemia (oxygen deprivation due to reduced blood flow) in the brain causes irreversible damage to nervous tissue. However, the ischemia is only the first step in a complex sequence of events which leads to irreversible damage. Although many pathologic changes occur in an environment of reduced oxygen, some researchers feel that the event leading directly to the death of neurons is the accumulation of calcium within the cell. Free calcium ions can accumulate within the cell by two basic mechanisms, the entry of calcium through receptor-operated channels, and entry through voltage-sensitive channels. Efforts to develop methods to reduce the rate at which irreversible damage occurs in starved brain tissue focus on blocking the entry of calcium into brain cells via these two pathways. In this research using an animal model (the cat) of ischemic brain damage, investigators tested the effects of nimodipine, a drug which blocks voltage-sensitive calcium channels, and MK-801, an antagonist of the neurotransmitter NMDA which blocks NMDA-receptor-operated calcium channels. While both MK-801 and nimodipine individually reduce the pathologic effects of ischemia somewhat, together the drugs are more effective. In the cats, the combination improved physiological measures of brain function, and also reduced the area of brain damaged by ischemia by more than a factor of five. The combination of the two drugs would seem to be a useful tool in the reduction of permanent damage resulting from brain ischemia. (Consumer Summary produced by Reliance Medical Information, Inc.)

In the May 2, 1991 issue of The New England Journal of Medicine a team of physicians report the results of a trial of the calcium-channel blocking drug lidoflazine for the prevention of death or brain damage after a heart attack. The treatment did not work, and the Journal is to be commended for publishing a negative result. Although negative results are often less exciting, they may be exceedingly important for the actual practice of medicine. However, the question must be asked, "Why didn't lidoflazine work?" In the laboratory, lidoflazine and other calcium channel blockers prevent the flow of calcium into cells, which harms cells and ultimately contributes to their death. In the real hospital setting, however, heart attacks do not occur according to a carefully planned laboratory protocol. The most likely explanation for the failure of the treatment is that, in the real world, the damage proceeds too quickly for intervention to be practical. In laboratory research, 15 to 20 minutes of interrupted blood supply is sufficient to cause extensive brain damage. And this, of course, is under controlled conditions in which the circulation is turned back to good-as-new when the 20 minutes are up, a condition which is not met when heart attacks occur on the ward. Curiously, though, in the enthusiasm to protect the brain against damage when the heart stops beating, some people seem to have forgotten that the heart itself is more sensitive to oxygen deprivation than the brain. While the search for drugs that might prevent brain damage is admirable, greater benefit might accrue from learning to prevent the heart attack in the beginning, or quickly reestablishing circulation to the heart muscle. Even at present, patients with good recovery of neurological function after a heart attack die a month or two later because of damage sustained by their hearts. (Consumer Summary produced by Reliance Medical Information, Inc.)

Byline: T. Murthy, Maj. Bhatia, Brig. Prabhakar Cerebral vasospasm is the prolonged, intense constriction of the larger conducting arteries in the subarachnoid space which are initially surrounded by subarachnoid clot. [...]