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PubMed2005

Functional recovery after embolic stroke in rodents by activated protein C.

A serine protease activated protein C has been shown to be a powerful neuroprotectant in stressed neurons and in hypoxic brain endothelium. In a clinically relevant model of embolic stroke in rodents, we now show that administration of activated protein C alone or in combination with tissue plasminogen activator, or both, 4 hours after embolic stroke improves the functional outcome and reduces brain infarction within 7 days of stroke. In contrast, tissue plasminogen activator alone was not protective. Thus, activated protein C may be useful as a new stand-alone therapy for clinical stroke and to extend the time window of thrombolytic therapy.

Animals↗
PubMed2006

Exercise preconditioning reduces brain damage and inhibits TNF-alpha receptor expression after hypoxia/reoxygenation: an in vivo and in vitro study.

Exercise reduces ischemia and reperfusion injury in rat stroke models. We investigated whether gradual increases in tumor necrosis factor-alpha (TNF-alpha) reported during exercise down-regulates expression of TNF-alpha receptors I and II (TNFRI and II) in stroke, leading to reduced brain damage. Adult male Sprague Dawley rats were subjected to 30 minutes of exercise on a treadmill each day for 3 weeks. Then, stroke was induced by a 2-hour middle cerebral artery (MCA) occlusion using an intra-luminal filament. Expressions of TNFRI and II mRNA in the brain were detected using a real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Protein expressions of TNFRI and II were determined by enzyme-linked immunoabsorbant assay (ELISA) in serum and brain homogenates. Spatial distribution of TNF-alpha receptors in brain regions was determined with immunocytochemistry. In human umbilical vein endothelial cells (HUVEC), we addressed the causal effect of TNF-alpha pretreatment on TNF I and II expression using ELISA and real-time PCR. In exercised rats after stroke, brain infarct was significantly (p<0.01) reduced in the entire MCA supplied regions, associated with a mild expression of TNFRI and II mRNA and protein. The TNF-alpha receptors were restricted to the ischemic core. In contrast, a robust expression of TNFRI and II molecules was found in non-exercised rats subjected to similar ischemia/reperfusion insults. An in vitro study revealed a causal link between TNF-alpha pretreatment and reduced cellular expression of TNF-alpha receptors under hypoxic/reoxygenated conditions. Our results suggest that reduced-brain damage in ischemic rats after exercise preconditioning may be attributable to the reduced expression of TNF-alpha receptors. Chronically increased TNF-alpha expression was also found to reduce TNFI and II responding to acute ischemia/reperfusion insult.

Animals↗
PubMed2006

Mucosal tolerance to E-selectin and response to systemic inflammation.

Mucosal tolerance to E-selectin has been shown to prevent stroke and reduce brain infarcts in experimental stroke models. However, the effective E-selectin dose range required to achieve mucosal tolerance and the precise mechanisms of neuroprotection remain unclear. We sought to examine the mechanisms of cytoprotection using gene expression profiling of tissues in the setting of mucosal tolerance and inflammatory challenge. Using spontaneously hypertensive rats (SHRs), we achieved immune tolerance with 0.1 to 5 microg E-selectin per nasal instillation and observed a dose-related anti-E-selectin immunoglobulin G antibody production. We also show the distinct patterns of gene expression changes in the brain and spleen with the different tolerizing doses and lipopolysaccharide (LPS) exposure. Prominent differences were seen with such genes as insulin-like growth factors in the brain and downregulation of those encoding the major histocompatibility complex class I molecules in the spleen. In all, mucosal tolerance to E-selectin and subsequent exposure to LPS resulted in significant tissue changes. These changes, while giving an insight to the underlying mechanisms, serve as possible targets for future studies to facilitate translation to human clinical trials.

Animals↗
PubMed2005

Synthesis and structure-activity relationships of novel selective factor Xa inhibitors with a tetrahydroisoquinoline ring.

A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 exhibited potent inhibitory activity against factor Xa (FXa) and good selectivity with respect to other serine proteases (thrombin, plasmin, and trypsin). In addition, compound 2 exhibited potent anti-FXa activity after intravenous and oral administration to cynomolgus monkeys, showed a dose-dependent antithrombotic effect at 0.1, 0.3, and 1 mg kg(-1) h(-1) in a rat model of venous thrombosis, and significantly reduced the size of brain infarction in a middle cerebral artery occlusion model at a dose of 0.1 mg kg(-1) h(-1). These results suggest that compound 2 (JTV-803) is likely to be useful as both a venous and arterial antithrombotic agent.

Administration, Oral↗
PubMed2004

Concepts on neurological disease evolution.

Degenerative neurological diseases evolve progressively with an insidious onset, while relapsing neurological diseases may remit completely or result in progressive deficits. Since the affected systems can be assessed by clinical evaluation and ascribed to disease-specific pathology--today already in vivo using neuroimaging, the mechanisms underlying neurological disease manifestation can also be studied. For the most frequent neurological diseases with a relapsing clinical course, such as multiple sclerosis, brain infarction and epilepsy, it is shown that disease-specific aetiopathogenesis, lesion-specific pathophysiology and unspecific bystanders determine disease manifestation. Nevertheless, prediction of progression or relapse of a neurological disease is poor due to ill-defined relations of molecular genetic markers and disease evolution. Recent research on aetiopathogenesis and pathophysiology providing new perspectives for selective therapeutic interventions and relapse prevention is discussed.

Biological Evolution↗
PubMed2004

Plasticity in the human cerebral cortex: lessons from the normal brain and from stroke.

The adult brain maintains the ability for reorganization or plasticity throughout life. Results from neurophysiological and neuroanatomical experiments in animals and noninvasive neuroimaging and electrophysiological studies in humans show considerable plasticity of motor representations with use or nonuse, skill learning, or injury to the nervous system. An important concept of reorganization in the motor cortex is that of a distributed neuronal network in which multiple overlapping motor representations are functionally connected through an extensive horizontal network. By changing the strength of horizontal connections between motor neurons, functionally different neuronal assemblies can form, thereby providing a substrate to construct dynamic motor output zones. Modulation of inhibition and synaptic efficacy are mechanisms involved. Recent evidence from animal experiments indicates that these functional changes are accompanied by anatomical changes. Because plasticity of the brain plays a major role in the recovery of function after stroke, the knowledge of the principles of plasticity may help to design strategies to enhance plasticity when it is beneficial, such as after brain infarction.

Animals↗
PubMed2004

Polymorphism R92Q of the tumour necrosis factor receptor 1 gene is associated with myocardial infarction and carotid intima-media thickness--the ECTIM, AXA, EVA and GENIC Studies.

The TNFRSF1A gene was screened for polymorphisms in 95 subjects with premature myocardial infarction (MI), who also had one parent who had an MI. A total of 10 polymorphisms were found: three in the promoter region, two in exons and five in introns. All polymorphisms were genotyped in ECTIM, a case-control study of MI (1815 subjects). The nonsynonymous 92Q allele was found in 1.8, 1.0 and 1.7% of controls from Strasbourg, Belfast and Glasgow - respectively; in cases: 4.2, 2.2 and 3.2%. The population-adjusted odds ratio (OR) for MI associated with allele Q carrying was 2.15 (95% CI: 1.09-4.23). To check its possible implication in atherosclerosis, this polymorphism was then genotyped in the AXA Study (ultrasound examinations of carotid and femoral arteries in the context of an employment medical examination, 733 subjects), the EVA Study (ultrasound examinations of carotid arteries in a study of cognitive and vascular ageing, 1092 subjects) and the GENIC Study (on brain infarction (BI), 912 subjects). In the AXA Study, among smokers, carrying the 92Q allele was positively associated with the presence of a carotid plaque (OR 5.07; 95% CI: 1.64-15.63) and with a thickening of the carotid intima-media thickness (IMT) (0.59 (0.11) vs 0.54 (0.11), P=0.045). In the EVA Study, carriers of allele 92Q had an increased mean carotid IMT (0.70 (0.09) vs 0.67 (0.13), P=0.02). No significant association of the 92Q allele was found with BI in the GENIC Study. Overall, these results may suggest that carriers of the 92Q allele may be at increased risk of atherosclerosis.

Adult↗
PubMed1997

Delayed triphenyltetrazolium chloride staining remains useful for evaluating cerebral infarct volume in a rat stroke model.

Sixteen of 24 Sprague-Dawley rats with permanent middle cerebral artery occlusion for 24 hours were subjected to immediate or 8-hour delayed 2,3,5-triphenyltetrazolium chloride (TTC) staining (n = 8 at each time point); the other 8 animals were subjected to immediate or 8-hour delayed measurement of succinate dehydrogenase activity (n = 4 at each time point). The TTC staining was of good quality good in all animals, and the infarcted region could be distinguished easily from normal tissue. There was no significant difference in corrected infarct volume between the two groups (263.8 +/- 43.1 versus 264.4 +/- 54.8 mm3 [mean +/- standard deviation]). The activity of succinate dehydrogenase was not significantly different when normal or infarcted tissue was measured immediately after death or with an 8 hour delay, although less activity was detected at both time points in the infarcted tissue. These results demonstrate that an 8-hour delay of TTC staining is reliable for evaluating brain infarct volume in a rat stroke model and this probably is attributable to the slow deterioration of mitochondrial enzyme activity in nonischemic brain over this time period.

Animals↗
PubMed2002

Lacunar stroke is the major cause of progressive motor deficits.

BACKGROUND AND PURPOSE: Severe motor deficits are the predominant cause of long-term disability in stroke patients. In particular, progressive hemiparesis in the initial stage after stroke onset is frequently devastating. Therefore, we attempted to define the population at risk with respect to the presumed pathogenesis. METHODS: Among 941 stroke patients hospitalized during a 3-year period, 92 patients (41 men, 51 women; mean age, 68 years) had a severe motor deficit (<25 of 42 points on the 7 motor items of the European Stroke Scale) resulting from brain infarcts. Risk factors, neurological examinations, comprehensive diagnostic tests, and therapy were documented. The study population was separated into patients with (group A) and without (group B) progressive motor deficits. Progression was defined as a further decrease of at least 5 points on the initial European Stroke Scale motor score during the first 5 days after stroke onset. RESULTS: Of the 92 patients, 23.9% had significant worsening of motor function with a decrease in the mean European Stroke Scale motor score from 20.3 to 12.9 points (P<0.01). Infarcts in group A patients were subcortical in 59.1%, whereas most infarcts were cortical in group B (61.4%, P<0.05). Progressive hemiparesis was also significantly associated with lacunar stroke (group A:, 59.1%; group B, 24.3%; P<0.01). With regard to risk factors, diagnostic studies, and neuroimaging, small-vessel disease was the predominant presumed cause of stroke in group A (63.6%, P<0.01), whereas infarcts in group B patients were frequently caused by embolism from cardiac or undetermined sources (61.4%, P<0.01). Prevalence of high-grade carotid stenosis was not significantly different between groups A and B; however, subtotal stenoses and complete internal carotid artery occlusions were found only among patients without progressive motor deficits. CONCLUSIONS: Lacunar stroke caused by small-vessel disease is the major cause of progressive motor deficits, probably because of stepwise occlusion of the branches of small penetrating arteries.

Adult↗
PubMed2004

Predictive values of lacunar transient ischemic attacks.

BACKGROUND AND PURPOSE: We postulated that a lacunar syndrome occurring with transient ischemic attacks (TIAs) or progressive nonsudden onset predicts a brain infarction (BI), presumably caused by a small artery disease (ie, lacunar BI) better than a lacunar syndrome with sudden onset. METHODS: We included 510 patients with BI. BI was classified into etiologic groups including lacunar BI group. We identified the patients with lacunar or nonlacunar syndrome, and those with TIAs preceding the BI or with symptoms of nonsudden onset. RESULTS: Nonlacunar syndrome had a negative predictive value for a lacunar BI of 95%. A lacunar syndrome had a positive predictive value (PPV) of 57% for lacunar infarction (n=109), and the PPV increased to 79% in the case of recent TIAs preceding the lacunar syndrome. Hypertension was present in 95% of cases with lacunar TIAs (odds ratio: 10.69; 95% confidence interval: 1.34 to 84.82; P=0.02). CONCLUSIONS: Lacunar TIAs are almost always associated with history of arterial hypertension and have a high PPV for lacunar BI. This subgroup of patients may reflect different underlying mechanisms than the group of patient with lacunar syndrome of sudden onset.

Adolescent↗
PubMed2001

Anti-inflammatory, antithrombotic, and neuroprotective effects of activated protein C in a murine model of focal ischemic stroke.

BACKGROUND: Activated protein C (APC) contributes to systemic anticoagulant and anti-inflammatory activities. APC may reduce organ damage by inhibiting thrombin generation and leukocyte activation. Neutrophils and cerebrovascular thrombosis contribute to ischemic neuronal injury, suggesting that APC may be a potential protective agent for stroke. METHODS AND RESULTS: We examined the effects of APC in a murine model of focal ischemia. After middle cerebral artery occlusion/reperfusion, the average survival time in controls was 13.6 hours. Animals that received purified human plasma-derived APC 2 mg/kg IV either 15 minutes before or 10 minutes after stroke induction survived 24 hours and were killed for neuropathological analysis. APC 2 mg/kg given before or after onset of ischemia restored cerebral blood flow, reduced brain infarct volume (59% to 69%; P:<0.003) and brain edema (50% to 61%; P:<0.05), eliminated brain infiltration with neutrophils, and reduced the number of fibrin-positive cerebral vessels by 57% (P:<0.05) and 25% (nonsignificant), respectively. The neuroprotective effect of APC was dose-dependent and associated with significant inhibition of ICAM-1 expression on ischemic cerebral blood vessels (eg, 61% inhibition with 2 mg/kg APC). Intracerebral bleeding was not observed with APC. CONCLUSIONS: APC exerts anti-inflammatory, antithrombotic, and neuroprotective effects in stroke. Central effects of APC are likely to be related to improved maintenance of the blood-brain barrier to neutrophils and to reduced microvascular obstructions and fibrin deposition.

Animals↗
PubMed2006

Vascular convolutes in the brain: a peculiar entity.

The present study intends to systematically assess a lesion with potential clinical expression - the vascular convolutes of the brain parenchyma. Those, firstly described by Gertz and Frydl in 1987, are frequently reported in various studies as being associated to aging. Their mechanism seems to be an arteriolar tortuosity. The association with pathologically important manifestations, as brain infarct or hemorrhage could be of clinical importance. The study was done on 70 consequently autopsied cases, on paraffin-embedded material, using the classical histological staining methods: Hematoxylin-Eosin and Masson's Trichrome, as well as the Gömöri silver method for reticulum. In our series, only two cases had specific features suggesting vascular convolutes. More frequently were encountered vascular tortuosities, which seems unrelated to the former. We conclude that vascular convolutes and vascular tortuosities are dissimilar lesions. Both are less represented in reality than reported in the literature. Possible mechanisms of the two changes and their pathogenic significance are discussed.

Age Distribution↗
PubMed2000

MCI-186: further histochemical and biochemical evidence of neuroprotection.

The bioactivity of 3-methyl-1-phenyl-pyrazolin-5-one (MCI-186) was examined based on histochemical changes in drastic global ischemic rat brains. Rats with mean arterial blood pressure reduction were subjected to 60 min cerebral ischemia/80 min reperfusion. Infusion of MCI-186 at 3.0 mg/Kg reduced brain infarction from 21 +/- 4% (saline control, n= 15) to 11 +/- 3% (n=16, p<0.05). By comparison, infusion of up to 20 mg/Kg propyl galalate (PG)--a well documented antioxidant--produced an infarct percentage of 14 +/- 5% (n=8), close to the saline control. Biochemically, the neuroprotective effect of MCI-186 was demonstrated by diminishing the release of creatine kinase (CK) in serum from 3363 +/- 608 U/L (n=14) in saline control to 1989 +/- 293 U/L (n= 15) in MCI group (p<0.05), while PG did not lower the activity of CK significantly. MCI-186 behaves as a free radical scavenger by suppressing the formation of superoxide anion in xanthine oxidase (XO)-hypoxanthine (HP) system (p<0.05). Our data supported our contention that MCI-186 has potent anti-stroke effect with antioxidant activities.

Animals↗
PubMed2005

[A case of motor disturbance in upper limb by parietal lesion; limb kinetic apraxia without visual compensation?].

We report a 75-year-old right-handed man who showed limbkinetic apraxia in the left hand caused by brain infarction of the right parietal lobe including postcentral gyrus. The hand shaping and posture preceding grasping was not appropriate, and clumsiness of the hand was not corrected by visual guidance. Fiber-tracking of the sensorimotor tract on diffusion tensor MRI and electrophysiological studies revealed that the lesion involved the area 1, 2, 5, and 7 of the cortices in Brodmann's nomenclature. In the most cases with limbkinetic apraxia caused by posterior lesion in the center region, hand clumsiness in manipulation should be corrected by visual guidance, which did not function in this case due to coexisting disturbances of kinesthesia with relatively large lesion in the parietal cortex.

Aged↗
PubMed2005

[Problems of emergency transfers of patients after a stroke. Results of a telemedicine pilot project for integrated stroke accommodation in southeast Bavaria (TEMPiS)].

BACKGROUND: Specific stroke subtypes like subarachnoid hemorrhages or malignant brain infarcts require immediate interventions, but treatment options are offered mainly in specialized centers. For this reason, interhospital transfers from primary hospitals need to be done without delay. METHODS: The telemedic pilot project for integrative stroke care (TEMPiS) connects 2 stroke centers and 12 regional hospitals in Bavaria (Germany). Core elements are the implementation of stroke wards, telemedic consultation and improvement of emergency interhospital transfers. Organization of patient transports is offered by the central telemedic service. During the first 12 months of the continuing project all interhospital transfers initiated by the central telemedic service were prospectively documented. Emergency transports were analysed according to diagnosis, type of transport, distance and time delays. RESULTS: A total of 252 interhospital transfers were recommended in teleconsultations; finally 221 transports took place. Median total duration of transfers (including the necessary arrangements) was 134 min (interquartile range: 105-219) for intracerebral hemorrhages (N = 58), 138 min (95-157) for subarachnoid hemorrhages (N = 31), 161 min (100-230) for malignant infarcts (N = 22) and 147 min (109-180) for suspected basilar artery occlusion (N = 28). Time from admission in the primary hospital to initiation of interhospital transfer was 135 min (median; interquartile range: 86-172), transport time was 81 min (60-116). Helicopter transport did not save time for transfer distances up to 50 kilometres, compared to transport via ambulance (including assistance of hospital physicians). Transport using a special intensive care vehicle was much more time consuming because of the longer transport preparation time. CONCLUSION: Emergency transfers of stroke patients are time consuming. This may contribute to additional harm being done to severely ill patients. Faster organization and conduct of transports is required.

Brain Infarction↗
PubMed1995

Animal model of spinal cord infarction induced by cholesterol embolization.

Though several animal models of ischemic brain infarction have been developed, no animal model of purely ischemic spinal cord infarction exists. In humans, such paralysis often occurs as a complication of aortic surgery. While working on an animal model of cholesterol embolic renal disease, the authors produced an animal model of ischemic spinal paralysis by direct intraaortic injection of cholesterol suspension. With histologic examination of spinal cords of the paralyzed rats, prominent cholesterol crystals were found obliterating the lumen of the anterior and/or posterior spinal arteries. Spinal cord infarction was seen most prominently in the lateral columns and anterior horns, though other areas also were affected. Permanent paraplegia developed in most rats, but transient paralysis developed in a few, followed by partial or full recovery. This model of spinal infarction in nonanesthetized rats can be used to study the pathophysiology and therapy of spinal infarction.

Animals↗
PubMed1985

Comparison of glucose metabolism, x-ray CT, and postmortem data in a patient with multiple cerebral infarcts.

We studied a 69-year-old man with multiple brain infarcts who died 8 days after being studied with positron emission tomography and (F-18)-fluorodeoxyglucose. Metabolic abnormalities were greater than structural changes in size and extent. They were found in areas with no gross pathologic abnormalities. Remote metabolic effects were attributed both to degeneration of fiber tracts with disconnection of remote structures, as demonstrated by hypometabolism in the left frontal cortex associated with an infarct in the genu of the left internal capsule, and to microscopic infarcts not apparent on gross examination but manifested as hypometabolic regions.

Aged↗
PubMed2001

Association studies between haemochromatosis gene mutations and the risk of cardiovascular diseases.

BACKGROUND: Haemochromatosis is a common genetic disorder, inherited as an autosomal recessive trait that results in a progressive accumulation of iron in most tissues of the body. Positive association studies have been recently published between cardiovascular diseases and heterozygosity for the major mutation C282Y in the haemochromatosis gene HFE. METHODS: In the present work, we have determined the HFE genotypes for C282Y and H63D in subjects from two case-control studies: the ECTIM and GENIC studies, designed to identify genetic variants associated with myocardial and brain infarction, respectively. In addition, we tested whether HFE mutations were associated with the degree of arteriosclerosis assessed non-invasively by Doppler ultrasonography on the carotid and femoral arteries, in a group of apparently healthy individuals (the AXA Study). RESULTS: The prevalence of 282Y, and 63D allele carriers, did not differ between cases and controls in the ECTIM and in the GENIC studies, while 63D but not 282Y carriers were more numerous among subjects with atherosclerotic plaques in the AXA Study. CONCLUSIONS: These three studies do not provide consistent evidence supporting the hypothesis that HFE mutations are associated with an increased risk of cardiovascular disease and with the development of arteriosclerosis.

Adolescent↗