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Thrombolysis and Neuroprotection in Cerebral Ischemia
Abstract
Stroke is a major cause of death and disability worldwide. The resulting burden on society grows with the increase in the incidence of stroke. The term brain attack was introduced to describe the acute presentation of stroke and emphasize the need for urgent action to remedy the situation. Though a large number of therapeutic agents, like thrombolytics, NMDA receptor antagonists, calcium channel blockers and antioxidants, have been used or are being evaluated, there is still a large gap between the benefits of these agents and the properties of an ideal drug for stroke. So far, only thrombolysis with rtPA within a 3-hour time window has been shown to improve the outcome of patients with ischemic stroke. Understanding the mechanisms of injury and neuroprotection in these diseases is important to target news sites for treating ischemia. Better evaluation of the drugs and increased similarity between the results of animal experimentation and in the clinical setting requires critical assessment of the selection of animal models and the parameters to be evaluated. Our laboratory has employed a rat embolic stroke model to investigate the combination of rtPA with citicoline as compared to monotherapy alone and investigated whether neuroprotection should be provided before or after thrombolysis in order to achieve a greater reduction of ischemic brain damage.
... Neuroprotection, as the term is most commonly used, is the practice of preventing or minimizing the effects of the extensive secondary or tertiary injury that occurs after ischemic, surgical, or traumatic CNS insult. Neuroprotection is, however, more accurately defined as the ability to protect the CNS (or other organ systems) before the injury occurs [1]. Fukuda and Warner [2] define neuroprotection as treatment initiated before an ischemic insult, with the goal of improving tolerance to ischemia or other significant ("nearlethal") stressors. ...
... Therapies for neuroresuscitation and neuroprotection will likely overlap, and therapies for both are dependent on a full understanding of the molecular biology of ischemic injury. Currently our arsenal for neuroresuscitation is limited, with some controversy, to adequate MAPs, moderate hypothermia, normoglycemia, reactive oxygen species (ROS) antagonists, steroids, Ca 2+ chelators, barbiturates, and possibly hyperbaric oxygen [1,3,4]. On the other hand, neuroprotection by anesthesiologists may in the near future include the administration of prophylactic drugs, gene expression, or other cellular manipulation before the stressor that leads to injury. ...
Ischemic central nervous system (CNS) events during neurosurgery are potentially devastating events for patients. Currently, anesthetic management or neuroresuscitation after such injury is limited to the acute management of physiologic variables to ensure oxygenation, ventilation, and perfusion while also maintaining cerebral autoregulation. The term neuroprotection is often used interchangeably with neuroresuscitation, but is perhaps more aptly used to mean treatment prior to an ischemic CNS insult. Pathways and potential mechanisms for resuscitation after, and protection before a CNS ischemic event, have considerable overlap. However, in the near future, true neuroprotection may include delivery of prophylactic drugs, gene delivery, or other cellular manipulations prior to injury. This chapter focuses on advances in the field of gene therapy for neuroanesthesia. Potential targets for such neuroprotective therapy as well as the benefits and risks of gene delivery by viral and nonviral vectors are discussed.
... Many attempts had been done to find the most suitable thrombolytic therapy regiment to obtain higher cerebral perfusion after ischemia. (7,8,9) So far only serine protease tissue-type plasminogen activator was approved by FDA as a thrombolytic agent for stroke treatment. Randomized controlled trials (RCT) data from European Cooperative Acute Stroke Study (ECASS) III and the Safe Implementation of Thrombolysis in Stroke International Stroke Treatment Registry (SITS-ISTR) showed that intravenous recombinant tissue plasminogen activator can effectively improve the outcome of patients with ischemic stroke when delivered within 3-4.5 hours after stroke onset. ...
... Randomized controlled trials (RCT) data from European Cooperative Acute Stroke Study (ECASS) III and the Safe Implementation of Thrombolysis in Stroke International Stroke Treatment Registry (SITS-ISTR) showed that intravenous recombinant tissue plasminogen activator can effectively improve the outcome of patients with ischemic stroke when delivered within 3-4.5 hours after stroke onset. (8,10) However, many patients with viable penumbra were not treated by reperfusion therapies. (6) In Gatot Soebroto Army Central Hospital, 57.33% ofstroke patients came in chronic phase (after 30 days). ...
BACKGROUND: Recently, stroke therapy is focused on reperfusion therapies for restoring cerebral blood flow (CBF) and minimizing the undesired effects of neuron ischemia. However, the thrombolytic therapy to restore CBF was restricted with narrow time window. On other hands, not many patients can reach the treatment immediately after the onset of stroke. A wider time window therapy that might increase CBF would probably helpful. This study aims to investigate the CBF improvement after intra arterial heparin flushing (IAHF) therapy in chronic stroke patients.
METHODS: A clinical trial was conducted with time sampling. We collected chronic ischemic stroke subjects (with stroke onset ≥30 days) within periods February-September 2015. We investigated CBF before and after IAHF treatment in 75 chronic stroke patients. The difference before and after IAHF treatment in subgroup which is classified with infarct size and lesion area was tested. CBF was measured using MRI Quality Arterial Spin Labeling (qASL) with region of interest around infarct lesion.
RESULTS: We found a significant CBF improvement (p
... Randomized controlled trials (RCTs) data from European Cooperative Acute Stroke Study (ECASS) III and the Safe Implementation of Thrombolysis in Stroke -International Stroke Treatment Registry (SITS-ISTR) showed that intravenous rtPA is an effective therapy to improve the outcome of patients with ischemic stroke if given within 3 until 4,5 hours after stroke onset. [10][11][12][13][14] Unfortunately, not many patients could have the thrombolytic treatment after stroke attack. In Gatot Soebroto Army Central Hospital, 57,33% stroke patients came in at chronic phase (> 30 days). ...
... Thus, new therapeutic strategies with a wider window time will be very useful to reduce ischemic morbidity in chronic phase. [13][14][15][16] Intra Arterial Heparin Flushing (IAHF) modified Digital Subtraction Angiography (DSA) in Gatot Soebroto Army Central Hospital showed a clinical improvement in chronic stroke patients empirically. Heparin usually used as flushing solution for catheterization. ...
Background: Muscle strength impairment in stroke patient affect the patient daily life, especially when it occurs on the extremities muscles. Manual Muscle Testing (MMT) is an examination method to measure muscle strength using standardized scoring. Objectives: To find possible improvement of Manual Muscle Test (MMT) Score after administration of Intra Arterial Heparin Flushing in chronic ischemic stroke patient. Methods: This is an experimental study using pretest-posttest group design, with randomized controlled clinical trial, conducted among patients in Cerebrovascular Center Unit in Army Central Hospital Gatot Soebroto starting from February 2014. With 75 patients included in this study. The examination of muscle strength was done by trained physicians. The MMT score were taken before and after the IAHF procedure is conducted. Results: This study found higher score of MMT-MRC scoring system on chronic stroke patient with IAHF procedure (mean MMT-MRC Score = 6,05 point. With p<0,05). Indicating that IAHF procedure is associated with better muscle strength improvement shown with higher MMT-MRC score on stroke patient, which will have better prognostic outcome in their recovery. Conclusions: Intra Arterial Heparin Flushing have significant effect on chronic stroke patient with decreased muscle strength, which shows a significant increase of MMT-MRC score.
... Previous studies reported that the pretreatment with PTX decreased the incidence and severity of hypoxic-ischemic injury in immature rat brain, by attenuating the expression of IL-1β and TNF-α gene [29]. Furthermore, several studies reported that the anti-inflammatory features of PTX include the inhibition of TNF-α production and the TNF-α inhibition and anti-inflammatory effect of PTX may be responsible for the neuroprotection provided by the drug [27,30]. ...
Despite important progress in obstetric and neonatal care, Hypoxic-Ischemic Encephalopathy (HIE) is one of the common causes of neonatal brain damage. The aim of the present study was to investigate the possible neuroprotective effects of two different dosages of pentoxifylline (60 and 100 mg/kg) (PTX) on a model of perinatal HIE. Seven-day-old Wistar rat pups were subjected to right common carotid artery ligation and hypoxia (92% nitrogen and 8% oxygen) for 2h. They were treated with PTX or saline both immediately after hypoxia-ischemia (HI) and after 2h. In sham group animals, neither ligation, nor hypoxia was performed. Neuronal apoptosis was evaluated by the caspase-3 immunostaining methods. The numbers of caspase-3 immunoreactive cells in the parietal cortex and dentate gyrus were observed to have significantly increased in the HI, PTX60 and PTX100 groups compared to the sham group, and, no differences were detected between the HI, PTX60 and PTX100 groups. The numbers of caspase-3 immunoreactive cells in the cornu ammonis regions of the hippocampus were significantly higher in the HI, PTX60 and PTX100 groups than in the sham group. But, elevated in the PTX60 group was significantly lower than that determined in the HI group. However, the number of necrotic cells in all regions of brain were significantly lower PTX60 than HI and PTX100 groups. These results show that PTX administration after hypoxia-ischemia reduces neuronal apoptosis and necrosis. Therefore, PTX may be an effective drug to use to decrease the severity of neonatal hypoxic-ischemic brain injury.
... La diminution du débit sanguin au cours de l'AVC s'accompagne d'une réduction de l'apport en oxygène et en glucose (Gutierrez et al., 2006). Le déficit énergétique qui s'ensuit va être à l'origine d'une acidose tissulaire, de perturbations des flux ioniques et hydriques, d'une excitotoxicité, d'un stress oxydant et d'une réponse inflammatoire. ...
Our objective was to test the hypothesis that the beneficial effect of the administration of the recombinant form of tissue plasminogen activator (rt-PA) in ischemic stroke patient not only results from its fibrinolytic activity but also from its ability to increase brain-derived neurotrophic factor (BDNF) in the brain. To this end, we conducted an initial study to evaluate the effect of rt-PA on brain BDNF levels in healthy animals. In a second study, we investigated the effect of rt-PA on serum BDNF levels in ischemic stroke patients and in animals subjected to permanent focal cerebral ischemia. Blood samples were obtained from patient on admission (D0), D1, D7 and D90 after stroke and in rats before and after (1h, 4h and 24h) ischemia. BDNF was measured in the brain by Western blot and in the blood by ELISA. In both studies, the rt-PA (Actilyse®) was administered as a bolus followed by an infusion of one hour. The first study evidences that 1) rt-PA increases the BDNF levels in the hippocampus, 2) treatment with MK801 (a NMDA receptor antagonist) but not with tranexamic acid (a plasmin inhibitor) canceled the effect of rt-PA on BDNF levels. The second study exhibits that 1) neurological recovery was higher in the patients receiving rt-PA, 2) treatment with rt-PA increases serum BDNF at D1 and D7 in patients, but does not change the blood BDNF levels in animals, 3) BDNF levels are not correlated with neurological recovery but are inversely correlated to the patient cardiovascular score. In conclusion, our results suggest that rt-PA may have a protective extra-fibrinolytic effect by increasing in BDNF levels through a potentiation of glutamatergic pathway. Although rt-PA induces a better neurological recovery and increases circulating BDNF levels in stroke patients, the lack of correlation between these two parameters is not in favor of using circulating BDNF as a predictive marker of neurological recovery, but could be a reflect of the endothelium ability to synthesize BDNF.
... In the previously noted meta-analysis of experimental data [41] greater reduction of infarct volume occurred in rats treated with larger doses of citicoline (300-500 mg/kg), along with superior recovery (27%; 95% CI 9-46) in comparison with animals treated with lower doses (100-300 mg/kg) with 18% recovery (95% CI 5-32; p > 0.001). Larger reduction of stroke volume was also documented in another study [61]; moreover, citicoline at high doses is as effective as i.v. thrombolysis in experimental stroke [62]. ...
Advances in acute stroke therapy resulting from thrombolytic treatment, endovascular procedures, and stroke units have improved significantly stroke survival and prognosis; however, for the large majority of patients lacking access to advanced therapies stroke mortality and residual morbidity remain high and many patients become incapacitated by motor and cognitive deficits, with loss of independence in activities of daily living. Therefore, over the past several years, research has been directed to limit the brain lesions produced by acute ischemia (neuroprotection) and to increase the recovery, plasticity and neuroregenerative processes that complement rehabilitation and enhance the possibility of recovery and return to normal functions (neurorepair). Citicoline has therapeutic effects at several stages of the ischemic cascade in acute ischemic stroke and has demonstrated efficiency in a multiplicity of animal models of acute stroke. Long-term treatment with citicoline is safe and effective, improving post-stroke cognitive decline and enhancing patients' functional recovery. Prolonged citicoline administration at optimal doses has been demonstrated to be remarkably well tolerated and to enhance endogenous mechanisms of neurogenesis and neurorepair contributing to physical therapy and rehabilitation.
... In order to increase the number of rt-PA treated patients, the objectives are to enlarge the time window for rt-PA administration and to reduce the risk of HT. This may be achieved by combining another drug treatment with rt-PA (Gutiérrez et al., 2006;Ishrat et al., 2012;Steiner and Hacke, 1998). ...
Recombinant tissue plasminogen activator (rt-PA) is the only pharmacological treatment approved for thrombolysis in patients suffering from ischemic stroke, but its administration aggravates the risk of hemorrhagic transformations. Experimental data demonstrated that rt-PA increases the activity of poly(ADP-ribose)polymerase (PARP). The aim of the present study was to investigate whether PJ34, a potent (PARP) inhibitor, protects the blood brain barrier components from rt-PA toxicity. In our mouse model of cerebral ischemia, administration of rt-PA (10 mg/kg, i.v.) 6 hours after ischemia aggravated the post-ischemic degradation of ZO-1, claudin-5 and VE-cadherin, increased the hemorrhagic transformations (assessed by brain hemoglobin content and magnetic resonance imaging). Furthermore, rt-PA also aggravated ischemia-induced functional deficits. Combining PJ34 with rt-PA preserved the expression of ZO-1, claudin-5 and VE-cadherin, reduced the hemorrhagic transformations and improved the sensorimotor performances. In vitro studies also demonstrated that PJ34 crosses the blood brain barrier and may thus exerts its protective effect by acting on endothelial and/or parenchymal cells. Thus, co-treatment with a PARP inhibitor seems to be a promising strategy to reduce rt-PA-induced vascular toxicity after stroke.
... Anti-inflammatory properties of PTX include the inhibition of TNF-alpha production which is expressed in brain after ischemia (23). ...
The brief interruption of cerebral blood flow causes permanent brain damage and behavioral dysfunction. The hippocampus is highly vulnerable to ischemic insults, particularly the CA1 pyramidal cell layer. There is no effective pharmacological strategy for improving brain tissue damage induced by cerebral ischemia. Previous studies reported that pentoxifylline (PTX) has a neuroprotective effect on brain trauma. The possible neuroprotector effects of PTX on behavioral deficit were studied in male Wistar rats subjected to a model of transient global brain ischemia.
Animals (n= 32) were assigned to control, sham-operated, vehicle, and PTX- treated (200 mg/kg IP) groups. PTX administered at 1hr before and 3 hr after ischemia. Global cerebral ischemia was induced by bilateral common carotid artery occlusion, followed by reperfusion.
Morris Water maze testing revealed that PTX administration in cerebral ischemia significantly improved hippocampal-dependent memory and cognitive spatial abilities after reperfusion as compared to sham-operated and vehicle-treated animals. After the behavioral test, the rats were sacrificed and brain sections were stained with Nissl staining. There were no significant differences between number of pyramidal cells in both control and PTX groups.
Our study demonstrated that pentoxifylline had a protective effect on rats with transient global ischemia and could reduce cognitive impairment.
CDP-choline is an essential element of the cell membrane-phospholipid biosynthesis, and hereby important for membrane regeneration after stroke or other neurological diseases. Recent studies showed, that CDP-choline exerts additional multimodal mechanisms of action after stroke such as anti-excitotoxic, anti-apoptotic and anti-oxidant effects. CDP-choline improves the neurological deficits and decreases the infarct volume in a number of preclinical studies. Due to its very good tolerability CDP-choline has been used used for the treatment of stroke in Europe, Latin America and Asia for more than 30 years. Controlled clinical studies recently showed first signs of improvement of the neurological deficits of stroke patients after treatment with this substance. CDP-choline may therefore be an alternative for the treatment of stroke, especially when considering the very good benefit-risk ratio.
This review focuses on the molecular stratagems utilized by bacteria, yeast, and mammals in their adaptation to hypoxia. Among this broad range of organisms, changes in oxygen tension appear to be sensed by heme proteins, with subsequent transfer of electrons along a signal transduction pathway which may depend on reactive oxygen species. These heme-based sensors are generally two-domain proteins. Some are hemokinases, while others are flavohemoproteins [flavohemoglobins and NAD(P)H oxidases]. Hypoxia-dependent kinase activation of transcription factors in nitrogen-fixing bacteria bears a striking analogy to the phosphorylation of hypoxia inducible factor-1 (HIF-1) in mammalian cells. Moreover, redox chemistry appears to play a critical role both in the trans-activation of oxygen-responsive genes in unicellular organisms as well as in the activation of HIF-1. In yeast and bacteria, regulatory operons coordinate expression of genes responsible for adaptive responses to hypoxia and hyperoxia. Similarly, in mammals, combinatorial interactions of HIF-1 with other identified transcription factors are required for the hypoxic induction of physiologically important genes.
Background and purpose:
The association between hyperthermia and early neurological deterioration, increased morbidity, and mortality in acute ischemic stroke is well known. However, the timing at which the cerebral lesion may be aggravated by high temperature has not been firmly established. The aim of this study was to determine the prognostic value of body temperature measured at different times after onset of stroke.
Methods:
Axillary temperature was recorded every 2 hour hours for 72 hours in 260 patients with a hemispheric cerebral infarction of <24 hours' duration. A potential infectious focus was examined in all patients with hyperthermia (temperature >37.5 degreesC in any of the assessments). Stroke severity was quantified with the Canadian Stroke Scale on admission. The relationship between the highest temperature recorded in each 6-hour interval from stroke onset and stroke outcome (Canadian Stroke Scale and Barthel Index at 3 months) or infarct volume was evaluated by correlation analyses. The importance of the time at which hyperthermia was first detected was assessed by logistic regression analysis.
Results:
During the first 72 hours, 158 patients (60.8%) had hyperthermia, and in 57.6% of them an infectious cause was identified. Mortality rate at 3 months was 1% in normothermic patients and 15.8% in hyperthermic patients (P<0.001). The correlation coefficients between the final infarct volume, Canadian Stroke Scale and Barthel Index scores at 3 months, and each temperature recording decreased progressively over time from symptom onset. Hyperthermia initiated within the first 24 hours from stroke onset, but not afterward, was independently related to larger infarct volume (odds ratio [OR]=3.23, 95% CI=1.63 to 6.43; P<0.001) and higher neurological deficit (OR=3.06, 95% CI=1.70 to 5.53; P<0. 001) and dependency (OR=3.41, 95% CI=1.69 to 6.88; P=0.002) at 3 months. The infectious origin of hyperthermia was not associated with poorer outcome or greater infarct volume.
Conclusions:
The relationship between brain damage and high temperature is greater the earlier the increase in temperature occurs. However, only body temperature within the first 24 hours from stroke onset is associated with poor outcome and large cerebral infarcts.
Spreading depressions (SDs) occur in experimental focal ischemia and contribute to lesion evolution. N-methyl-D-aspartate (NMDA) antagonists inhibit SDs and reduce infarct size. The glycine site on the NMDA receptor complex offers a therapeutic target for acute focal ischemia, potentially devoid of many side effects associated with competitive and non-competitive NMDA antagonists. We evaluated the effect of the glycine antagonist, ZD9379, on SDs and brain infarction. Male Sprague-Dawley rats (n = 18) weighing 290 to 340 g undergoing permanent middle cerebral artery occlusion (MCAO) were randomly and blindly assigned to receive drug or placebo: Group 1 (pre-MCAO treatment group, n = 5) a 5 mg/kg bolus of ZD9379 over 5 minutes followed by 5 mg/kg/hour drug infusion for 4 hours beginning 30 minutes before MCAO; Group 2 (post-MCAO treatment group, n = 7) a 5 mg/kg bolus of ZD9379 30 minutes after MCAO followed by 5 mg/kg/hour drug infusion for 4 hours; and Group 3 (control group, n = 6) vehicle for 5 hours beginning 30 minutes before MCAO. SDs were monitored electrophysiologically for 4.5 hours following MCAO by continuous recording of cortical direct current (DC) potentials and electrocorticogram (ECoG). Infarct volume was measured 24 hours after MCAO by 2,3,5 triphenyltetrazolium chloride (TTC) staining. Corrected infarct volume was 90 ± 72 mm3 (mean ± standard deviation) in Group 1, 105 ± 46 mm3 in Group 2, and 226 ± 41 mm3 in Group 3 (P < .001). The corresponding numbers of SDs in the 3 groups were 8.2 ± 5.8, 8.1±2.5, and 16.0 ±5.1, respectively (P < .01). When all animals (n = 18) were analyzed, infarct volumes and the number of SDs were significantly correlated (r = .68, P = .002). This study demonstrated that ZD9379 initiated before or after MCAO significantly reduced the number of SDs and infarct volume in a permanent focal ischemia model, implying that ZD9379 is neuroprotective and its neuroprotective effect may be related to inhibiting ischemia-related SDs.
