scholarly journals Effects of Tissue Type Plasminogen Activator in Embolic versus Mechanical Models of Focal Cerebral Ischemia in Rats

1999 ◽  
Vol 19 (12) ◽  
pp. 1316-1321 ◽  
Author(s):  
Wei Meng ◽  
Xiaoying Wang ◽  
Minoru Asahi ◽  
Tsuneo Kano ◽  
Kazuko Asahi ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Cerebral Perfusion ◽  
Focal Cerebral Ischemia ◽  
Focal Ischemia ◽  
Tissue Type ◽  
Negative Effects ◽  
Tissue Type Plasminogen Activator ◽  
Rat Models ◽  
Type Plasminogen Activator ◽  
Transient Focal Ischemia

Tissue type plasminogen activator (tPA) can be effective therapy for embolic stroke by restoring cerebral perfusion. However, a recent experimental study showed that tPA increased infarct size in a mouse model of transient focal ischemia, suggesting a possible adverse effect of tPA on ischemic tissue per se. In this report, the effects of tPA in two rat models of cerebral ischemia were compared. In experiment 1, rats were subjected to focal ischemia via injection of autologous clots into the middle cerebral artery territory. Two hours after clot injection, rats were treated with 10 mg/kg tPA or normal saline. Perfusion-sensitive computed tomography scanning showed that tPA restored cerebral perfusion in this thromboembolic model. Treatment with tPA significantly reduced ischemic lesion volumes measured at 24 hours by >60%. In experiment 2, three groups of rats were subjected to focal ischemia via a mechanical approach in which a silicon-coated filament was used intraluminally to occlude the origin of the middle cerebral artery. In two groups, the filament was withdrawn after 2 hours to allow for reperfusion, and then rats were randomly treated with 10 mg/kg tPA or normal saline. In the third group, rats were not treated and the filament was not withdrawn so that permanent focal ischemia was present. In this experiment, tPA did not significantly alter lesion volumes after 2 hours of transient focal ischemia. In contrast, permanent ischemia significantly increased lesion volumes by 55% compared with transient ischemia. These results indicate that in these rat models of focal cerebral ischemia, tPA did not have detectable negative effects. Other potentially negative effects of tPA may be dependent on choice of animal species and model systems.

scholarly journals Modulation by Nitric Oxide of Cerebral Neutrophil Accumulation after Transient Focal Ischemia in Rats

2000 ◽  
Vol 20 (5) ◽  
pp. 812-819 ◽  
Author(s):  
Sophie Batteur-Parmentier ◽  
Isabelle Margaill ◽  
Michel Plotkine
Keyword(s):  
Nitric Oxide ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neutrophil Infiltration ◽  
Focal Ischemia ◽  
Left Middle Cerebral Artery ◽  
No Production ◽  
Myeloperoxidase Activity ◽  
Transient Focal Ischemia

A beneficial role of nitric oxide (NO) after cerebral ischemia has been previously attributed to its vascular effects. Recent data indicate a regulatory role for NO in initial leukocyte-endothelial interactions in the cerebral microcirculation under basal and ischemic conditions. In this study, the authors tested the hypothesis that endogenous NO production during and/or after transient focal cerebral ischemia can also be neuroprotective by limiting the process of neutrophil infiltration and its deleterious consequences. Male Sprague-Dawley rats were subjected to 2 hours occlusion of the left middle cerebral artery and the left common carotid artery. The effect of NG-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg, intraperitoneally), an NO synthase inhibitor, was examined at 48 hours after ischemia on both infarct size and myeloperoxidase activity, an index of neutrophil infiltration. L-NAME given 5 minutes after the onset of ischemia increased the cortical infarct volume by 34% and increased cortical myeloperoxidase activity by 60%, whereas administration of L-NAME at 1, 7, and 22 hours of reperfusion had no effect. Such exacerbations of infarction and myeloperoxidase activity produced when L-NAME was given 5 minutes after the onset of ischemia were not observed in rats rendered neutropenic by vinblastine. These results suggest that after transient focal ischemia, early NO production exerts a neuroprotective effect by modulating neutrophil infiltration.

scholarly journals Update on therapies for acute ischemic stroke

2000 ◽  
Vol 8 (5) ◽  
pp. 1-5 ◽  
Author(s):  
Dean D. Kindler ◽  
George A. Lopez ◽  
Bradford B. Worrall ◽  
Karen C. Johnston
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Acute Ischemic Stroke ◽  
Plasminogen Activator ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Emerging Therapies ◽  
Type Plasminogen Activator ◽  
Acute Cerebral Ischemia ◽  
Promising Treatment

Acute ischemic stroke is now considered a neurological emergency for which there are new therapies. Neurosurgeons and neurologists need to remain apprised of advances in this field. The authors discuss approved and emerging therapies for patients suffering from acute ischemic stroke, based on a review of recent publications. Currently, intravenous tissue-type plasminogen activator is the only Food and Drug Administration–approved therapy for acute ischemic stroke. Intraarterial delivery of thrombolytics is a promising treatment and may be effective in selected patients. Other therapies for acute cerebral ischemia are intriguing but still in the investigational stages.

scholarly journals Deficiency of Intercellular Adhesion Molecule 1 Attenuates Microcirculatory Disturbance and Infarction Size in Focal Cerebral Ischemia

1998 ◽  
Vol 18 (12) ◽  
pp. 1336-1345 ◽  
Author(s):  
Kazuo Kitagawa ◽  
Masayasu Matsumoto ◽  
Takuma Mabuchi ◽  
Yoshiki Yagita ◽  
Toshiho Ohtsuki ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Adhesion Molecules ◽  
Adhesion Molecule ◽  
Knockout Mice ◽  
Focal Cerebral Ischemia ◽  
Focal Ischemia ◽  
Intercellular Adhesion Molecule ◽  
Wild Type ◽  
Intercellular Adhesion Molecule 1 ◽  
Transient Focal Ischemia

Recent evidence has shown crucial roles for cell-adhesion molecules in inflammation-induced rolling, adhesion, and accumulation of neutrophils in tissue. Intercellular adhesion molecule-1 (ICAM-1) is one of these adhesion molecules. Previous studies have shown marked reduction in the size of infarction after focal cerebral ischemia by depletion of granulocytes and administration of the antibody against ICAM-1. In the present study we investigated the role of ICAM-1 in the size of ischemic lesions, accumulation of granulocytes, and microcirculatory compromise in focal cerebral ischemia by using ICAM-1–knockout mice. Ischemic lesions were significantly mitigated in knockout mice after permanent and transient focal ischemia, even though the number of granulocytes in the infarcted tissue was almost the same between knockout and wild-type mice. Depletion of granulocytes further decreased the size of ischemic lesions after transient focal ischemia in ICAM-1–knockout mice. Microcirculation was reduced after focal ischemia, but it was better preserved in the cerebral cortex of knockout mice than that of wild-type mice. The present study demonstrated that ICAM-1 played a role in microcirculatory failure and subsequent development and expansion of infarction after focal cerebral ischemia. However, it is highly unlikely that ICAM-1 played a key role in accumulation of granulocytes after focal cerebral ischemia.

Neuroserpin: a selective inhibitor of tissue-type plasminogen activator in the central nervous system

2004 ◽  
Vol 91 (03) ◽  
pp. 457-464 ◽  
Author(s):  
Manuel Yepes ◽  
Daniel Lawrence
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Synaptic Plasticity ◽  
Cerebral Ischemia ◽  
Inclusion Bodies ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
The Central Nervous System ◽  
The Brain

SummaryNeuroserpin is a member of the serine proteinase inhibitor (serpin) gene family that reacts preferentially with tissue-type plasminogen activator (tPA) and is primarily localized to neurons in regions of the brain where tPA is also found. Outside of the central nervous system (CNS) tPA is predominantly found in the blood where its primary function is as a thrombolytic enzyme. However, tPA is also expressed within the CNS where it has a very different function, promoting events associated not only with synaptic plasticity but also with cell death in a number of settings, such as cerebral ischemia and seizures. Neuroserpin is released from neurons in response to neuronal depolarization and plays an important role in the development of synaptic plasticity. Following the onset of cerebral ischemia there is an increase in both tPA activity and neuroserpin expression in the area surrounding the necrotic core (ischemic penumbra), and treatment with neuroserpin following ischemic stroke or overexpression of the neuroserpin gene results in a significant decrease in the volume of the ischemic area as well as in the number of apoptotic cells. TPA activity and neuroserpin expression are also increased in specific areas of the brain by seizures, and treatment with neuroserpin slows the progression of seizure activity throughout the CNS and results in significant neuronal survival in the hippocampus. Mutations in human neuroserpin result in a form of autosomal dominant inherited dementia which is characterized by the presence of intraneuronal inclusion bodies and is known as Familial Encephalopathy with Neuroserpin Inclusion Bodies.

scholarly journals Tissue-type plasminogen activator protects the postsynaptic density in the ischemic brain

2018 ◽  
Vol 38 (11) ◽  
pp. 1896-1910 ◽  
Author(s):  
Valerie Jeanneret ◽  
Juan P Ospina ◽  
Ariel Diaz ◽  
Luis G Manrique ◽  
Paola Merino ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Plasminogen Activator ◽  
Ampa Receptors ◽  
Postsynaptic Density ◽  
Scaffolding Protein ◽  
Tissue Type ◽  
Ischemic Brain ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Presynaptic Release

Cerebral ischemia causes the presynaptic release of tissue-type plasminogen activator (tPA). The postsynaptic density (PSD) is a postsynaptic structure that provides a matrix where signaling transduction of excitatory synapses takes place. The postsynaptic density protein-95 (PSD-95) is the most abundant scaffolding protein in the postsynaptic density (PSD), where it modulates the postsynaptic response to the presynaptic release of glutamate by regulating the anchoring of glutamate receptors to the PSD. We found that tPA induces the local translation of PSD-95 mRNA and the subsequent recruitment of PSD-95 protein to the PSD, via plasminogen-independent activation of TrkB receptors. Our data show that PSD-95 is removed from the PSD during the early stages of cerebral ischemia, and that this effect is abrogated by either the release of neuronal tPA, or intravenous administration of recombinant tPA (rtPA). We report that the effect of tPA on PSD-95 is associated with inhibition of the phosphorylation and recruitment of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors to the PSD, known to amplify the effect of the excitotoxic injury, and that this is followed by TrkB-mediated protection of dendritic spines from the harmful effects of the hypoxic insult. These data reveal that tPA is a synaptic protector in the ischemic brain.

scholarly journals Decrease of Fibrinolytic Potential in the Occurence of Cerebral Ischemia

2008 ◽  
Vol 27 (1) ◽  
pp. 40-45
Author(s):  
Biljana Vučković ◽  
Mirjana Đerić ◽  
Tatjana Ilić ◽  
Višnja Čanak ◽  
Marija Žarkov
Keyword(s):  
Cerebral Ischemia ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Plasminogen Activator Inhibitor 1 ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Cerebrovascular Insult ◽  
Fibrinolytic Potential ◽  
Activator Inhibitor

Decrease of Fibrinolytic Potential in the Occurence of Cerebral Ischemia One of the most present clinical manifestations of long and progressive atherothrombotic occurrences is the ischemic cerebrovascular insult, one of the leading causes of death and illness in the world. Lately, a growing number of scientists believe that disorders in the fibrinolytic mechanism function are the key to the occurrence of cerebral ischemia. The goal of this study is to investigate whether the disorder of the fibrinolytic mechanism has influence on the occurrence of ischemic cerebrovascular insult. Our study includes 90 examinees, 60 of which suffer from ischemic cerebrovascular insult and 30 are clinically healthy examinees forming the control group. The results of our investigation show that statistically a significantly larger number of patients has decreased fibrinolytic potential comparing with controls (p < 0.01). According to this, it has been noted that euglobulin lysis clot time in the patient group is significantly longer (p = 0.005). Statistically, no significant difference has been noted related to the activity of plasminogen (p = 0.085). Further on, the plasminogen activator inhibitor-1 values among the patients have been significantly higher (p = 6.20 x 10-11). Moreover, significantly higher values of tissue-type plasminogen activator antigen have been statistically noted in the patient group (p = 5.20 x 10-5). The results of this investigation impose the conclusions that the decrease in fibrinolytic potential affects the occurrence of ischemic cerebrovascular insult, that it is directly connected to the higher levels of plasminogen activator inhibitor-1 and that the growth of tissue-type plasminogen activator antigen concentration participates in the decrease of fibrinolytic potential among patients suffering from cerebral ischemia.

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