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T-pa bbb

Christopher Jan Schwarzbach, Anne Ebert, Michael G Hennerici, Eva Neumaier-Probst, Michael Platten, Marc Fatar
Background: The safety of systemic thrombolysis in patients with intracranial tumor and cavernoma are unknown. So far evidence is limited to a number of case reports and few case series or unspecified data based on population-based analysis. Our aim was to comprehend the risk of systemic thrombolysis in these patients. Methods: Patients with additional evidence of intracranial tumor or cavernoma who received IV tissue plasminogen activator (t-PA) treatment at our comprehensive stroke center over a period of 7 years were identified in our stroke database and compared to the same number of matched control subjects without any evidence of intracranial tumor and cavernoma...
2018: Therapeutic Advances in Neurological Disorders
Hansen Chen, Binghe Guan, Xi Chen, Xingmiao Chen, Caiming Li, Jinhua Qiu, Dan Yang, Ke Jian Liu, Suhua Qi, Jiangang Shen
Tissue plasminogen activator (t-PA) has a restrictive therapeutic window within 4.5 h after ischemic stroke with the risk of hemorrhagic transformation (HT) and neurotoxicity when it is used beyond the time window. In the present study, we tested the hypothesis that baicalin, an active compound of medicinal plant, could attenuate HT in cerebral ischemia stroke with delayed t-PA treatment. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 4.5 h and then continuously received t-PA infusion (10 mg/kg) for 0...
December 23, 2017: Translational Stroke Research
Newshan Behrangi, Nabiyollah Namvar, Mitra Ataei, Sakineh Dizaji, Golshid Javdani, Mahommad Hossein Sanati
Matrix metalloproteinase-9 (GELB) as a member of gelatinases plays key role in the destruction of blood-brain barrier (BBB), T cells migration into the CNS, and demyelination induction. Considering remyelination induction in response to tart cherry extract and pure p-coumaric acid ingestion via tracking MMP9 gene expression in the cuprizone mouse model. Firstly, predicting the chemical interaction between p-coumaric acid and MMP9 protein was conducted through PASS and Swiss dock web services. Next, the content of p-coumaric acid in the tart cherry extract was analyzed by HPLC...
September 2017: Acta Medica Iranica
Bing Yang, Weilang Li, Nikunj Satani, Duyen M Nghiem, XiaoPei Xi, Jaroslaw Aronowski, Sean I Savitz
Tissue plasminogen activator (t-PA) is the only FDA-approved drug for acute ischemic stroke but poses risk for hemorrhagic transformation (HT). Cell therapy has been investigated as a potential therapy to improve recovery after stroke by the modulation of inflammatory responses and the improvement of blood-brain barrier (BBB) integrity, both of which are associated with HT after t-PA. In our present study, we studied the effect of autologous bone marrow mononuclear cells (MNCs) in an embolic stroke model. We administered MNCs in a rat embolic stroke 2 h after administering t-PA...
August 23, 2017: Translational Stroke Research
Winfried Neuhaus, Tobias Krämer, Anja Neuhoff, Christina Gölz, Serge C Thal, Carola Y Förster
The blood-brain barrier (BBB) is damaged during ischemic insults such as traumatic brain injury or stroke. This contributes to vasogenic edema formation and deteriorate disease outcomes. Enormous efforts are pursued to understand underlying mechanisms of ischemic insults and develop novel therapeutic strategies. In the present study the effects of PPARα agonist WY-14643 were investigated to prevent BBB breakdown and reduce edema formation. WY-14643 inhibited barrier damage in a mouse BBB in vitro model of traumatic brain injury based on oxygen/glucose deprivation in a concentration dependent manner...
2017: Frontiers in Molecular Neuroscience
Be'eri Niego, Natasha Lee, Pia Larsson, T Michael De Silva, Amanda E-Ling Au, Fiona McCutcheon, Robert L Medcalf
Rho-kinase (ROCK) inhibition, broadly utilised in cardiovascular disease, may protect the blood-brain barrier (BBB) during thrombolysis from rt-PA-induced damage. While the use of nonselective ROCK inhibitors like fasudil together with rt-PA may be hindered by possible hypotensive side-effects and inadequate capacity to block detrimental rt-PA activity in brain endothelial cells (BECs), selective ROCK-2 inhibition may overcome these limitations. Here, we examined ROCK-2 expression in major brain cells and compared the ability of fasudil and KD025, a selective ROCK-2 inhibitor, to attenuate rt-PA-induced BBB impairment in an in vitro human model...
2017: PloS One
Karen-Sue B Carlson, Lan Nguyen, Kat Schwartz, Daniel A Lawrence, Bradford S Schwartz
Tissue-type plasminogen activator (t-PA), initially characterized for its critical role in fibrinolysis, also has key functions in both physiologic and pathologic processes in the CNS. Neuroserpin (NSP) is a t-PA specific serine protease inhibitor (serpin) found almost exclusively in the CNS that regulates t-PA's proteolytic activity and protects against t-PA mediated seizure propagation and blood-brain barrier disruption. This report demonstrates that NSP inhibition of t-PA varies profoundly as a function of pH within the biologically relevant pH range for the CNS, and reflects the stability, rather than the formation of NSP: t-PA acyl-enzyme complexes...
2016: Frontiers in Cellular Neuroscience
Han-Sen Chen, Su-Hua Qi, Jian-Gang Shen
Tissue plasminogen activator (t-PA) is the only FDA-approved drug for acute ischemic stroke treatment, but its clinical use is limited due to the narrow therapeutic time window and severe adverse effects, including hemorrhagic transformation (HT) and neurotoxicity. One of the potential resolutions is to use adjunct therapies to reduce the side effects and extend t-PA's therapeutic time window. However, therapies modulating single target seem not to be satisfied, and a multitarget strategy is warranted to resolve such complex disease...
2017: Current Neuropharmacology
Marianne Petro, Hayder Jaffer, Jun Yang, Shushi Kabu, Viola B Morris, Vinod Labhasetwar
Inherent neuronal and circulating progenitor cells play important roles in facilitating neuronal and functional recovery post stroke. However, this endogenous repair process is rather limited, primarily due to unfavorable conditions in the infarcted brain involving reactive oxygen species (ROS)-mediated oxidative stress and inflammation following ischemia/reperfusion injury. We hypothesized that during reperfusion, effective delivery of antioxidants to ischemic brain would create an environment without such oxidative stress and inflammation, thus promoting activation and mobilization of progenitor cells in the infarcted brain...
March 2016: Biomaterials
Han-Sen Chen, Su-Hua Qi, Jian-Gang Shen
Tissue plasminogen activator (t-PA) is the only FDA approved drug for acute ischemic stroke treatment, but its clinical use is limited due to the narrow therapeutic time window and severe adverse effects, including hemorrhagic transformation (HT) and neurotoxicity. One of the potential resolutions is to use adjunct therapies to reduce the side effects and extend t-PA's therapeutic time window. However, therapies modulating single target seems not satisfying, and a multi-target strategy is warranted to resolve such complex disease...
December 7, 2015: Current Neuropharmacology
Tatsuya Fukuta, Takayuki Ishii, Tomohiro Asai, Akihiko Sato, Takashi Kikuchi, Kosuke Shimizu, Tetsuo Minamino, Naoto Oku
Since the proportion of patients given thrombolytic therapy with tissue plasminogen activator (t-PA) is very limited because of the narrow therapeutic window, the development of new therapies for ischemic stroke has been desired. We previously reported that liposomes injected intravenously accumulate in the ischemic region of the brain via disruption of the blood-brain barrier that occurs under cerebral ischemia. In the present study, we investigated the efficacy of a liposomal neuroprotective agent in middle cerebral artery occlusion (MCAO) rats to develop ischemic stroke therapy prior to the recovery of cerebral blood flow...
November 2015: European Journal of Pharmaceutics and Biopharmaceutics
Juhua Pan, Xiaoming Lei, Jialong Wang, Shijing Huang, Yanyun Wang, Ying Zhang, Wen Chen, Duojiao Li, Jun Zheng, Hanming Cui, Qihua Liu
BACKGROUND: Kaixinjieyu (KJ), derived from Kaixin and Sini powder, is an effective Chinese herbal medicine preparation used in the treatment of vascular depression (VD). We hypothesize that broad antidepressant effect of KJ results from the improved neurovascular unit (NVU) function via neurogenesis, permeability of blood-brain barrier (BBB) and balance of the fibrinolytic system. METHODS: A VD model of rat was established by chronic unpredictable mild stress and separation after ligation of the bilateral common carotid arteries...
2015: BMC Complementary and Alternative Medicine
Li Ma, Hui Zhang, Yong-zhe Liu, Yan-ling Yin, Ya-qun Ma, Sheng-suo Zhang
Tissue-type plasminogen activator (t-PA) and matrix metalloproteinase-9 (MMP-9) have been reported to play important roles in increased permeability of blood-brain barrier (BBB) under many pathological circumstances. We have showed that Ulinastatin, a broad-spectrum serine protease inhibitor, could alleviate inflammation in the hippocampus of aged rats following partial hepatectomy. In this study, we investigate the expression and potential roles of t-PA and MMP-9 in the protective effect of Ulinastatin. We found that partial hepatectomy increased Evans blue leakage in hippocampus at day 1 and 3 postoperatively...
2016: International Journal of Neuroscience
Yolanda Cruz, Jonathan Lorea, Humberto Mestre, Jennifer Hyuna Kim-Lee, Judith Herrera, Raúl Mellado, Vanesa Gálvez, Leopoldo Cuellar, Carolina Musri, Antonio Ibarra
Stroke triggers a systemic inflammatory response that exacerbates the initial injury. Immunizing with peptides derived from CNS proteins can stimulate protective autoimmunity (PA). The most renowned of these peptides is copolymer-1 (Cop-1) also known as glatiramer acetate. This peptide has been approved for use in the treatment of multiple sclerosis. Cop-1-specific T cells cross the blood-brain barrier and secrete neurotrophins and anti-inflammatory cytokines that could stimulate proliferation of neural precursor cells and recruit them to the injury site; making it an ideal therapy for acute ischemic stroke...
2015: PloS One
Winfried Neuhaus, Fabian Gaiser, Anne Mahringer, Jonas Franz, Christoph Riethmüller, Carola Förster
Stabilization of the blood-brain barrier during and after stroke can lead to less adverse outcome. For elucidation of underlying mechanisms and development of novel therapeutic strategies validated in vitro disease models of the blood-brain barrier could be very helpful. To mimic in vitro stroke conditions we have established a blood-brain barrier in vitro model based on mouse cell line cerebEND and applied oxygen/glucose deprivation (OGD). The role of astrocytes in this disease model was investigated by using cell line C6...
2014: Frontiers in Cellular Neuroscience
Brandon J Thompson, Patrick T Ronaldson
Cerebral ischemia occurs when blood flow to the brain is insufficient to meet metabolic demand. This can result from cerebral artery occlusion that interrupts blood flow, limits CNS supply of oxygen and glucose, and causes an infarction/ischemic stroke. Ischemia initiates a cascade of molecular events in neurons and cerebrovascular endothelial cells including energy depletion, dissipation of ion gradients, calcium overload, excitotoxicity, oxidative stress, and accumulation of ions and fluid. Blood-brain barrier (BBB) disruption is associated with cerebral ischemia and leads to vasogenic edema, a primary cause of stroke-associated mortality...
2014: Advances in Pharmacology
Takehiko Nagao
Thrombolytic agents positively resolve existing thrombi by accelerating the activity of plasmin, a key enzyme of the fibrinolytic pathway. The main drug in use is a plasminogen activator (PA) which degrades plasminogen to plasmin. PA is classified into urokinase-type (u-PA) and tissue-type (t-PA). Because t-PA more selectively activates plasmin onto the surface of thrombi, it induces less in terms of systemic hemorrhagic complications. Beside the main effects, some articles have reported that t-PA causes damage to blood brain barrier structures and has a level of neuron toxicity...
July 2014: Nihon Rinsho. Japanese Journal of Clinical Medicine
Roxann Freeman, Be'eri Niego, David R Croucher, Lars O Pedersen, Robert L Medcalf
Tissue-type plasminogen activator (t-PA) is the only thrombolytic treatment available for patients with acute ischaemic stroke. However, t-PA can increase permeability of the blood-brain barrier (BBB). Desmoteplase is a plasminogen activator derived from the common vampire bat, currently under clinical development for ischaemic stroke. We compared how t-PA and desmoteplase influenced BBB permeability using a human in vitro model where primary brain endothelial cells (BEC) and astrocytes are co-cultured on the opposite sides of a porous membrane...
May 27, 2014: Brain Research
Laura Bana, Stefania Minniti, Elisa Salvati, Silvia Sesana, Vanessa Zambelli, Alfredo Cagnotto, Antonina Orlando, Emanuela Cazzaniga, Rob Zwart, Wiep Scheper, Massimo Masserini, Francesca Re
Targeting amyloid-β peptide (Aβ) within the brain is a strategy actively sought for therapy of Alzheimer's disease (AD). We investigated the ability of liposomes bi-functionalized with phosphatidic acid and with a modified ApoE-derived peptide (mApoE-PA-LIP) to affect Aβ aggregation/disaggregation features and to cross in vitro and in vivo the blood-brain barrier (BBB). Surface plasmon resonance showed that bi-functionalized liposomes strongly bind Aβ (kD=0.6 μM), while Thioflavin-T and SDS-PAGE/WB assays show that liposomes inhibit peptide aggregation (70% inhibition after 72 h) and trigger the disaggregation of preformed aggregates (60% decrease after 120 h incubation)...
October 2014: Nanomedicine: Nanotechnology, Biology, and Medicine
Zhongling Zhang, Xuhui Chen, Le Li, Keling Zhang, Shuqing Tian, Hongmei Gao, Hulun Li
Cerebral ischemic stroke is one of the most prevalent diseases in senior individuals. Its therapeutical strategies include anticoagulation, thrombolysis and cell protection. Tissue-type plasminogen activator (t-PA) that interacts with thrombin for the lysis of thrombosis is widely used to treat stroke patients in early stage. The mechanism of action of t-PA is not clear. Here, we report a novel role of t-PA in protecting blood-brain barrier and its potential mechanisms. In a model of the blood-brain barrier with human umbilical vascular epithelium cells, we found that t-PA in low concentrations prevented the impairment of the blood-brain barrier as a result of oxygen and glucose deprivation...
September 2013: Neurological Sciences
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