- Email: [email protected]
P66 Quantification of neuronal and microvascular damage after focal cerebral ischemia and reperfusion
Session Xl: Miscellaneous 113
P66 Quantification of neuronal and microvascular damage after focal cerebral ischemia and reperfusion B STAUFER, C ZIMMERMANN, M LIEBETRAU, G BULTEMEIER, G H HAMANN Neurologische Klinik, Klinikum Groflhadem, LMU MOnchen
enced an immediate preclincal emergency treatment and direct admission to our hospital; being the only institution offering thrombolysis in our district . Simultaneously, as part of a cooperating model, patients being first admitted to hospitals with a lower level of supply are immediately transferred to our stroke center.
The development of vasogenic brain edema and hemorrhagic complications after cerebral ischemia is connected to disturbances of the microvascular integrity. Therefore, the aim of this study was to determine (a) the extent and 00) the localisation of neuronal and microvascular damage after experimental cerebral ischemia.
Results: The medium latency until onset of symptoms could be reduced to 5 hours in 1997 compared with Z8 hours in 1996. Simultaneously, the number of patients receiving thrombolytic therapy increased from less than 3% to about 18%. The neurological status of these patients improved comparably to results presented by the NINDS-study group (1). Conclusions: Optimizing the process quality with existing EMS systems in acute stroke management is a cost-effective option to reduce prehospital time delay in case of acute stroke. However, additional efforts must be undertaken in order to further reduce preclhaical latencies in acute stroke. Continuous public education seems to be the most suitable way (3) to achieve this goal. Literature: (1) The NINDS rt-PA Stroke Study Group.N Engl J Med, 1995 (333): 1581-158Z (2) Adams HP, Brott TG, Crowell RM et al., Stroke, 1994 (25): I901-1914. (3) Feldmann et al., Stroke 1993 (24): 1805-1810.
Using the MCAO (middle cerebral artery occlusion) intraluminal thread modell five male Wistar rats were subjected to a transient focal cerebral ischemia (3 h occlusion + 6 h reperfusion). On coronary sections (10 ~tm) the neuronal damage was documented by using a monoclonal antibody against MAP2 (microtubuli-associated protein-2). Alterations of the extracellular matrix of microvessels were quantified by application of a polyclonal antibody against collagen-type 1V. Within the ischemic hemisphere a deficit of MAP2-staining could be shown in the entire basal ganglia region. In contrast the staining was only faded in discrete areas of the cortex. In accordance to these results the number of collagen containing microvessels on the ischemic side was reduced by 18.9 +_3.1% (means + SD) within the basal ganglia and by 8.1 + Z5% within cortical regions. By statistical analysis (spearman-rank-test) we could show a significant correlation between the infarct area (MAP2) and the loss of microvessels (P< 0.05). This study demonstrates the close relationship between neuronal and microvascular damage. Further investigations should elucidate the involved mechanisms and their causative dependency.
P67 Optimized preclinical management of acute stroke TH LU/Z~, CH KOCH1, K ELLINGER~ Department of Anesthesiology and Operative Intensive Care Medicine, University Hospital Mannheim
Background: Cerebral infarction is the most common cause for disablement and dependancy on nursery among adults. Recently, it could be demonstrated that systemic thrombolysis with rt-PA is able to improve prognosis. However a favorable benefit-risk-ratio in selected patients is limited to a time window of 3h after onset of symptoms (1). Furthermore, according to a consensus agreement stabilization of impaired vital functions with acute cerebral ischemia has a significant influence on outcome (2). Up to now preclinical management of stroke (delayed EMS response by ambulance, insufficient stabilization of vital functions) often did not fulfill those requirements, In order to establish an optimized preclinical therapy we initiated a regional model of preclinical stroke management. Methods: Emergency physicians and paramedics of our district have been educated in the diagnosis and acute therapy of stroke EMS. Consequently, all patients presenting with stroke-like symptoms experi-
© Harcourt Brace & Co. Ltd 1998
P68 Plasminogen Activator Inhibitor-1 is a Major Determinant of Arterial Thrombolysis Resistance YANHONG ZHU AND WILLIAM P. FAY, UNIVERSITY OF MICHIGAN, ANN ARBOR, MI, USA
Platelet-rich thrombi are resistant to lysis by tissue-type plasminogen activator (tPA). However, mechanisms underlying arterial thrombolysis resistance are poorly understood. We developed a routine model of carotid artery injury to test the hypothesis that plasminogen activator inhibitor-1 (PAI-1) inhibits pharmacologic thrombolysis. Platelet-fich thrombi were induced in wild-type (PAl-l+/+, n=l 1) and PAI-l-deficient (PAI-1-/-, n=l 1) mice with ferric chloride. Carotid blood flow was monitored with a flowprobe. Mean occlusion time did not differ between PAIl +/+ (14.4+/-2 min) and PAI-1-/- (13.5+/-2 rain) mice (P>0.2). Clot lysis was induced by infusing heparin (200 U/kg bolus, 70 U/kg/hr drip), human plasminogen (HPg, 50 mg/kg), and human tPA at 20 (LD, n=10) or 100 (HD, n=12) mcg/kg/min. Mean plasma tPA antigen was 2.7 mcg/ml for LD tPA and 5.5 mcg/mL for HD tPA, with no differences between PAIl+/+ and PAI-I-/- mice. Reperfnsion after LD tPA occurred in 1/5 PAIl+/+ mice vs. 5/5 PAI-1-/- mice (P<0.02). Reperfusion occurred in all mice with HD tPA, but reperfusion times were significantly shorter in PAIl - / - mice (18.7+/-3 rain, n=6) than PAI-I+/+ mice (35.7+/-5.1 mill, n=6, P<0.005). No reperfusion occurred if t-PA or HPg was not infused. Lysates of PAI-I+/+ platelets inhibited human t-PA in vitro, whereas PAI-1-/platelet lysates did not. We conclude that 1) PAI-1 is a major determinant of the resistance of platelet-fich arterial thrombi to lysis by pharmacologic concentrations of t-PA; 2) strategies for inhibiting PAI-1 may enhance thrombolysis; and 3) the mouse is an excellent model for studying the molecular determinants of thrombolysis resistance.
Fibrinolysis & Proteolysis (1998) 12(Suppl 2), 91-113
P66 Quantification of neuronal and microvascular damage after focal cerebral ischemia and reperfusion B STAUFER, C ZIMMERMANN, M LIEBETRAU, G BULTEMEIER, G H HAMANN Neurologische Klinik, Klinikum Groflhadem, LMU MOnchen
enced an immediate preclincal emergency treatment and direct admission to our hospital; being the only institution offering thrombolysis in our district . Simultaneously, as part of a cooperating model, patients being first admitted to hospitals with a lower level of supply are immediately transferred to our stroke center.
The development of vasogenic brain edema and hemorrhagic complications after cerebral ischemia is connected to disturbances of the microvascular integrity. Therefore, the aim of this study was to determine (a) the extent and 00) the localisation of neuronal and microvascular damage after experimental cerebral ischemia.
Results: The medium latency until onset of symptoms could be reduced to 5 hours in 1997 compared with Z8 hours in 1996. Simultaneously, the number of patients receiving thrombolytic therapy increased from less than 3% to about 18%. The neurological status of these patients improved comparably to results presented by the NINDS-study group (1). Conclusions: Optimizing the process quality with existing EMS systems in acute stroke management is a cost-effective option to reduce prehospital time delay in case of acute stroke. However, additional efforts must be undertaken in order to further reduce preclhaical latencies in acute stroke. Continuous public education seems to be the most suitable way (3) to achieve this goal. Literature: (1) The NINDS rt-PA Stroke Study Group.N Engl J Med, 1995 (333): 1581-158Z (2) Adams HP, Brott TG, Crowell RM et al., Stroke, 1994 (25): I901-1914. (3) Feldmann et al., Stroke 1993 (24): 1805-1810.
Using the MCAO (middle cerebral artery occlusion) intraluminal thread modell five male Wistar rats were subjected to a transient focal cerebral ischemia (3 h occlusion + 6 h reperfusion). On coronary sections (10 ~tm) the neuronal damage was documented by using a monoclonal antibody against MAP2 (microtubuli-associated protein-2). Alterations of the extracellular matrix of microvessels were quantified by application of a polyclonal antibody against collagen-type 1V. Within the ischemic hemisphere a deficit of MAP2-staining could be shown in the entire basal ganglia region. In contrast the staining was only faded in discrete areas of the cortex. In accordance to these results the number of collagen containing microvessels on the ischemic side was reduced by 18.9 +_3.1% (means + SD) within the basal ganglia and by 8.1 + Z5% within cortical regions. By statistical analysis (spearman-rank-test) we could show a significant correlation between the infarct area (MAP2) and the loss of microvessels (P< 0.05). This study demonstrates the close relationship between neuronal and microvascular damage. Further investigations should elucidate the involved mechanisms and their causative dependency.
P67 Optimized preclinical management of acute stroke TH LU/Z~, CH KOCH1, K ELLINGER~ Department of Anesthesiology and Operative Intensive Care Medicine, University Hospital Mannheim
Background: Cerebral infarction is the most common cause for disablement and dependancy on nursery among adults. Recently, it could be demonstrated that systemic thrombolysis with rt-PA is able to improve prognosis. However a favorable benefit-risk-ratio in selected patients is limited to a time window of 3h after onset of symptoms (1). Furthermore, according to a consensus agreement stabilization of impaired vital functions with acute cerebral ischemia has a significant influence on outcome (2). Up to now preclinical management of stroke (delayed EMS response by ambulance, insufficient stabilization of vital functions) often did not fulfill those requirements, In order to establish an optimized preclinical therapy we initiated a regional model of preclinical stroke management. Methods: Emergency physicians and paramedics of our district have been educated in the diagnosis and acute therapy of stroke EMS. Consequently, all patients presenting with stroke-like symptoms experi-
© Harcourt Brace & Co. Ltd 1998
P68 Plasminogen Activator Inhibitor-1 is a Major Determinant of Arterial Thrombolysis Resistance YANHONG ZHU AND WILLIAM P. FAY, UNIVERSITY OF MICHIGAN, ANN ARBOR, MI, USA
Platelet-rich thrombi are resistant to lysis by tissue-type plasminogen activator (tPA). However, mechanisms underlying arterial thrombolysis resistance are poorly understood. We developed a routine model of carotid artery injury to test the hypothesis that plasminogen activator inhibitor-1 (PAI-1) inhibits pharmacologic thrombolysis. Platelet-fich thrombi were induced in wild-type (PAl-l+/+, n=l 1) and PAI-l-deficient (PAI-1-/-, n=l 1) mice with ferric chloride. Carotid blood flow was monitored with a flowprobe. Mean occlusion time did not differ between PAIl +/+ (14.4+/-2 min) and PAI-1-/- (13.5+/-2 rain) mice (P>0.2). Clot lysis was induced by infusing heparin (200 U/kg bolus, 70 U/kg/hr drip), human plasminogen (HPg, 50 mg/kg), and human tPA at 20 (LD, n=10) or 100 (HD, n=12) mcg/kg/min. Mean plasma tPA antigen was 2.7 mcg/ml for LD tPA and 5.5 mcg/mL for HD tPA, with no differences between PAIl+/+ and PAI-I-/- mice. Reperfnsion after LD tPA occurred in 1/5 PAIl+/+ mice vs. 5/5 PAI-1-/- mice (P<0.02). Reperfusion occurred in all mice with HD tPA, but reperfusion times were significantly shorter in PAIl - / - mice (18.7+/-3 rain, n=6) than PAI-I+/+ mice (35.7+/-5.1 mill, n=6, P<0.005). No reperfusion occurred if t-PA or HPg was not infused. Lysates of PAI-I+/+ platelets inhibited human t-PA in vitro, whereas PAI-1-/platelet lysates did not. We conclude that 1) PAI-1 is a major determinant of the resistance of platelet-fich arterial thrombi to lysis by pharmacologic concentrations of t-PA; 2) strategies for inhibiting PAI-1 may enhance thrombolysis; and 3) the mouse is an excellent model for studying the molecular determinants of thrombolysis resistance.
Fibrinolysis & Proteolysis (1998) 12(Suppl 2), 91-113