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K A Hossmann

Publications and source records attributed to K A Hossmann.

At least 19 recordsLinked to original sources
PubMed2001

Aggravation of brain injury after transient focal ischemia in p53-deficient mice.

The transcriptional factor p53 is a regulatory protein which contributes to the preservation of tissue integrity by promoting either DNA repair or apoptosis. To establish the pathophysiological role of this protein in ischemia, we produced 1 h transient middle cerebral artery (MCA) occlusion in normal and in p53-deficient mice and investigated the resulting tissue damage by multiparametric imaging. Possible genetic influences on the angioarchitecture of the MCA territory and blood flow were examined by intravascular latex infusion and laser-Doppler flowmetry. Wild-type (p53(+/+)), heterozygous (p53(+/-)) and homozygous (p53(-/-)) mice deficient for the p53 gene did not differ in respect to angioarchitecture or the effect of vascular occlusion on blood flow and general physiological parameters. Twenty-four hours after 1 h MCA occlusion, mice revealed a gene dose-dependent decline in the size of metabolic disturbances (ATP depletion and inhibition of protein synthesis) and histological injury (Cresyl Violet staining). DNA fragmentations detected by terminal deoxynucleotidyl transferase-mediated UTP nick end labeling (TUNEL) did not differ in the three groups and were only present in ATP-depleted tissue. Our findings suggest that after transient focal brain ischemia p53 prevents rather than aggravates brain injury, and that this effect is brought about by mechanisms that are unrelated to the pro-apoptotic properties of this gene.

Adenosine Triphosphate↗
PubMed2001

GTPase RhoB: an early predictor of neuronal death after transient focal ischemia in mice.

Applying the recently developed DNA array technique to a murine stroke model, we found that the gene coding for RhoB, a member of the family of GTPases that regulate a variety of signal transduction pathways, is upregulated in ischemia-damaged neurons. RhoB immunoreactivity precedes DNA single-strand breaks and heralds the evolving infarct, making it an early predictor of neuronal death. Expression of RhoB colocalized with drastic rearrangement of the actin cytoarchitecture indicates a role for Rho in postischemic morphological changes. Apoptosis in a murine hippocampal cell line was also associated with an early increase in RhoB protein. Activation of caspase-3, a crucial step in apoptosis, could be inhibited by cytochalasin D, a substance that counteracts the actin-modulating activity of Rho GTPases, indicating that Rho proteins may have impact on injury-initiated neuronal signal transduction. Our findings make Rho GTPases potential targets for the development of drugs aimed at limiting neuronal death following brain damage.

Actin Cytoskeleton↗
PubMed2001

Electron microscopic investigation of rat brain after brief cardiac arrest.

Rats were submitted to 10-min cardiac arrest, followed by resuscitation and survival for 1 day, 3 days or 1 week. Five regions of interest (CA1 and CA3 sector of hippocampus, dentate gyrus, reticular nucleus of thalamus and parietal cortex) where studied by light and electron microscopy at each of the survival times, and compared with non-ischemic control rats. Cell counts revealed delayed neuronal loss of about 30% after 3 days in both CA1 and CA3 sectors. Ischemic cell changes consisting of cytoplasmic condensation and nuclear pyknosis appeared in these regions on day 7 and --to a lesser degree-- also affected dentate gyrus, the reticular nucleus of thalamus and cerebral cortex. Ultrastructural alterations were evaluated using an ultrastructural injury catalogue. In all brain regions similar, although quantitatively differently expressed, changes occurred except ribosomal disaggregation, which was restricted to neurons of hippocampal CA1 sector on the first day after cardiac arrest. Progressive alterations included swelling of mitochondria and endoplasmic reticulum, which was most pronounced in CA1 and CA3 sectors of hippocampus, as well as chromatin aggregation and alterations of neuronal volume, which affected mainly the granule cells of dentate gyrus. Other alterations, such as osmiophilic inclusions or the formation of nuclear pore complexes, were transient with a maximum on the first day after cardiac arrest. Treatment with the free-radical scavenger alpha-phenyl-N-tert-butyl nitrone (PBN) suppressed the formation of nuclear pores but otherwise did not markedly change the morphological outcome. In comparison to previous studies of global brain ischemia induced by arterial inflow occlusion of the same duration, the present data demonstrate remarkable preservation of tissue integrity in CA1 sector but also distinct changes in brain regions considered to be resistant to ischemic injury. Morphological alterations of brain after cardiac arrest do not follow the established pattern of selective vulnerability.

Animals↗
PubMed2001

Relationship between metabolic dysfunctions, gene responses and delayed cell death after mild focal cerebral ischemia in mice.

The evolution of brain injury was examined in mice subjected to focal cerebral ischemia as induced by 30 min of intraluminar thread occlusion of the middle cerebral artery, followed by 3 h to 3 days of reperfusion. Metabolic dysfunctions were studied by 3H-leucine autoradiography for the measurement of cerebral protein synthesis and by regional ATP bioluminescent imaging. Metabolic changes were compared with responses of the genes c-fos, c-jun, heat-shock protein gene (hsp)72, p53-activated gene (pag)608 and caspase-3, which were investigated by in situ hybridization histochemistry and immunocytochemistry, and correlated with the degree of DNA fragmentation, as assessed by the terminal TdT-mediated dUTP-biotin nick end labeling method. Intraluminar thread occlusion led to a reproducible reduction of cerebral laser Doppler flow to 20-30% of control. Thread withdrawal was followed by a short-lasting post-ischemic hyperperfusion to approximately 120%. In non-ischemic control animals, fractional protein synthesis values of 0.81+/-0.26 and 0.94+/-0.23 were obtained. Thread occlusion resulted in a suppression of protein synthesis throughout the territory of the middle cerebral artery after 3 h of reperfusion (0.04+/-0.08 in caudate-putamen and 0.14+/-0.19 in somatosensory cortex, P<0.05). Protein synthesis partly recovered in the cortex after 24 h and 3 days (0.71+/-0.40 and 0.63+/-0.26, respectively), but remained suppressed in the caudate-putamen (0.14+/-0.22 and 0.28+/-0.28). Regional ATP levels did not show any major disturbances at the reperfusion times examined. Thread occlusion resulted in a transient increase of c-fos mRNA levels in ischemic and non-ischemic parts of the cortex and caudate-putamen at 3 h after ischemia, which suggests that spreading depressions were elicited in the tissue. At the same time, c-jun and hsp72 mRNAs were elevated only in ischemic brain areas showing inhibition of protein synthesis. C-fos and c-jun responses completely disappeared within 24 h of reperfusion. Hsp72 mRNA levels remained elevated in the cortex after 24 h, but decreased to basal values in the caudate-putamen. Twenty-four hours after reperfusion, pag608 and caspase-3 mRNA levels increased in the caudate-putamen, where protein synthesis rates were still reduced, and remained elevated even after 3 days. However, pag608 and caspase-3 mRNA levels did not increase in the cortex, where protein synthesis recovered. After 24 h and 3 days, functionally active p20 fragment of caspase-3 was detected in the caudate-putamen, closely associated with the appearance of DNA fragmented cells. Neither activated caspase-3 nor DNA fragmentation were noticed in the cortex.In summary, the suppression of protein synthesis is reversible in the ischemia-resistant cortex following 30 min of thread occlusion in mice, but persists in the vulnerable caudate-putamen. In the caudate-putamen, apoptotic programs are induced, closely in parallel with the manifestation of delayed cell death. Thus, the recovery of protein synthesis may be a major factor influencing tissue survival after transient focal ischemia.

Adenosine Triphosphate↗
PubMed2001

Gene expressions after thrombolytic treatment of middle cerebral artery clot embolism in mice.

BACKGROUND AND PURPOSE: Thrombolytic treatment of stroke may result in reperfusion injury. To investigate the role of selective gene expressions, C57Bl/6J mice were subjected to middle cerebral artery (MCA) clot embolism, followed after 1 hour by intracarotid infusion of 10 mg/kg recombinant tissue plasminogen activator (rtPA) or vehicle. METHODS: Before the onset of treatment and at 1, 3, 6, and 24 hours of recirculation, animals were frozen in situ and hsp70, c-fos, junB, and NSE mRNAs were imaged on cryostat sections using in situ hybridization autoradiography. Cerebral protein synthesis (CPS) and ATP content were measured on adjacent brain sections. RESULTS: hsp70 mRNA was upregulated in the penumbral cortex of untreated animals and in the MCA core region of animals receiving rtPA (ie, regions characterized by a mismatch between high ATP levels and suppressed CPS). c-fos and junB mRNAs were transiently expressed mainly in the peri-infarct intact cortex for up to 3 to 6 hours in the treated and up to 24 hours in the untreated animals. In both groups, NSE mRNA declined in the central parts of the MCA territory together with a loss of silver impregnation, but this decline was more pronounced in the untreated animals. CONCLUSIONS: The genomic expression pattern after thrombolytic recanalization of clot embolism resembles that of other types of transient ischemia such as reversible thread occlusion, although the outcome is markedly different. The investigated gene expressions, notably hsp70 mRNA, reflect the kind and severity of the ischemic stress, but they do not predict reversibility of the ischemic injury.

Adenosine Triphosphate↗
PubMed2000

Microglial and astrocytic reactions prior to onset of thalamic cell death after traumatic lesion of the rat sensorimotor cortex.

The temporospatial relationship between microglial and astrocytic reactions and delayed thalamic cell death was examined 1-7 days following a traumatic cold lesion of the rat sensorimotor cortex using immunocytochemistry in combination with terminal deoxynucleotidyltransferase-mediated biotinylated dUTP nick end labeling (TUNEL) of nuclear DNA fragmentation. No or only occasional TUNEL-positive cells were found in the thalamic relay nuclei up to 3 days after trauma. After 7 days, on the other hand, a considerable number of TUNEL-positive cells were seen in the ventrobasal, the ventrolateral and posterior thalamic nuclei. Already 3 days after trauma, i.e., before cell injury was detectable, many protoplasmic astrocytes, which were reactive for glial fibrillary acidic protein, and ramified microglia, which were positive for complement receptor type 3b (CR3b) but negative for major histocompatibility complex (MHC) class II antigen, were noticed in the thalamus. The number of labeled astro- and microglia further increased after 7 days, when DNA fragmentation became evident. At this time, the morphology of microglia shifted towards bushy and rod-like cells, and microglia became also reactive for MHC class II antigen. Clusters of CR3b- and MHC class II-positive microglia were found in the ventrobasal thalamus. The present findings demonstrate that trauma-induced microglial and astrocytic reactions appear in the thalamus prior the onset of cell damage.

Animals↗
PubMed2000

Recombinant tissue-plasminogen activator-induced thrombolysis after cerebral thromboembolism in mice.

The effects of intracarotid thrombolysis with recombinant tissue-plasminogen activator (rt-PA) on cerebral laser Doppler flow (LDF) and the degree of ischemic injury, as revealed by triphenyltetrazolium chloride (TTC) staining, were studied 24 h following cerebral thromboembolism in mice. Thromboembolization with fibrin-rich clot material (0.28-microl clot volume) led to an LDF decline to about 20-30% of baseline in untreated mice, which resulted in reproducible infarcts of the middle cerebral artery (MCA) territory (122.8 +/- 29.4 mm(3)). Administration of rt-PA (10 mg/kg) 15 min after clot injection induced a progressive LDF restoration to approximately 115% of control values after 2 h, and brought about a significant reduction of the infarct volume (62.3 +/- 42.4 mm(3)). Our results indicate that ischemic injury may be significantly attenuated by intracarotid thrombolysis. However, injury is not completely reversed, even if reperfusion is initiated as early as 15 min after embolization.

Animals↗
PubMed2000

Treatment with an endothelin type A receptor-antagonist after cardiac arrest and resuscitation improves cerebral hemodynamic and functional recovery in rats.

OBJECTIVE: Successful resuscitation of the brain after cardiac arrest requires unimpaired microcirculatory reperfusion. Postischemic cerebral hypoperfusion presumably is mediated through activation of endothelin type A receptors (ET(A)). The effect of the selective ET(A) antagonist BQ123 on cerebral blood flow and function was studied in a rat model of cardiac arrest. DESIGN: Prospective, randomized trial. SETTING: Experimental animal laboratory. SUBJECTS: Twelve male Sprague-Dawley rats (290-350 g). INTERVENTIONS: Cardiac arrest for 12 mins was induced by electrical fibrillation of the heart, followed by standardized cardiopulmonary resuscitation. BQ123 (0.8 mg/kg; n = 6) or its vehicle (saline; n = 6) was injected intravenously at 15 mins after the return of spontaneous circulation. MEASUREMENTS: Cortical blood flow was measured by laser-Doppler flowmetry, electrophysiological function by recording the amplitude of somatosensory evoked potentials, vascular reactivity by ventilation with 6% CO2, and the functional coupling of blood flow by recording the laser-Doppler flow (LDF) changes during somatosensory stimulation. Hemodynamic and functional cerebral recovery was monitored for 3 hrs after the return of spontaneous circulation. MAIN RESULTS: Forty-five minutes after the return of spontaneous circulation, postischemic hypoperfusion developed in both groups, as reflected by a decrease of the LDF signal to about 60% of the preischemic level. In untreated animals, hypoperfusion persisted throughout the observation time, but in animals receiving BQ123, LDF gradually returned to normal. CO2 reactivity in untreated animals was severely reduced for 2-3 hrs after the onset of recirculation, whereas after BQ123 treatment it returned to normal and after 2 hrs even above normal. The ET(A) antagonist also induced a more rapid recovery of the somatosensory evoked potentials amplitude and of the functional blood flow response to somatosensory stimulation, but these parameters did not recover completely within the observation period. CONCLUSIONS: Application of the ET(A) antagonist BQ123 during the early reperfusion period after cardiac arrest shortens postischemic cerebral hypoperfusion and accelerates the restoration of the cerebrovascular CO2 reactivity and the recovery of electrophysiologic function.

Animals↗
PubMed2000

Endothelin type A-antagonist improves long-term neurological recovery after cardiac arrest in rats.

OBJECTIVE: Antagonists of endothelin (ET(A)) receptors improve postischemic hypoperfusion. In this study we investigated whether the selective ET(A)-antagonist BQ123 also improves postischemic functional recovery. STUDY DESIGN: Cardiac arrest of 12 mins duration was induced in rats by electrical fibrillation of the heart, followed by advanced cardiopulmonary resuscitation. BQ123 (0.8 mg/kg; n = 9) or its vehicle (saline; n = 9) was injected intravenously at 15 mins after the return of spontaneous circulation. The neurologic deficit was scored daily for 7 days after resuscitation by rating consciousness, various sensory and motor functions, and coordination tests. On day 7, we measured functional coupling of cerebral blood flow under halothane anesthesia by recording laser-Doppler flow during electrical forepaw stimulation, and we measured vascular reactivity to CO2 by measuring the laser-Doppler flow change during ventilation with 6% CO2. The brains were perfusion-fixated with 4% paraformaldehyde, and the histopathologic damage was evaluated in the CA1 sector of hippocampus, in the motor cortex, and in the cerebellum. RESULTS: Treatment with BQ123 had no effect on histopathologic damage, but it significantly improved neurologic recovery. In all nine treated rats, neurologic performance returned to near normal within 2 days whereas four of nine untreated animals developed spastic paralysis of the hind limbs and severe coordination deficits. BQ123 also normalized CO2 reactivity and improved the functional cerebral blood flow response to somatosensory stimulation. CONCLUSIONS: The ET(A)-antagonist BQ123 significantly improves neurologic outcome after 12 mins of cardiac arrest. The apparent restoration of vascular reactivity demonstrates a correlation between hemodynamic factors and functional recovery.

Animals↗
PubMed2000

Quantitative measurement of local cerebral blood flow in the anesthetized mouse using intraperitoneal [14C]iodoantipyrine injection and final arterial heart blood sampling.

Autoradiographic measurement of local cerebral blood flow (CBF) with [14C]iodoantipyrine (IAP) is limited in mice by the difficulty in cannulating vessels and the blood loss for repeated blood sampling. The authors modified and validated the method to measure local CBF with [14C]IAP in mice by combining intraperitoneal tracer application with a single blood sampling from the heart at the end of the experiment. Experiments were carried out in male SV129 mice under halothane anesthesia. After intraperitoneal administration of 15 microCi [14C]IAP, arterial blood samples were collected repeatedly and anesthetized animals were immersed in liquid nitrogen. In addition, frozen blood from the heart was sampled to obtain the final blood [14C]radioactivity. Correlation analysis between the sampling time and [14C]radioactivity of the arterial blood revealed a highly significant linear relationship (P < 0.001, r = 0.978) and a lag time of the [14C]tracer in arterial blood of 3.3 +/- 0.6 seconds. [14C]radioactivity of the final arterial blood sample (444 +/- 264 nCi/mL) was almost equal to that of the heart blood (454 +/- 242 nCi/mL), and the absolute difference in each animal was 3.3 +/- 4.2% (mean +/- SD). The convolution integrals for the CBF calculation were determined either by integrating the radioactivity of individual arterial blood samples or by assuming a linear rise from [14C]tracer lag time after intraperitoneal [14C]IAP injection to the value measured in the blood sample from the frozen heart. Regional flow values calculated by the two methods differed by less than 11% (not significant). This method allows the quantitative measurement of local CBF in anesthetized mice without any vessel catheterization and will make mutant mice a more powerful tool to elucidate the molecular mechanisms of brain injuries by combining flow studies with molecular-biological methods.

Animals↗
PubMed2000

Dynamics of regional brain metabolism and gene expression after middle cerebral artery occlusion in mice.

The evolution of brain infarcts during permanent occlusion of the middle cerebral artery (MCA) was studied in mice using multiparametric imaging techniques. Regional protein synthesis and the regional tissue content of ATP were measured on adjacent cryostat sections at increasing intervals after vascular occlusion ranging from 1 hour to 3 days. The observed changes were correlated with the expression of the mRNA of hsp70, c-fos, c-jun, and junB, as well as the distribution of DNA double-strand breaks visualized by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL). One hour after MCA occlusion, the tissue volume with suppressed protein synthesis was distinctly larger than that in which ATP was depleted. With ongoing ischemia time, the ATP-depleted area gradually expanded and, within 1 day, merged with the region of suppressed protein synthesis. Expression of hsp70 mRNA occurred mainly in the penumbra (defined as the region of suppressed protein synthesis but preserved ATP), peaking at 3 hours after vascular occlusion. Expression of the immediate-early genes c-jun, c-fos, and junB increased both in the penumbra and the periinfarct normal tissue already at 1 hour after vascular occlusion, with slightly different regional and temporal patterns for each of these genes. DNA fragmentations were clearly confined to neurons; they appeared after 1 day in the infarct core (defined as the region of suppressed ATP) and never were detected in the penumbra. The late appearance of TUNEL after infarcts had reached their final size and the absence in the penumbra points against a major pathogenetic role of apoptosis. Permanent MCA occlusion in mice thus produces a gradually expanding infarct, the final size of which is heralded by the early inhibition of protein synthesis.

Adenosine Triphosphate↗
PubMed2000

Evolution of brain infarction after transient focal cerebral ischemia in mice.

The evolution of brain infarction after transient focal cerebral ischemia was studied in mice using multiparametric imaging techniques. One-hour focal cerebral ischemia was induced by occluding the middle cerebral artery using the intraluminal filament technique. Cerebral protein synthesis (CPS) and the regional tissue content of adenosine triphosphate (ATP) were measured after recirculation times from 0 hours to 3 days. The observed changes were correlated with the expression of the mRNAs of hsp-70, c-fos, and junB, as well as the distribution of DNA double-strand breaks, visualized by TUNEL. At the end of 1 hour of ischemia, protein synthesis was suppressed in a larger tissue volume than ATP in accordance with the biochemical differentiation between core and penumbra. Hsp70 mRNA was selectively expressed in the cortical penumbra, whereas c-fos and junB mRNAs were increased both in the lateral part of the penumbra and in the ipsilateral cingulate cortex with normal metabolism. During reperfusion after withdrawal of the intraluminal filament, suppression of CPS persisted except in the most peripheral parts of the middle cerebral artery territory, in which it recovered between 6 hours and 3 days. ATP, in contrast, returned to normal levels within 1 hour but secondarily deteriorated from 3 hours on until, between 1 and 3 days, the ATP-depleted area merged with that of suppressed protein synthesis leading to delayed brain infarction. Hsp70 mRNA, but not c-fos and junB, was strongly expressed during reperfusion, peaking at 3 hours after reperfusion. TUNEL-positive cells were detected from 3 hours on, mainly in areas with secondary ATP depletion. These results stress the importance of an early recovery of CPS for the prevention of ischemic injury and suggest that TUNEL is an unspecific response of delayed brain infarction.

Adenosine Triphosphate↗
PubMed2000

Effect of thrombolysis on the dynamics of infarct evolution after clot embolism of middle cerebral artery in mice.

Reversible focal ischemia may lead to delayed tissue injury despite primary restoration of blood flow and metabolism. The authors investigated whether such delayed changes also occur after thrombolytic treatment of thromboembolic stroke. Clot embolism of the middle cerebral artery (MCA) was produced in C57/B16J mice by intracarotid injection of heterologous clots. One hour after embolism, one group was treated with intracarotid infusion of rt-PA (10 mg/kg). The untreated control group received an equal amount of vehicle. Just before onset of treatment and after 1, 3. 6, and 24 hours, animals were frozen in situ and cerebral blood flow (CBF), cerebral protein synthesis (CPS), ATP content, and DNA fragmentations (TUNEL) were imaged on cryostat sections using double tracer autoradiography. bioluminescence, and immunohistochemical techniques, respectively. In untreated animals (n = 20), CPS was suppressed in approximately 68% of hemispheric transsection at 1 hour after embolization. The ATP depleted area was smaller (approximately 58%), but between 6 and 24 hours it merged with that of CPS suppression. TUNEL-positive neurons became visible between 6 and 24 hours exclusively in regions with ATP depletion. rt-PA-induced thrombolysis (n = 20) led to the gradual improvement of blood flow. At 24 hours. ATP depletion was fully reversed and the CPS suppression area declined to approximately 16% of hemispheric transsection. Despite progressive metabolic recovery, large numbers of neurons became TUNEL-positive and animals died between 24 and 48 hours. Thrombolysis after clot embolism restores metabolic activity including protein synthesis, but the therapeutic benefit is limited by secondary injury that requires additional treatment to improve final outcome.

Animals↗
PubMed2000

Penumbral tissue alkalosis in focal cerebral ischemia: relationship to energy metabolism, blood flow, and steady potential.

The effect of focal ischemia on tissue pH was studied at various times up to 6 hours after permanent middle cerebral artery occlusion in rats. Tissue pH was imaged by using umbelliferone fluorescence and correlated with cerebral blood flow, ATP content, and recordings of the steady potential. Circumscribed foci of allalosis (pH 7.32+/-0.11) were detected with increasing frequency in penumbral regions having near-to-normal ATP concentrations and cerebral blood flow values between 20% and 40% of control. Both the infarct core, defined by ATP loss and cerebral blood flow values of less than 20% of control, and the inner peri-infarct rim were consistently acidic (pH 6.03+/-0.36 and 6.53+/-0.24, respectively). Treatment with the glutamate antagonist dizocilpine (MK-801) suppressed negative shifts of the steady potential and reduced significantly the occurrence of alkalosis observed in 90% of untreated but only in 44% of treated animals. Penumbral alkalosis appeared to be a time-dependent event occurring 30 to 60 minutes after the passage of peri-infarct depolarizations. The diversity of penumbral pH changes reflects the local disturbance of pH regulation and, possibly, the differential fate of penumbral subareas.

Acidosis↗
PubMed1999

Expression of cell death-associated phospho-c-Jun and p53-activated gene 608 in hippocampal CA1 neurons following global ischemia.

Persistent activation of c-Jun N-terminal kinases (JNKs) and phosphorylation of c-Jun has been shown in various cell death paradigms. Inhibition of the JNK signal transduction pathway prevented neuronal cell death both in vitro and in vivo. In the present study, nuclear phospho-c-Jun immunoreactivity became apparent selectively in vulnerable hippocampal CA1 neurons at 24 h after transient global cerebral ischemia. A high constitutive expression of phospho-JNK1 was detected by immunoblot analysis of hippocampal extracts. Expression of JNK interacting protein-1 (JIP-1), which facilitates JNK signaling, remained unchanged in post-ischemic hippocampal neurons. By contrast, p53-activated gene 608 (PAG608), which promotes cell death in vitro, was strongly induced in post-ischemic CA1 neurons. Our data suggest that transcription factors p53 and phospho-c-Jun may contribute to programmed CA1 cell death following ischemia.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Thrombolysis of cerebral clot embolism in rat: effect of treatment delay.

Rats submitted to focal cerebral ischemia by middle cerebral artery clot embolism were treated with recombinant tissue plasminogen activator (rt-PA) at increasing delays (1.5, 3 and 4.5 h) after the onset of ischemia. Treatment efficacy was evaluated by NMR imaging of the apparent diffusion coefficient of water (ADC). In untreated animals the size of the ADC-detectable lesion gradually increased after clot embolism, expanding over 8 h to 174 +/- 17% of the volume visible at 30 min. Thrombolysis initiated 1.5 h after embolism did not reverse the ischemic lesion but reduced its growth to 113 +/- 19% (p < 0.05). Lesion size increased to 135 +/- 14% after 3 h (NS) and to 214 +/- 35% after 4.5 h delay (NS). Thrombolysis with rt-PA attenuates infarct expansion but does not reverse ischemic injury.

Animals↗
PubMed1999

Brain hemorrhages after rt-PA treatment of embolic stroke in spontaneously hypertensive rats.

Intracerebral hemorrhage is a major complicating factor of thrombolytic therapy of stroke. To investigate the incidence of bleeding in animals with a diseased vascular system, thrombolysis was carried out in spontaneously hypertensive rats (SHR) after clot embolism of the right middle cerebral artery (MCA). Three hours after embolism SHR were treated with either recombinant tissue-plasminogen activator (rt-PA) or saline, and neurological deficits and intracerebral hemorrhages were evaluated after 3 days survival. Rt-PA-treated SHR exhibited a significantly higher incidence of hemorrhages than untreated rats but neurological deficits and survival rates showed a non-significant trend for improvement. This model offers the possibility of investigating the pathophysiology of post-thrombolytic complications in a clinically relevant small animal model.

Animals↗