Biomedical subjects

K A Hossmann

Publications and source records attributed to K A Hossmann.

At least 37 records · Page 2Linked to original sources

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↗

PubMed1999

Lesion-remote metabolic changes after neocortical cold injury in rats.

Lesion-remote metabolic changes were examined 1-7 days after neocortical cold injury using tissue ATP, glucose and lactate bioluminescent imaging, pH-dependent fluoroscopy and cerebral protein synthesis (CPS) autoradiography. One day after lesioning an alkaline pH shift (0.35 +/- 0.19 units above contralateral) was noticed in the lesion-remote cortex, the underlying white matter, the striatum, hippocampus and thalamus, which slowly resolved within 7 days and probably reflected the spread of vasogenic edema. Closely associated with the pH shift, elevations in tissue glucose and lactate levels were found, which reached maximum levels after 3 days (7.4 +/- 2.4 vs 4.2 +/- 1.2 micromol/g glucose, 6.6 +/- 2.3 vs 2.1 +/- 0.6 micromol/g lactate) but, in contrast to the alkalosis, remained elevated after 1 week. Thus, neocortical trauma is associated with long-lasting metabolic changes, which are intimately linked with the distribution of post-traumatic alkalosis.

Adenosine Triphosphate↗

PubMed1999

Recombinant tissue plasminogen activator reduces infarct size after reversible thread occlusion of middle cerebral artery in mice.

It has been suggested that tissue plasminogen activator (tPA), which is widely used for the thrombolytic treatment of stroke, exhibits neurotoxic side effects. To test this hypothesis, mice exposed to 90 min nonthrombotic middle cerebral artery thread occlusion were treated with 10 mg/kg recombinant tPA (rt-PA) at 15 min after the onset of vascular occlusion. Measurements of blood flow, infarct volume, brain swelling and neurological performance revealed faster recirculation and a significant reduction of ischemic injury in rt-PA-treated animals. These data are at variance with previous reports on tPA neurotoxicity and demonstrate, on the contrary, that tPA protects the brain even after non-thrombotic vascular occlusion.

Animals↗

PubMed1999

Diffusion- and perfusion-weighted MR imaging of transient focal cerebral ischaemia in mice.

Temporary focal ischaemia was induced in wild-type C57Black/6 mice by thread occlusion of the middle cerebral artery (MCA). Recirculation was started after 60 min and maintained for 24 h, after which the mouse brain was frozen in situ. Development of the cerebral infarct was monitored by diffusion-, perfusion- and T(2)-weighted magnetic resonance imaging (MRI) during ischaemia, during the early reperfusion period of 90 min, and at 24 h after reperfusion. Ischaemia caused a marked reduction of the perfusion signal intensity and of the apparent diffusion coefficient (ADC) of tissue water in the ipsilateral MCA territory. In sham-operated control animals ADC remained unchanged. Hemispheric lesion volume after 1 h MCA occlusion was 53 +/- 6% (n = 6), as defined by an ADC decrease of more than 20%. Recirculation reduced hemispheric lesion volume to only 27 +/- 13%, while there was a trend towards secondary lesion growth at 24 h. Post-ischaemic recovery of perfusion was slow, heterogeneous and incomplete. A region-of-interest analysis showed only partial and transient recovery of the ADC, particularly in the dorsolateral cortex and lateral caudate putamen, which may be explained by inadequate reperfusion in these regions. Detailed MRI studies of cerebral ischaemia and reperfusion may now also be performed in the transgenic mice.

Animals↗

PubMed1999

Simultaneous recording of evoked potentials and T2*-weighted MR images during somatosensory stimulation of rat.

Somatosensory evoked potentials (SEP) and T2*-weighted nuclear magnetic resonance (NMR) images were recorded simultaneously during somatosensory stimulation of rat to investigate the relationship between electrical activation of the brain tissue and the signal intensity change in functional NMR imaging. Electrical forepaw stimulation was performed in Wistar rats anesthetized with alpha-chloralose. SEPs were recorded with calomel electrodes at stimulation frequencies of 1.5, 3, 4.5, and 6 Hz. At the same time, T2*-weighted imaging was performed, and the signal intensity increase during stimulation was correlated with the mean amplitude of the SEP. Both the stimulation-evoked signal intensity increase in T2*-weighted images and the amplitude of SEPs were dependent on the stimulation frequency, with the largest signals at a stimulation frequency of 1.5 Hz and decreasing activations with increasing frequencies. The feasibility of simultaneous, artifact-free recordings of T2*-weighted NMR images and of evoked potentials is proved. Furthermore, the study demonstrates-in the intact brain-the validity of functional magnetic resonance imaging for estimating the intensity of electrocortical activation.

Animals↗

PubMed1999

Regional metabolic disturbances and cerebrovascular anatomy after permanent middle cerebral artery occlusion in C57black/6 and SV129 mice.

C57Black/6 and SV129 mice are widely used for the production of transgenic mutants in molecular stroke research but the ischemic susceptibility of these strains is influenced by differences in vascular anatomy and the responsiveness to excitotoxins and vasodilatory stimuli. To differentiate between these opposing effects on infarct size, the vascular territory of the two strains was correlated with the hemodynamic, metabolic, and morphological consequences of permanent middle cerebral artery (MCA) occlusion. The vascular anatomy was studied by latex infusion, brain infarction by vital staining, the size of the ischemic penumbra by imaging of ATP and protein synthesis, and blood flow by laser-Doppler flowmetry. In C57Black/6 mice the MCA-supplied vascular territory and the size of brain infarcts were significantly larger than in SV129 mice but the size of the penumbra and the residual blood flow in the center of the MCA-supplying territory were similar in both strains. These findings suggest that differences in infarct size in C57Black/6 and SV129 mice are determined mainly by the vascular anatomy and not by differences in collateral vascular responsiveness or excitotoxicity.

Adenosine Triphosphate↗

PubMed1999

Expression of c-fos, junB, c-jun, MKP-1 and hsp72 following traumatic neocortical lesions in rats--relation to spreading depression.

The effects of a traumatic neocortical lesion on c-fos, junB, c-jun, MKP-1 and hsp72 expression were examined by in situ hybridization and immunocytochemistry 1-6 h following transcranial cold injury. The direct current potential was recorded in the injury-remote cortex to evaluate the role of transient direct current shifts, i.e. spreading depressions, in gene expression. In 14 out of 21 injured rats, spreading depression-like depolarizations of the direct current potential were noticed, which were accompanied by a transient decrease in electroencephalographic activity and increase in laser Doppler flow. In seven injured animals, no spontaneous spreading depressions were seen. In animals without spreading depressions, only a short-lasting response of c-fos, junB, c-jun and MKP-1 messenger RNAs as well as c-Fos protein was bilaterally found in the piriform cortex, and--with ipsilateral dominance--the dentate gyrus and hippocampal CA3/4 fields at 1 h after lesioning. In injured animals with spreading depressions however, a strong elevation was seen in layers II-IV and VI of the injury-remote ipsilateral cerebral cortex, which persisted over as long as 6 h. Messenger RNA levels for c-fos, junB and MKP-1 were closely related to the time interval between the last depolarization and the end of experiment. Levels were highest shortly after transient direct current shifts, and decreased thereafter mono-exponentially with half-lives of 48, 75 and 58 min for c-fos, junB and MKP-1 messenger RNAs, respectively. In 6 h animals with spreading depressions, hsp72 messenger RNA was slightly elevated in layer II of the injury-remote cortex, but heat shock protein 72 was not increased. The present results demonstrate that spreading depression is the most prominent factor influencing the trauma-related gene response in the lesion-remote cortical tissue.

Animals↗

PubMed1999

Inhibition of caspases prevents cell death of hippocampal CA1 neurons, but not impairment of hippocampal long-term potentiation following global ischemia.

An essential role for caspases in programmed neuronal cell death has been demonstrated in various in vitro studies, and synthetic caspase inhibitors have recently been shown to prevent neuronal cell loss in animal models of focal cerebral ischemia and traumatic brain injury, respectively. The therapeutic utility of caspase inhibitors, however, will depend on preservation of both structural and functional integrity of neurons under stressful conditions. The present study demonstrates that expression and proteolytic activity of caspase-3 is up-regulated in the rat hippocampus after transient forebrain ischemia. Continuous i.c.v. infusion of the caspase inhibitor N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone significantly attenuated caspase-3-like enzymatic activity, and blocked delayed cell loss of hippocampal CA1 neurons after ischemia. Administration of N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone, however, did not prevent impairment of induction of long-term potentiation in post-ischemic CA1 cells, suggesting that caspase inhibition alone does not preserve neuronal functional plasticity.

Animals↗

PubMed1999

Targeted disruption of the bcl-2 gene in mice exacerbates focal ischemic brain injury.

Neuronal death after brain ischemia is mainly due to necrosis but there is also evidence for involvement of apoptosis. To test the importance of apoptosis, we investigated the effect of targeted disruption of the apoptosis-suppressive gene bcl-2 on the severity of ischemic brain injury. Transient focal ischemia for 1 hour was induced by occlusion of the middle cerebral artery in homozygous (n=7) and heterozygous (n=6) bcl-2 knockout mice as well as in their wildtype littermates (n=5). Bcl-2 ablation did not influence cerebral blood flow but it significantly increased infarct size and neurological deficit score at 1 day after reperfusion in a gene-dose dependent manner. The exacerbation of tissue damage in the absence of Bcl-2 underscores the importance of apoptotic pathways for the manifestation of ischemic injury after transient vascular occlusion.

Animals↗

PubMed1999

Larger anastomoses in angiotensinogen-knockout mice attenuate early metabolic disturbances after middle cerebral artery occlusion.

Abnormalities in the homeostasis of the renin-angiotensin system have been implicated in the pathogenesis of vascular disorders, including stroke. The authors investigated whether angiotensinogen (AGN) knockout mice exhibit differences in brain susceptibility to focal ischemia, and whether such differences can be related to special features of the collateral circulation. Wild-type and AGN-knockout mice were submitted to permanent suture occlusion of the middle cerebral artery (MCA). The collateral vascular system was visualized by systemic latex infusion, and the ischemic lesions were identified by cresyl-violet staining. The core and penumbra of the evolving infarct were differentiated by bioluminescence and autoradiographic imaging of ATP and protein biosynthesis, respectively. In wild-type mice, mean arterial blood pressure was 95.0 +/- 8.6 mm Hg, and the diameter of fully relaxed anastomotic vessels between the peripheral branches of the anterior and middle cerebral arteries 26.6 +/- 4.0 microm. In AGN knockouts, mean arterial blood pressure was significantly lower, 71.5 +/- 8.5 mm Hg (P < .01), and the anastomotic vessels were significantly larger, 29.4 +/- 4.6 microm (P < .01). One hour after MCA occlusion, AGN-knockout mice exhibited a smaller ischemic core (defined as the region of ATP depletion) but a larger penumbra (the area of disturbed protein synthesis with preserved ATP). At 24 hours after MCA occlusion, this difference disappeared, and histologically visible lesions were of similar size in both strains. The observations show that in AGN-knockout mice the more efficient collateral blood supply delays ischemic injury despite the lower blood pressure. Pharmacologic suppression of angiotensin formation may prolong the therapeutic window for treatment of infarcts.

Acute Disease↗

PubMed1999

Hemodynamics and metabolism in stroke-prone spontaneously hypertensive rats before manifestation of brain infarcts.

Genomic screening of hybrids from stroke-prone (SHR-SP) and stroke-resistant spontaneously hypertensive rats (SHR) identified a STR1 locus on the rat chromosome 1, which correlates with the susceptibility to cerebral stroke but not with hypertension. The authors examined whether this genetic abnormality is associated with hemodynamic or metabolic alterations in the brain that can be detected before the manifestation of brain infarction. Starting at 6 weeks of age, SHR-SP were fed with a salt-rich diet to accelerate arterial hypertension. At the age of 12 weeks, animals developed functional symptoms and were age-matched with symptom-negative SHR-SP to differentiate between presymptomatic and postsymptomatic changes. Brains were investigated by multiparametric imaging comprising quantitative double-tracer autoradiography of CBF and cerebral protein synthesis (CPS); bioluminescence imaging of regional ATP, glucose, and lactate content; and umbelliferone fluoroscopic imaging of tissue pH. None of the animals exhibited focal hemodynamic or biochemical abnormalities. In symptom-negative SHR-SP, global CBF was 1.1+/-0.3 mL x g(-1) x min(-1), cortical CPS was 10.1+/-3.1 nmol x g(-1) x min(-1), and cortical ATP, glucose, lactate, and pH levels were in the normal range. In SHR-SP with functional symptoms, ATP, glucose, and lactate levels also were normal, but tissue pH exhibited periventricular alkalosis, CBF was significantly reduced to 0.7+/-0.2 mL x g(-1) x min(-1) (P < 0.001), and cortical CPS was significantly reduced to 6.7+/-2.1 nmol x g(-1) x min(-1) (P < 0.001). The decline in brain perfusion of SHR-SP correlated significantly with both the severity of functional deficits and the decline of protein synthesis. Our observations demonstrate that SHR-SP had already developed functional symptoms before the manifestation of overt brain infarcts and that the symptoms are initiated by a decline in global CBF and cortical CPS. Genetic abnormalities in SHR-SP are associated with a diffuse vascular process that results in global decompensation of blood flow well before the onset of focal brain infarction.

Animals↗

PubMed1999

The hypoxic brain. Insights from ischemia research.

The high energy requirements compared to the low energy reserves render the brain particularly vulnerable to hypoxic conditions. To protect the brain against hypoxia, powerful cerebrovascular regulatory systems assure an increase of blood flow to compensate for the reduced arterial oxygen content. This system is so efficient that during respiratory hypoxia brain metabolism is little disturbed as long as cardiac function does not fail. Only with declining blood pressure cerebral blood flow also declines, and brain energy metabolism rapidly collapses. Under experimental conditions, oxygen delivery to the brain is therefore more readily impaired by reducing blood flow in the first place, e.g. by occluding a supplying brain artery. With declining flow values metabolic and electrophysiological functions stepwise disappear according to the threshold concept of brain ischemia: first the most complex functions such as protein synthesis or the spontaneous electrical activity are suppressed, followed at much lower flow values by the breakdown of energy state and the depolarisation of cell membranes. The tissue supplied at a flow range between functional impairment and the suppression of vital functions has been called penumbra to characterize its potential revivability, provided oxygen supply is resumed. Besides its immediate effects, hypoxia causes delayed functional and metabolic disturbances which may even progress to cell death. The brain regions most sensitive to this type of injury are parts of the hippocampus, the dorsolateral caudate nucleus and the reticular nucleus of thalamus. Mechanisms contributing to delayed injury include coupling disturbances between brain function and blood flow, glutamate-propagated functional disturbances such as spreading depression, free radical mediated changes, disturbances of signal transduction pathways and complex abnormalities in the genomic expression patterns leading, in the worst case, to programmed cell death. A key mechanism in this complex stress response is the disturbed calcium homoeostasis of the endoplasmic reticulum which, among others, leads to the inhibition of protein synthesis at the translational level. Modulations of these pathological interactions are a major area of current ischemia research.

Animals↗

PubMed1998

Delayed up-regulation of Zac1 and PACAP type I receptor after transient focal cerebral ischemia in mice.

The Zac1 gene encodes a zinc finger protein that regulates both apoptosis and cell cycle arrest in vitro. Furthermore, Zac1 protein seems to trans-activate the gene encoding the type I receptor for pituitary adenylate cyclase activating polypeptide (PACAP). Northern blot analysis revealed high levels of Zac1 mRNA in the rodent brain. In the present study, we demonstrate by in situ hybridization histochemistry a progressive increase in Zac1 transcripts in the mouse brain from day 1 to day 3 following transient focal cerebral ischemia. Moreover, we observed an up-regulation of PACAP type I receptor mRNA expression showing a similar temporospatial distribution. Late induction of cell death promoting Zac1 in the post-ischemic brain may be attributed to delayed or secondary cell death. Co-induction of the type I receptor for neurotrophic PACAP however, points to a role in restorative processes.

Animals↗

PubMed1998

A reproducible model of thromboembolic stroke in mice.

AN experimental mouse model of thromboembolic stroke is presented, in which standardized fibrin-rich emboli (150 microm diameter, 1.5 mm or 4 mm length) are injected into the internal carotid artery. Injection of six or eight 1.5 mm clots (corresponding to 0.16 or 0.21 microl clot material) led to a variable decrease in laser Doppler flow (LDF), but did not result in reproducible infarcts of the middle cerebral artery (MCA) territory, as determined by triphenyltetrazolium chloride (TTC) staining 24 h after embolization. Injection of ten 1.5 mm clots (0.27 microl) or four 4 mm clots (0.28 microl), however, caused a persistent LDF decline to about 20-30% of baseline and led to reproducible infarcts covering the entire MCA territory. The method establishes a clinically relevant, reproducible stroke model for the study of molecular mechanisms of ischemic brain injury in genetically engineered mice.

Animals↗

PubMed1998

Effects of a traumatic neocortical lesion on cerebral metabolism and gene expression of rats.

The effects of a traumatic neocortical lesion, induced by transcranial cold injury, on brain metabolism and gene expression were examined. The surrounding of the lesions was characterized by increased glucose and lactate levels without major disturbances of protein synthesis or energy state. A transient pH decrease by 0.4 units was noticed 1 h post-injury, which shifted towards alkaline values by 3 h. The metabolic disturbances did not differ between injured animals with spontaneous spreading depressions (SD, n = 14) and those without SD (n = 7). In SD animals, c-fos mRNA was strongly elevated in the injury-remote cortex, but hsp72 mRNA was not enhanced. Thus, in contrast to focal ischemia, the metabolic dysfunction around traumatic cortical lesions is not aggravated by SD.

Adenosine Triphosphate↗

PubMed1998

Differences in the cerebrovascular anatomy of C57black/6 and SV129 mice.

The vascular architecture of the brain of C57Black/6 and SV129 mice was studied following microvascular injection of carbon black stained latex. The dorsal brain surface was photographed to determine the number, diameter, and position of pial anastomotic vessels between the middle and anterior cerebral arteries. The mean number and diameter of anastomoses were not significantly different, but the line of anastomoses interconnecting the half way points of anastomotic vessels was located significantly closer to the midline in C57Black/6 mice, demonstrating that the middle cerebral artery had a larger vascular supplying territory than in SV129 mice. This explains the larger infarct volume previously reported in C57Black/6 mice, and raises concerns about the use of C57Black/6 and SV129 mice as parent strains for genetically modified animals in stroke research.

Animals↗

PubMed1998

Effects of a traumatic neocortical lesion on cerebral metabolism and gene expression of rats.

The effects of a traumatic neocortical lesions, induced by transcranial cold injury, on brain metabolism and gene expression were examined. The surrounding of the lesions was characterized by increased glucose and lactate levels without major disturbances of protein synthesis or energy state. A transient pH decrease by 0.4 units was noticed 1 h post-injury, which shifted towards alkaline values by 3 h. The metabolic disturbances did not differ between injured animals with spontaneous spreading depressions (SD, n = 14) and those without SD (n = 7). In SD animals, c-fos mRNA was strongly elevated in the injury-remote cortex, but hsp72 mRNA was not enhanced. Thus, in contrast to focal ischemia, the metabolic dysfunction around traumatic cortical lesions is not aggravated by SD.

Adenosine Triphosphate↗