Biomedical subjects

Dirk M Hermann

Publications and source records attributed to Dirk M Hermann.

27 records · Page 2Linked to original sources

PubMed2004

VEGF overexpression induces post-ischaemic neuroprotection, but facilitates haemodynamic steal phenomena.

Therapeutic angiogenesis with vascular endothelial growth factor (VEGF) is a clinically promising strategy in ischaemic disease. The pathophysiological consequences of enhanced vessel formation, however, are poorly understood. We established mice overexpressing human VEGF165 under a neuron-specific promoter, which exhibited an increased density of brain vessels under physiological conditions and enhanced angiogenesis after brain ischaemia. Following transient intraluminal middle cerebral artery (MCA) occlusions, VEGF overexpression significantly alleviated neurological deficits and infarct volume, and reduced disseminated neuronal injury and caspase-3 activity, confirming earlier observations that VEGF has neuroprotective properties. Brain swelling was not influenced in VEGF-overexpressing animals, while sodium fluorescein extravasation was moderately increased, suggesting that VEGF induces a mild blood-brain barrier leakage. To elucidate whether enhanced angiogenesis improves regional cerebral blood flow in the ischaemic brain, [14C]iodoantipyrine autoradiography was performed. Autoradiographies revealed that VEGF induces haemodynamic steal phenomena with reduced blood flow in ischaemic areas and increased flow values only outside the MCA territory. Our data demonstrate that VEGF protects neurons from ischaemic cell death by a direct action rather than by promoting angiogenesis, and suggest that strategies aiming at increasing vascular density in the whole brain, e.g. by VEGF overexpression, may worsen rather than improve cerebral haemodynamics after stroke.

Animals↗

PubMed2004

Intravenously administered recombinant tissue-plasminogen activator attenuates neuronal injury after mild focal cerebral ischemia in mice.

Recombinant tissue-plasminogen activator (t-PA) increases brain injury after focal ischemias leading to overt tissue infarcts. The question arose, whether t-PA may also be detrimental after mild ischemias. To clarify this issue, we submitted mice to 30 min intraluminal thread occlusions and administered normal saline or t-PA (10 mg/kg, i.v.) after reperfusion onset. Thread occlusions resulted in reproducible ischemias, followed by hyperperfusion reactions immediately after thread withdrawal. Post-ischemic LDF did not differ between saline- and t-PA-treated animals. In contrast to earlier studies, where t-PA exacerbated injury, t-PA treatment did not increase, but attenuated disseminate neuronal death in the striatum, as shown by cresyl violet, TUNEL and activated caspase-3 staining 1 and 3 days after the ischemic event (p < 0.05). Our data argue against major detrimental actions of t-PA after mild focal ischemia.

Animals↗

PubMed2004

Melatonin reduces disseminate neuronal death after mild focal ischemia in mice via inhibition of caspase-3 and is suitable as an add-on treatment to tissue-plasminogen activator.

The effects of i.p. melatonin (4 + 4 mg/kg, after induction of ischemia and at reperfusion onset) administered either alone or in combination with the thrombolytic tissue-plasminogen activator (t-PA, 10 mg/kg), on cerebral laser Doppler flow (LDF) and ischemic injury were studied after 30 min of middle cerebral artery (MCA) thread occlusion in male C57BL/6 mice. Thread occlusions resulted in reproducible focal ischemias, followed by hyperperfusion reactions immediately after thread withdrawal, as revealed by LDF measurements. Compared with animals receiving normal saline (peak LDF after reperfusion: 172.0 +/- 24.2%), postischemic LDF was significantly attenuated in animals treated with melatonin (105.1 +/- 6.7%, P < 0.05). Delivery of t-PA (132.8 +/- 22.3%) or t-PA plus melatonin (164.7 +/- 36.7%), on the contrary, did not influence postischemic LDF recordings. Twenty-four hours after reperfusion, melatonin treated mice had significantly increased neuronal survival and decreased disseminate cell injury in the ischemia-vulnerable striatum, as investigated by cresyl violet and terminal transferase biotinylated-dUTP nick end labeling stainings. The protective effects were associated with inhibition of caspase-3 activity. Melatonin administration also increased neuronal survival after 30 min MCA occlusion in animals treated with t-PA, although t-PA itself already decreased the degree of injury in a significant manner. Our data demonstrate that melatonin reduces disseminated neuronal injury in the striatum after mild focal ischemia. Brain protection is independent of hemodynamic changes and involves inhibition of caspase-3.

Animals↗

PubMed2004

Prophylactic use of melatonin protects against focal cerebral ischemia in mice: role of endothelin converting enzyme-1.

Melatonin has previously been shown to be neuroprotective in rodent models of ischemic stroke. Herein, we tested whether this antioxidant may also be suitable for prophylactic use against stroke. To clarify this issue, melatonin was administrated orally for 9 wk (4 mg/kg/day) in mice and its effects on subsequent injury development after 90 min of intraluminal middle cerebral artery (MCA) occlusion were tested. To evaluate its neuroprotective properties, the protective actions of prophylactic melatonin were compared with both acute melatonin (4 mg/kg, i.p.) administration and with a diluent (sham)-treated control condition. MCA occlusion resulted in reproducible ischemia, as revealed by laser Doppler flowmetry; this was followed by a rapid restoration of blood flow immediately after reperfusion onset. Laser Doppler flow values after reperfusion onset were moderately elevated by melatonin, both when the indole was given prophylactically and when acutely administrated after stroke. In control animals, reproducible brain infarcts were observed 24 hr after reperfusion onset. Treatment with melatonin significantly reduced the infarct size by approximately 30-35%, independent of whether the indole was given prophylactically before or acutely after ischemia. To test whether brain protection involved vascular mechanisms, as suggested earlier, the effects of melatonin on endothelin converting enzyme-1 (ECE-1) levels were studied using Western blots. Interestingly, delivery of melatonin was accompanied by a marked inhibition of ECE-1 levels, which was similarly seen after both acute and chronic melatonin treatment. Our data suggest that melatonin, given at pharmacological doses, may be suitable as a prophylaxis against stroke. Tissue protection may involve an inhibition of ECE-1, which improves vasodilation, after ischemia.

Animals↗

PubMed2004

Uptake of 18F-fluorocholine, 18F-fluoroethyl-L-tyrosine, and 18F-FDG in acute cerebral radiation injury in the rat: implications for separation of radiation necrosis from tumor recurrence.

UNLABELLED: Differentiation between posttherapy radiation necrosis and recurrent tumor in humans with brain tumor is still a difficult diagnostic task. The new PET tracers (18)F-fluoro-ethyl-l-tyrosine (FET) and (18)F-fluorocholine (N,N-dimethyl-N-(18)F-fluoromethyl-2-hydroxyethylammonium [FCH]) have shown promise for improving diagnostic accuracy. This study assessed uptake of these tracers in experimental radiation injury. METHODS: In a first model, circumscribed lesions were induced in the cortex of 35 rats using proton irradiation of 150 or 250 Gy. After radiation injury developed, uptake of (18)F-FET, (18)F-FCH, and (18)F-FDG was measured using autoradiography and correlated with histology and disruption of the blood-brain barrier as determined with Evans blue. In a second model, uptake of the tracers was assessed in acute cryolesions, which are characterized by the absence of inflammatory cells. RESULTS: Mean (18)F-FET, (18)F-FCH, and (18)F-FDG standardized uptake values in the most active part of the radiation lesion and the contralateral normal cortex (in parentheses) were 2.27 +/- 0.46 (1.42 +/- 0.23), 2.52 +/- 0.42 (0.61 +/- 0.12), and 6.21 +/- 1.19 (4.35 +/- 0.47). The degree of uptake of (18)F-FCH and (18)F-FDG correlated with the density of macrophages. In cryolesions, (18)F-FET uptake was similar to that in radiation lesions, and (18)F-FCH uptake was significantly reduced. CONCLUSION: Comparison of tracer accumulation in cryolesions and radiation injuries demonstrates that (18)F-FET uptake is most likely due to a disruption of the blood-brain barrier alone, whereas (18)F-FCH is additionally trapped by macrophages. Uptake of both tracers in the radiation injuries is generally lower than the published uptake in tumors, suggesting that (18)F-FET and (18)F-FCH are promising tracers for separating radiation necrosis from tumor recurrence. However, the comparability of our data with the literature is limited by factors such as different species and acquisition protocols and modalities. Thus, more studies are needed to settle this issue. Nevertheless, (18)F-FCH and (18)F-FET seem superior to (18)F-FDG for this purpose.

Acute Disease↗

PubMed2003

Sleep-disordered breathing and stroke.

PURPOSE OF REVIEW: A growing number of studies suggest that there is a close relationship between sleep-disordered breathing (SDB) and stroke. Since the prevalence of SDB is high among acute stroke patients and since oxygen desaturations are potentially dangerous, SDB may influence not only stroke risk, but also stroke outcome and recurrence. This review summarizes recent data on this issue, pointing out existing evidence but also defining issues that still need to be clarified. RECENT FINDINGS: Recent studies further supported the hypothesis of a link between SDB and stroke: (1) although stroke occurs most frequently in the morning hours, i.e. shortly after awakening, stroke events take place predominantly during sleep in SDB patients; (2) a large cross-sectional study confirmed the association of SDB not only with coronary heart disease but also with stroke; (3) several works suggest that SDB may increase stroke risk through various mechanisms including blood pressure swings, endothelial dysfunctions, prothrombotic coagulation shifts, pro-inflammatory states, increased platelet aggregation and atherosclerosis; (4) one study in acute stroke patients demonstrated that SDB is associated with early neurological worsening although not with final stroke outcome; (5) treatment trials with continuous positive airway pressure (CPAP) have demonstrated mild reductions of diastolic and systolic blood pressure in SDB patients, an effect that is expected, however unproven, to decrease stroke risk. SUMMARY: Despite considerable progress regarding our understanding about the role of SDB in vascular disease, further studies are needed to determine whether cerebrovascular morbidity is related to SDB independent of associated vascular risk factors, whether SDB has indeed a negative impact on stroke progression and whether CPAP treatment ameliorates stroke outcome.

Cerebral Infarction↗

PubMed2002

Intravenous TAT-Bcl-Xl is protective after middle cerebral artery occlusion in mice.

The delivery of proteins across the blood-brain barrier is severely limited by the proteins' size and biochemical properties. Eleven-amino acid human immunodeficiency virus TAT protein is able to cross cell membranes even when coupled with larger peptides. We evaluated whether TAT-Bcl-X(L) fusion protein is protective in focal ischemia. Mice underwent 30 or 90 minutes of intraluminal middle cerebral artery thread occlusion. TAT-Bcl-X(L), TAT-beta-galactosidase, or TAT-GFP (0.6 nmol each) were applied intravenously over 10 minutes either 1 hour before or immediately after ischemia. Additional animals received no TAT protein infusions. We show that the brain tissue is progressively transduced with TAT proteins within 3 to 4 hours after intravenous delivery. We provide evidence that TAT-Bcl-X(L) treatment reduces infarct volume and neurological deficits after long ischemic insults lasting 90 minutes, when applied both before and after ischemia. After short insults, lasting only 30 minutes, TAT-Bcl-X(L) further diminishes the number of caspase-3-reactive and DNA fragmented cells and increases the number of viable neurons in the striatum. Our results indicate that TAT fusion proteins are elegant and powerful tools that might be of clinical interest for stroke treatment, because factors may be intravenously applied. Thus, fusion proteins may open fascinating perspectives for future research.

Animals↗

PubMed2002

Adenovirus-mediated Bcl-X(L) expression using a neuron-specific synapsin-1 promoter protects against disseminated neuronal injury and brain infarction following focal cerebral ischemia in mice.

The effects of an adenovirus-mediated Bcl-X(L) expression, driven by a neuron-specific human synapsin-1 promoter, on the degree of injury, were examined after transient focal ischemia in mice. Therefore, injections of vehicle, of an adenoviral E1-deleted control vector (Ad-dE1), or a Bcl-X(L) vector (Ad-Syn-Bcl-X(L)) were stereotactically made in the striatum. Seven days later, focal ischemia was induced either by 30 min or 2 h of intraluminal thread occlusion. In line with previous data, 30 min of middle cerebral artery (MCA) occlusion reproducibly resulted in disseminated neuronal injury of the striatum, as revealed by cresyl violet and TUNEL 3 days after ischemia. The degree of cell injury was significantly reduced in Ad-Syn-Bcl-X(L) treated as compared with Ad-dE1 and vehicle-treated animals. On the other hand, 2 h of MCA occlusion produced reproducible infarcts both in vehicle and Ad-dE1 treated animals 24 h after ischemia. The infarct area at the level of the striatum was significantly decreased by Ad-Syn-Bcl-X(L) treatment. The present data demonstrate that an adenoviral Bcl-X(L) expression with a neuron-specific synapsin-1 promoter provides a powerful tool, which not only diminishes disseminated neuronal injury, but also protects against tissue infarction.

Adenoviridae↗

PubMed2002

Effects of pinealectomy and melatonin on the retrograde degeneration of retinal ganglion cells in a novel model of intraorbital optic nerve transection in mice.

The effects of pinealectomy and of intraperitoneally administered melatonin on the retrograde degeneration of retinal ganglion cells (RGCs) were examined in a novel model of optic nerve (ON) transection in C57BL/16J mice. RGCs were prelabeled with the fluorescent tracer 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate (Di-I), and the ON was cut inside the orbital cavity 7 days later. The degree of RGC injury was assessed by counting viable Di-I labeled RGCs in various locations of the retina. In unlesioned control eyes, a mean ganglion cell density of 1,891 +/- 30/mm2 (mean +/- S.E.M.) was determined. The cell density markedly declined at 14 days after axotomy (295 +/- 9 cells/mm2; 15.6% of contralateral). Sham-pinealectomy did not influence the density of RGCs at 14 days after ON transection (382 +/- 37 cells/mm2). In pinealectomized animals, on the other hand, the RGC number was significantly reduced as compared with untreated and sham-pinealectomized animals (91 +/- 33 RGCs/mm2). The effect of pinealectomy was reversed after i.p. administration of melatonin (4 mg/kg bw bolus followed by continuous infusion of 8 mg/kg bw/day) (286 +/- 27 cells/mm2). In nonpinealectomized animals, on the contrary, i.p. melatonin did not influence the RGC density (344 +/- 20 cells/mm2). The present results suggest that endogenous melatonin prevents the delayed degeneration of adult central nervous system (CNS) neurons in vivo, and that exogenous substitution of melatonin may be useful to protect injured neurons against cell death under conditions of melatonin deficiency, e.g. in the aged brain, when melatonin synthesis and secretion have decreased.

Animals↗