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Biomedical subjects

Harald D Müller

Publications and source records attributed to Harald D Müller.

7 recordsLinked to original sources
PubMed2006

Neuroprotective cannabinoid receptor antagonist SR141716A prevents downregulation of excitotoxic NMDA receptors in the ischemic penumbra.

Whether cannabinoids act as neuroprotectants or, on the contrary, even worsen neuronal damage after cerebral ischemia is currently under discussion. We have previously shown that treatment with the cannabinoid (CB1) receptor antagonist SR141716A reduces infarct volume by approximately 40% after experimental stroke. Since it is suggested that SR141716A may exert neuroprotection besides its cannabinoid receptor-blocking effect, we addressed the question whether SR141716A may act via modulation of postischemic ligand binding to excitatory NMDA and/or alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptors. For this purpose, rats (n = 12) were treated with either intravenous saline (control) or CB1 receptor antagonist SR141716A (1 mg/kg) 30 min after permanent middle cerebral artery occlusion. Five hours after ischemia, quantitative receptor autoradiography was performed using [(3)H]CP 55,940, [(3)H]MK-801, and [(3)H]AMPA for labeling of CB1, NMDA, and AMPA receptors, respectively. Ligand binding was analyzed within the infarct core, cortical penumbra, and corresponding areas of the contralateral hemisphere and compared to that of sham-operated rats (n = 5). Both in ischemic controls and SR141716A-treated rats [(3)H]CP 55,940 ligand binding was not specifically regulated in the cortical penumbra or contralateral cortex. Importantly, reduced infarct volumes in SR141716A-treated rats were associated with maintained [(3)H]MK-801 binding to excitotoxic NMDA receptors in the penumbra, compared to a decrease in the control group. In summary, our data suggest that SR141716A may possess additional intrinsic neuroprotective properties independent of receptor-coupled pathways or due to action as a partial agonist.

Animals↗
PubMed2006

Protein aggregate myopathies.

Protein aggregate myopathies (PAMs) based on the morphologic phenomenon of aggregation of proteins within muscle fibers may occur in children (selenoproteinopathies, actinopathies, and myosinopathies) or adults (certain myofibrillar myopathies and myosinopathies). They may be mutation related, which includes virtually all childhood forms but certain other forms as well, or sporadic, which are largely seen in adults. Their classification as myofibrillar or desmin-related myopathies, actinopathies, or myosinopathies is based on the identification of respective mutant proteins, most of them components of the sarcomeres. Recognition of PAM requires muscle biopsy and an extensive immunohistochemical and electron microscopic workup of the biopsied muscle tissue after which molecular analysis of morphologically ascertained proteins should ensue to permit recognition of individual entities and genetic counseling of patients and families. Because pathogenetic principles in PAMs are still incompletely known, causative therapy, at this time, is not available.

Animals↗
PubMed2005

Short-term ischemia usually used for ischemic preconditioning down-regulates central cannabinoid receptors in the gerbil hippocampus.

Transient forebrain ischemia of 5-min duration causes delayed neuronal death (DND) of vulnerable CA1 neurons in the gerbil hippocampus, which can be prevented by "preconditioning" with a short ischemic stimulus of 2.5-min duration. While a key role of excitatory glutamate receptors for both phenomena has been widely accepted, little is known about the postischemic regulation of central cannabinoid (CB1) receptors. The present study was designed to test whether ischemic preconditioning is associated with specific alterations of protein expression and/or ligand binding of these receptors compared to ischemia severe enough to induce DND. Gerbils were subjected to either a 5-min ischemic period resulting in DND of CA1 neurons, or a 2.5-min period of ischemia usually used for preconditioning. Postischemic hippocampal CB1 receptor protein expression was investigated immunohistochemically, while postischemic ligand binding of [3H]CP 55940 to CB1 receptors was analyzed by quantitative receptor autoradiography in both experimental groups after 24, 48, and 96 h (n=4-5 per time point), respectively, and compared to sham-treated gerbils (n=10). Short-term ischemia of 2.5-min duration caused a transient reduction of hippocampal CB1 receptor protein expression, while receptor binding density was permanently decreased. In contrast, 5-min ischemia did not alter protein expression or ligand binding up to 48 h. Based on these data, postischemic down-regulation of hippocampal CB1 receptors, specifically seen after short-term ischemia usually used for preconditioning, may participate in the mechanisms of endogenous postischemic neuroprotection.

Animals↗
PubMed2005

Minor inflammation after surgical evacuation compared with fibrinolytic therapy of experimental intracerebral hemorrhages.

OBJECTIVES: Toxic components released from the intracerebral blood clot, such as thrombin and hemoglobin, potentially trigger brain edema formation and therefore favor an early evacuation of the clot. Despite a significant reduction in hematoma size in our porcine model of hematoma induction by injecting autologous blood ICP-controlled into the right frontal white matter with subsequent fibrinolysis using recombinant tissue-plasminogen activator (rt-PA) and aspiration of the liquefied clot (n = 9), local rt-PA promoted delayed perihematomatous edema formation and invoked a substantial inflammatory reaction compared with controls (n = 11). METHODS: We therefore modified our formerly developed porcine model of intracerebral hemorrhage in removing the hematoma by open craniotomy and suction of the clot in seven animals. The residual hematoma size and extent of perifocal edema were evaluated over 10 days on planimetry of the MRI data, and correlated to the histopathological changes of edema and inflammation found at autopsy. RESULTS: The edema volume on day 4 was significantly less in the surgical group compared with the lysis group (p < 0.03). On day 10, however, the difference in edema size was not statistically significant compared with the lysis group (p < 0.07) and the control group (p < 0.09). The inflammatory response was minor compared with the lysis and control group. DISCUSSION: In conclusion, despite a significant reduction in hematoma size by surgical removal of the clot, only the inflammatory response, but not the extent of delayed edema can be positively influenced.

Analysis of Variance↗
PubMed2003

The long-term effect of recombinant tissue-plasminogen-activator (rt-PA) on edema formation in a large-animal model of intracerebral hemorrhage.

Hematoma puncture, fibrinolysis, and aspiration of the liquefied clot is a promising new treatment strategy for large intracerebral hemorrhages (ICH). Characteristics of the cellular injury and neuronal and glial cell death associated with ICH and the administration of fibrinolytic agents still need to be defined. We developed a porcine model to study the histopathological effects of recombinant tissue-Plasminogen-Activator (rt-PA) on perihematomatous cell integrity. In 20 pigs, lobar hematomas were induced by intracranial pressure (ICP)-controlled injections of 7.6 +/- 1.6 ml of autologous blood into the white matter of the right frontal hemisphere. In nine animals, the clots were lysed with rt-PA, thereby facilitating aspiration 2 h after hematoma induction. In 11 control pigs, the hematoma resorption followed its natural course. The rate of hematoma reduction and edema formation over 10 days was evaluated on planimetry of the MRI data and correlated to the histopathological changes found at autopsy. Although rt-PA significantly accelerated clot resolution compared to controls (p < 0.02), the increase of perihematomatous edema volume within 10 days was not significantly ameliorated in rt-PA-treated animals compared to controls on MRI. The extent of inflammatory infiltrates on histology was more pronounced in animals treated with rt-PA. In conclusion, despite significant reduction in the size of the hematoma clot liquefication with rt-PA and aspiration invokes a substantial inflammatory response when studied after 10 days and does not result in a reduction of the perihematomatous edema.

Animals↗
PubMed2002

Fibrinolysis therapy achieved with tissue plasminogen activator and aspiration of the liquefied clot after experimental intracerebral hemorrhage: rapid reduction in hematoma volume but intensification of delayed edema formation.

OBJECT: Fibrinolysis therapy accomplished using tissue plasminogen activator (tPA) and aspiration is considered to be a viable alternative to microsurgery and medical therapy for the treatment of deep-seated spontaneous intracerebral hematomas (SICHs). Tissue plasminogen activator is a mediator of thrombin- and ischemia-related delayed edema. Because both thrombin release and ischemia occur after SICH, the authors planned to investigate the effect of fibrinolytic therapy on hematoma and delayed edema volume. METHODS: A spherical hematoma was created in the frontal white matter of 18 pigs. In the tPA-treated group (nine pigs), a mean of 1.55 ml tPA was injected into the clot and the resulting liquefied blood was aspirated. Magnetic resonance (MR) imaging was performed on Days 0 (after surgery), 4, and 10, and the volumes of hematoma and edema were determined. In the animals not treated with tPA (untreated group; nine pigs), the volume of hematoma dropped from 1.43+/-0.42 ml on Day 0 to 0.85+/-0.28 ml on Day 10. In the tPA-treated group, the volume of hematoma was reduced from 1.51 +/- 0.28 ml on Day 0 to 0.52 +/- 0.39 ml on Day 10. In comparison with the untreated group, the reduction in hematoma volume was significantly accelerated (p = 0.02). In the untreated group, perihematomal edema increased from 0.32 +/- 0.61 ml to 1.73 +/- 0.73 ml on Day 4, before dropping to 1.17 +/- 0.92 ml on Day 10. In the tPA-treated group, the volume of the edema increased from 0.09 +/- 0.21 ml on Day 0 to 1.93 +/- 0.79 ml on Day 4, and further to 3.34 +/- 3.21 ml on Day 10. The increase in edema volume was significantly more pronounced in the tPA-treated group (p = 0.04). CONCLUSIONS: Despite a significantly accelerated reduction in hematoma volume, the development of delayed perifocal edema was intensified by fibrinolytic therapy, which is probably related to the function of tPA as a mediator of edema formation after thrombin release and ischemia. Further experimental and clinical investigations are required to establish the future role of fibrinolysis in the management of SICH.

Animals↗