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Biomedical subjects

U Dirnagl

Publications and source records attributed to U Dirnagl.

At least 91 records · Page 5Linked to original sources
PubMed1997

Heparin inhibits leukocyte rolling in pial vessels and attenuates inflammatory changes in a rat model of experimental bacterial meningitis.

Heparin is a natural proteoglycan that was first described in 1916. In addition to its well characterized effect on blood coagulation, it is becoming clear that heparin also modulates inflammatory processes on several levels, including the interference with leukocyte-endothelium interaction. Anecdotal observations suggest a better clinical outcome of heparin-treated patients with bacterial meningitis. The authors demonstrate that heparin, a glycosaminoglycan, inhibits significantly in the early phase of experimental pneumococcal meningitis the increase of 1) regional cerebral blood flow (125 +/- 18 versus 247 +/- 42%), 2) intracranial pressure (4.5 +/- 2.0 versus 12.1 +/- 2.2 mm Hg), 3) brain edema (brain water content: 78.23 +/- 0.33 versus 79.49 +/- 0.46%), and 4) influx of leukocytes (571 +/- 397 versus 2400 +/- 875 cells/microL) to the cerebrospinal fluid compared with untreated rats. To elucidate the possible mechanism of this observation, the authors investigated for the first time leukocyte rolling in an inflammatory model in brain venules by confocal laser scanning microscopy in vivo. Heparin significantly attenuates leukocyte rolling at 2, 3, and 4 hours (2.8 +/- 1.3 versus 7.9 +/- 3.2/100 microm/min), as well as leukocyte sticking at 4 hours (2.1 +/- 0.4 versus 3.5 +/- 1.0/100 microm/min) after meningitis induction compared with untreated animals. The authors conclude that heparin can modulate acute central nervous system inflammation and, in particular, leukocyte-endothelium interaction, a key process in the cascade of injury in bacterial meningitis. They propose to evaluate further the potential of heparin in central nervous system inflammation in basic and clinical studies.

Animals↗
PubMed1997

Laminar analysis of cerebral blood flow in cortex of rats by laser-Doppler flowmetry: a pilot study.

Laser-Doppler flowmetry (LDF) is a reliable method for estimation of relative changes of CBF. The measurement depth depends on wavelength of the laser light and the separation distance of transmitting and recording optical fibers. We designed an LDF probe using two wavelengths of laser light (543 nm and 780 nm), and three separation distances of optical fibers to measure CBF in four layers of the cerebral cortex at the same time. In vitro comparison with electromagnetic flow measurements showed linear relationship between LDF and blood flow velocity at four depths within the range relevant to physiologic measurements. Using artificial brain tissue slices we showed that the signal for each channel decreased in a theoretically predictable fashion as a function of slice thickness. Application of adenosine at various depths in neocortex of halothane-anesthetized rats showed a predominant CBF increase at the level of application. Electrical stimulation at the surface of the cerebellar cortex demonstrated superficial predominance of increased CBF as predicted from the distribution of neuronal activity. In the cerebellum, hypercapnia increased CBF in a heterogeneous fashion, the major increase being at apparent depths of approximately 300 and 600 microns, whereas in the cerebral cortex, hypercapnia induced a uniform increase. In contrast, the CBF response to cortical spreading depression in the cerebral cortex was markedly heterogeneous. Thus, real-time laminar analysis of CBF with spatial resolution of 200 to 300 microns may be achieved by LDF. The real-time in depth resolution may give insight into the functional organization of the cortical microcirculation and adaptive features of CBF regulation in response to physiologic and pathophysiologic stimuli.

Animals↗
PubMed1997

Assessment of local brain activation. A simultaneous PET and near-infrared spectroscopy study.

In five healthy human subjects, near-infrared spectroscopy (NIRS) and positron emission tomography (PET) examinations were performed simultaneously. Changes in [oxy-Hb], [deoxy-Hb] and [total-Hb] as measured by NIRS over the left forehead were compared to measurements of cerebral blood flow by PET during rest and during performance of a calculation task and a Stroop task. When a penetration depth of near-infrared light 0.9 cm into the brain cortex was assumed, a statistically significant correlation between changes in CBF and changes in [total-Hb] was found. These data confirm the validity of NIRS measurements in human adults.

Aged↗
PubMed1996

Nitric oxide synthase inhibition does not affect somatosensory evoked potentials in the rat.

Nitric oxide synthase (NOS) inhibition reduces the regional cerebral blood flow (rCBF) responses to somatosensory stimulation. It is controversial whether this is caused by a signalling role of nitric oxide (NO) between neurons and vascular smooth muscle, or by effects of NOS inhibition on neuronal activity. We here report that more than 85% inhibition of NOS activity by topical application of the NOS inhibitor N omega-nitro-L-arginine (L-NNA) for 2 h does not affect somatosensory evoked potentials (SEPs) elicited by vibrissal deflection or electrical forepaw stimulation in choloralose anaesthetised rats equipped with a closed cranial window, whereas cerebral blood flow (CBF) responses due to these stimulation paradigms are reduced by approximately 60%. We conclude that the decrease of the regional vascular response to increased neuronal activity during NOS inhibition is not caused by a suppression of neuronal activity.

Animals↗
PubMed1996

Non-invasive functional mapping of the human motor cortex using near-infrared spectroscopy.

We applied non-invasive multisite near-infrared spectroscopy (NIRS) to assess oxygenation changes during performance of a sequential finger opposition task in five healthy human adults. Oxygenation response was localized anatomically using three-dimensional high-resolution magnetic resonance imaging (3D MRI). NIRS measurements showed a localized increase in [oxy-Hb] and a decrease in [deoxy-Hb] in all subjects. The largest response was obtained when the measurement position was over the primary motor and sensory cortex hand area. Interestingly, changes in [deoxy-Hb] seemed to be more localized than changes in [oxy-Hb]. We conclude that this simple, non-invasive and flexible optical bedside method may be used for functional brain mapping.

Adult↗
PubMed1996

Near infrared spectroscopy in the diagnosis of Alzheimer's disease.

Near infrared spectroscopy (NIRS) is a new technique that permits noninvasive monitoring of cerebral blood and tissue oxygenation. Recently, we and others have shown that NIRS measurements are sensitive enough to follow changes in cerebral hemoglobin oxygenation due to activation of brain function. Based on these findings we have assessed the influence of aging as well as the influence of neurodegeneration on cerebral hemoglobin oxygenation during mental work. The typical NIRS pattern in young healthy subjects while performing calculation tasks measured in the frontal cortex were increases in oxygenated hemoglobin [HbO2] and total hemoglobin [HbT] while reduced hemoglobin [HbR] decreased. Elderly healthy subjects showed a significant lower mean increase in [HbO2] and [HbT] levels. Regression analysis revealed an age-dependent decline in activation-induced local increase of [HbO2] as well as [HbT]. Furthermore, we monitored changes in cerebral hemoglobin oxygenation in the frontal cortex while patients with probable Alzheimer's disease (AD) performed cognitive tasks. Whereas elderly healthy subjects (as well as patients with major depression, age-associated memory impairments or vascular dementia) again showed clear increases in the local concentrations of [HbO2] and [HbT] during brain activation, AD patients showed significant decreases compared to the baseline levels in both variables that were most pronounced in the parietal cortex. To clarify whether the different patterns in cerebral hemoglobin oxygenation during cognitive activation were due to an altered functional brain organization in AD or to alterations in the cerebrovascular response to neuronal activation, we are currently performing simultaneous NIRS and (015-H20-)PET measurements during performance of a cognitive task (Stroop test). Our finding of a regional reduced oxygen supply during activation of brain function may be of relevance to the development and the time course of neurodegeneration.

Aging↗
PubMed1996

Pneumococcal cell wall components induce nitric oxide synthase and TNF-alpha in astroglial-enriched cultures.

Astroglia and microglia, the most numerous cells in the central nervous system (CNS), have been shown to produce the inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) upon stimulation with the cytokines IFN-gamma, IL-1-beta, or bacterial lipopolysaccharides (LPS). However, it is not known whether gram-positive bacteria like Streptococcus pneumoniae cause astroglial cells to release nitric oxide (NO) and TNF-alpha. S. pneumoniae meningitis still has a high incidence and mortality in spite of antibiotic therapy. Cell wall components from S. pneumoniae (pneumococcal cell-wall components, PCW) and TNF-alpha have been shown to cause meningeal inflammation and cerebrovascular changes in experimental meningitis. Addition of PCW to cultured rat astroglial cells increased nitrite in the supernatant significantly after 24 h, from 17 +/- 21 to 133 +/- 62 nM/micrograms protein. Nitrite release was dose-dependent in a range shown to cause meningeal inflammation in vivo and was inhibited by the competitive NO synthase inhibitor NW-nitro-L-arginine (L-NA 10(-4 M)) and dexamethasone (10(-6 M)), with transcriptional and translational inhibition by actinomycin D and cycloheximide, respectively. PCW caused a significant increase in the release of TNF-alpha from astroglial cells after 4 h, from 2 +/- 3.5 pg/ml to 102 +/- 13.5 pg/ml, which was inhibited by dexamethasone (10(-6 M)). Our results suggest a role for astroglial-derived NO and TNF-alpha as mediators of vascular and inflammatory response in the early phase of experimental pneumococcal meningitis.

Animals↗
PubMed1996

Simultaneous recording of cerebral blood oxygenation changes during human brain activation by magnetic resonance imaging and near-infrared spectroscopy.

Changes in cerebral blood oxygenation due to functional activation of the primary sensorimotor cortex during a unilateral finger opposition task were simultaneously mapped by deoxyhemoglobin-sensitive magnetic resonance imaging (MRI) and monitored by near-infrared spectroscopy (NIRS). Activation foci along the contralateral central sulcus displayed task-associated increases in MRI signal intensity, indicating a concomitant decrease of the focal concentration of deoxyhemoglobin. This interpretation was confirmed by simultaneous reductions in deoxyhemoglobin measured optically. Since observation of the latter effect required exact spatial matching of the MRI-detected activation foci and position of the fiber optic bundles ("optodes") used for transmitting and receiving light, it may be concluded that optical recordings of changes in deoxyhemoglobin during functional challenge probe only a restricted brain tissue region. While deoxyhemoglobin responses seen by NIRS were smaller for ipsi- than for contralateral finger movements, task-related increases in oxyhemoglobin were rather similar between both conditions and, thus, seem to be less specific. Furthermore, no consistent changes were obtained for total hemoglobin during task performance, possibly due to the short timing of the repetitive protocol. In general, results underline, in humans, the hitherto assumed signal physiology for functional brain mapping by oxygenation-sensitive MRI and allow assessment of both constraints and practicability of functional studies by NIRS.

Adult↗
PubMed1996

Systemic nitric oxide synthase inhibition does not affect brain oxygenation during cortical spreading depression in rats: a noninvasive near-infrared spectroscopy and laser-Doppler flowmetry study.

Cortical spreading depression (CSD) has been implicated in the migraine aura and in stroke. This study demonstrates near-infrared spectroscopy (NIRS) for the first time as capable of noninvasive on-line detection of CSD in the pentobarbital-anesthetized rat. CSD was accompanied by a brief and rapid increase of regional CBF (by laser-Doppler flowmetry) to 200-400% baseline. NIRS demonstrates that this hyperperfusion is associated with concentration increases of oxyhemoglobin, while deoxyhemoglobin decreases. Simultaneously, oxygen partial pressure, measured on the brain surface with a solid-state polarographic probe, was shown to be raised by at least 14 mm Hg during CSD. Oxygen-dependent phosphorescence life-time quenching measurements confirmed this finding. NIRS data on cytochrome aa3, however, showed a CSD-related shift toward a more reduced state, despite raised blood oxygenation. This may suggest either limited O2 transport from the blood to mitochondria or decreased oxygen utilization during CSD as supposed by theories about compartmentalization of energy metabolism favoring glycolytic rather than aerobic energy supply during CSD. However, the data on cytochrome aa3 warrant caution and are discussed critically. Nitric oxide synthase inhibition by systemic application of N'-nitro-L-arginine had no significant effect on the perfusion response or the tissue PO2 during CSD. During most CSD episodes, a brief decrease in MABP by 4-8 mm Hg was noted that might be caused by functional decortication during CSD.

Animals↗
PubMed1996

Role of nitric oxide synthase inhibition in leukocyte-endothelium interaction in the rat pial microvasculature.

We investigated the role of nitric oxide (NO) in leukocyte-endothelium interaction, blood-brain barrier (BBB) function and oxygen free-radical production in the rat pial microcirculation. In a closed cranial window preparation (dura removed) over the parietal cortex of pentobarbital-anesthetized Wistar rats, NO synthase (NOS) was inhibited by systemic and/or topical application of N omega-nitro-L-arginine (L-NNA) under physiological conditions and during leukotriene B4 (LTB4) activation. Circulating leukocytes were labeled by intravenous injection of rhodamine 6G. We used a confocal laser scanning microscope (CLSM) and studied leukocyte rolling and sticking in pial veins and arteries before and after NOS inhibition. At the end of the experiments, sodium-fluorescein was injected intravenously to test BBB integrity. Brain cortex oxygen free-radical production was investigated in the cranial window preparation using lucigenin-enhanced chemiluminescence (CL). L-NNA application did not lead to significant changes in leukocyte-endothelium interaction, BBB function, and oxygen free-radical production under physiological conditions [leukocyte-endothelium interaction: control (n = 5), L-NNA systemically (n = 5), L-NNA topically (n = 5): at baseline rollers/100 microns: 0.76 +/- 0.55, 0.64 +/- 0.94, 0.44 +/- 0.55 and stickers/100 microns: 0.90 +/- 0.28, 0.76 +/- 0.24, 0.84 +/- 0.42; at 60 min rollers/100 microns: 1.49 +/- 0.66, 1.21 +/- 0.99, 0.67 +/- 0.66 and stickers/100 microns: 1.04 +/- 0.20, 1.19 +/- 0.23, 1.21 +/- 0.54; oxygen free-radical production (n = 4): CL count before L-NNA application 35 +/- 17 cps, after 1 h of topical superfusion of L-NNA 38 +/- 14 cps; p < 0.05]. In contrast to the results achieved under physiological conditions, a significant further increase of rolling leukocytes and BBB permeability occurred due to NOS inhibition under LTB4-activated conditions [76 +/- 47% significant (p < or = 0.01, n = 7) further increase of rollers/100 microns due to 60 min L-NNA application following the activation period of 120 min LTB4 superfusion]. Our results support a modulatory role for NO in leukocyte-endothelium interaction and BBB permeability in the pial microcirculation when this interaction is increased.

Animals↗
PubMed1996

The trigeminal nerve and augmentation of regional cerebral blood flow during experimental bacterial meningitis.

We investigated whether trigeminal nerve fibers contribute to enhanced regional cerebral blood flow (rCBF) in a rat model of experimental bacterial meningitis. rCBF was measured continuously for 6 h by laser Doppler flowmetry through thinned bone over the frontal cortex. Meningitis was induced with pneumococcal cell wall components and confirmed by a significant increase of (a) leukocytes within the cerebrospinal fluid, (b) brain water content, (c) intracranial pressure and (d) rCBF. The increase of rCBF was significantly attenuated (p < 0.05) at 3, 4, 5, and 6 h in animals after a chronic (200 +/- 21% versus 138 +/- 13% at 6 h on the intact and denervated sides, respectively) but not after an acute section of the nasociliary branch of the trigeminal nerve. We conclude that elevations in blood flow during the early phase of bacterial meningitis are mediated in part by the trigeminal nerve, probably by local perivascular release of neuropeptides from afferent axons innervating the meninges.

Animals↗
PubMed1996

Cerebral oxygenation changes in response to motor stimulation.

We studied cerebral hemodynamic response to a sequential motor task in 56 subjects to investigate the time course and distribution of blood oxygenation changes as monitored by near-infrared spectroscopy (NIRS). To address whether response is modulated by different performance velocities, a group of subjects (n = 12) was examined while performing the motor task at 1, 2, and 3 Hz. The results demonstrate that 1) the NIRS response reflects localized changes in cerebral hemodynamics, 2) the response, consisting of an increase in oxygenated hemoglobin concentration [oxy-Hb] and a decrease in deoxygenated hemoglobin concentration ([deoxy-Hb]), is lateralized and increases in amplitude with higher performance rates, and 3) changes in [oxy-Hb] and [deoxy-Hb] differ in time course. Changes in [oxy-Hb] are biphasic, with a fast initial increase and a pronounced poststimulus undershoot. The stimulus-associated decrease in [deoxy-Hb] is monophasic, and response latency is greater. We conclude that NIRS is able to detect even small changes in cerebral hemodynamic response to functional stimulation.

Adult↗
PubMed1995

Age-related changes of oxygen free radical production in the rat brain slice after hypoxia: on-line measurement using enhanced chemiluminescence.

Superoxide radical production in brain slices of 12-, 24- and 60-day-old rats was measured online during and after 15 min of hypoxia with lucigenin enhanced chemiluminescence. We found a typical radical burst after reoxygenation which developed with aging and is almost nonexistent in the youngest and most prominent in the oldest group. This cannot be explained by a decreasing tissue superoxide dismutase (SOD) concentration in the brain with aging, since the concentration of the enzyme, determined in the same age groups, increased with age.

Aging↗
PubMed1995

Fucoidin, a polysaccharide inhibiting leukocyte rolling, attenuates inflammatory responses in experimental pneumococcal meningitis in rats.

It is presumed that adjuvant therapy rather than new antibiotics will improve the prognosis of pneumococcal meningitis. We investigated the effect of fucoidin, a polysaccharide inhibiting leukocyte rolling, on inflammatory changes in experimental meningitis in rats. After induction of meningitis by pneumococcal cell wall components, regional cerebral blood flow and intracranial pressure increased over the observation period of 6 h. At the end of the experiments, cerebrospinal fluid pleocytosis and brain water content were higher in animals with meningitis than without. Fucoidin treatment in the meningitis group reduced all inflammatory changes, whereas fucoidin treatment of animals without meningitis increased blood white cell count, but had no effect on any other parameter. Our results confirm that selectins are involved in the early phase of pneumococcal meningitis and possibly are a target for adjunctive therapy.

Animals↗
PubMed1995

Anti ICAM-1 (CD 54) monoclonal antibody reduces inflammatory changes in experimental bacterial meningitis.

We investigated whether monoclonal antibodies directed against intracellular adhesion molecule 1 (ICAM-1 mAb) inhibit brain edema, increase of intracranial pressure (ICP), regional cerebral blood flow (rCBF) and recruitment of white blood cells (WBC) into the cerebrospinal fluid (CSF) in the rat model of the early phase of bacterial meningitis. Brain edema was assessed by brain water content determinations. rCBF measured by laser Doppler flowmetry and ICP were recorded continuously for 6 h after intracisternal challenge. Meningitis was induced with pneumococcal cell walls (PCW). Increase of ICP and brain water content were significantly inhibited (P <0.05) by intravenous treatment with ICAM-1 mAb (TM-8, 1 mg/kg). Furthermore, ICAM-1 mAb treatment profoundly attenuated (P <0.05) rCBF increase and WBC invasion into the CSF. These results suggest that the ICAM-1 pathway is critically involved in the early phase of bacterial meningitis.

Animals↗
PubMed1995

Nitric oxide modulates the CBF response to increased extracellular potassium.

The response of the regional cerebral blood flow (rCBF) to brain topical superfusion of 20 mM K+ was characterized in a closed cranial window preparation in barbiturate anesthetized and ventilated rats: Increasing K+ in the artificial cerebrospinal fluid (ACSF) induced a rCBF elevation (measured by laser-Doppler flowmetry) of +85 +/- 37% above baseline (n = 19). This elevation was stable for > 3 h with continuous superfusion of increased K+ (n = 5) and partially reversible to a level of +18 +/- 19% above baseline when returning to a physiological K+ concentration. Nitric oxide synthase (NOS) inhibition by brain topical superfusion with N omega-nitro-L-arginine (L-NA) revealed (a) Addition of L-NA to high-potassium ACSF reduced the rCBF increase from +94 +/- 36% to +21 +/- 18% (p < or = 0.01, n = 7). (b) When L-NA was superfused for 60 min before increasing K+, rCBF decreased to -17 +/- 7% below baseline. Subsequent coapplication of L-NA and increased K+ induced only an elevation of +7 +/- 4% above baseline (n = 4). (c) When the NO donor S-nitroso-N-acetylpenicillamine (SNAP) was added during NOS inhibition to restore basal tissue NO levels, the resultant level of rCBF was +28 +/- 54% above baseline. Subsequent increase of K+ in the presence of NOS inhibition and SNAP elevated rCBF to +137 +/- 89% above baseline (n = 4).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗