Biomedical subjects

U Koedel

Publications and source records attributed to U Koedel.

47 records · Page 3Linked to original sources

PubMed1996

Mannitol, but not allopurinol, modulates changes in cerebral blood flow, intracranial pressure, and brain water content during pneumococcal meningitis in the rat.

OBJECTIVE: To investigate the benefit of the hyperosmolar agent, mannitol, and the xanthine oxidase inhibitor, allopurinol, in experimental pneumococcal meningitis in the rat. DESIGN: A prospective, randomized, controlled experimental study. SETTING: Experimental animal laboratory in a university hospital. SUBJECTS: Sixty-five anesthetized and artificially ventilated adult male Wistar rats, weighing 250 to 300 g. INTERVENTIONS: Meningitis was induced by intracisternal injection of live pneumococci. Infected rats were randomized to receive mannitol or allopurinol. MEASUREMENTS AND MAIN RESULTS: There were marked increases in regional cerebral blood flow (measured by laser-Doppler flowmetry), intracranial pressure, brain water content, and cerebrospinal fluid white blood cell count in infected rats within 6 hrs after infection (p < .05, compared with uninfected controls). Continuous infusion of mannitol (0.6 g/kg/hr iv), started just before infection, attenuated the increases of regional cerebral blood flow, intracranial pressure, and brain water content (p < .05, compared with untreated infected rats 6 hrs after infection). When continuous mannitol treatment was started 4 hrs after infection, intracranial pressure at 6 hrs was significantly lower than in untreated infected rats. When mannitol was given by a bolus injection (1.5 g/ kg iv) at 4 hrs after infection, intracranial pressure measured 0.5 hr thereafter was consistently reduced in all animals (intracranial pressure reduction by 21.3 +/- 5.1 [SEM]%). Pretreatment with allopurinol (150 mg/kg iv) did not significantly influence regional cerebral blood flow, intracranial pressure, and brain water content in pneumococci-injected rats. Both agents, mannitol and allopurinol, did not inhibit cerebrospinal fluid pleocytosis in infected rats. In uninfected rats, mannitol significantly increased regional cerebral blood flow by a nitric oxide-independent mechanism, whereas allopurinol slightly decreased blood flow. CONCLUSIONS: Mannitol attenuated pathophysiologic changes in experimental pneumococcal meningitis. One possible mechanism of the mannitol effect might be scavenging of hydroxyl radicals which have been shown to be involved in the pathophysiology of pneumococcal meningitis. The failure of allopurinol to modulate pathophysiologic parameters may suggest that during early experimental pneumococcal meningitis in the rat, the xanthine oxidase pathway seems not to be a major source of reactive oxygen species.

Allopurinol↗

PubMed1995

Involvement of substance P in pial arteriolar vasodilatation during pneumococcal meningitis in the rat.

The present study investigated whether the endogenous vasodilating neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) contribute to pial arteriolar vasodilatation in the early phase of pneumococcal meningitis in the rat. Using a closed cranial window preparation we measured the diameters of pial arterioles during 4 h after pneumococcal infection. Arteriolar vasodilatation in infected rats was significantly attenuated by pretreatment with the SP-antagonist spantide up to 3 h after infection. Neither post-treatment with spantide (administered 2 h after infection) nor pretreatment with the CGRP antagonist CGRP(8-37) affected the pneumococci-induced pial arteriolar dilatation. These data suggest that SP is involved as a mediator in early pneumococci-induced dilatation of pial arterioles.

Animals↗

PubMed1995

Experimental pneumococcal meningitis: cerebrovascular alterations, brain edema, and meningeal inflammation are linked to the production of nitric oxide.

We investigated whether treatment with the nitric oxide synthase inhibitor N-nitro-L-arginine (L-NA) and the free radical scavenger superoxide dismutase influences cerebral blood flow changes, brain edema, and cerebrospinal fluid pleocytosis in early experimental pneumococcal meningitis. Compared to untreated infected rats, superoxide dismutase given 3 hours after infection significantly attenuated the increase of brain water content, intracranial pressure, and cerebrospinal fluid white blood cell count, but did not modulate the increase in regional cerebral blood flow. N-Nitro-L-arginine treatment (5 mg/kg intravenously, followed by 5 mg/kg/hour) reversed the increase in regional cerebral blood flow; prevented an increase in brain water content, intracranial pressure, and cerebrospinal fluid nitrite concentrations; and reduced cerebrospinal fluid white blood cell count. With a closed cranial window preparation, N-nitro-L-arginine prevented pneumococci-induced dilatation of pial arterioles. When the effective dose was increased twofold, the effects of N-nitro-L-arginine became more pronounced but resulted in the death of 4 of 5 rats, probably due to hemodynamic side effects. In primary cultures of rat cerebral endothelial cells, nitrite concentrations increased after pneumococcal stimulation, which could be prevented by N-nitro-L-arginine and cycloheximide. These data suggest that (a) nitric oxide accounts for regional cerebral blood flow changes and pial arteriolar dilatation in the early phase of experimental pneumococcal meningitis; (b) both superoxide radical and nitric oxide are involved as mediators of brain edema and meningeal inflammation; and (c) cerebral endothelial cells can be stimulated by pneumococci to release nitric oxide presumably via the inducible nitric oxide synthase.

Amino Acid Oxidoreductases↗

PubMed1995

Global cerebral ischemia in the rat: online monitoring of oxygen free radical production using chemiluminescence in vivo.

Using online in vivo chemiluminescence (CL), we studied for the first time continuously the production of reactive oxygen species (ROS) after global cerebral ischemia and the relationship of ROS production to CBF. In anesthetized rats equipped with a closed cranial window, the CL enhancer, lucigenin (1 mM), was superfused onto the brain topically. CL was measured through the cranial window with a cooled photomultiplier, and CBF was measured simultaneously with laser-Doppler flowmetry. Reperfusion after 10 min (n = 8) of global cerebral ischemia led to a CL peak to 188 +/- 77% (baseline = 100%) within 10 +/- 4 min. After 2 h of reperfusion, CL had returned to 102 +/- 28%. Reperfusion after 20 min (n = 8) of ischemia increased CL to 225 +/- 48% within 12 +/- 3 min. After 2 h, CL was still increased (150 +/- 44%, p < 0.05 compared with 10 min of ischemia). CL after 10 min of ischemia was neither affected by brain topical free CuZn-superoxide dismutase (SOD) (100 U/ml, n = 3) nor by i.v. administration of free CuZn-SOD (104 U/kg, followed by 104 U/kg/h, n = 3). The CBF hyperfusion peak on reperfusion preceded the CL peak in all experiments by several minutes. In additional in vitro experiments we investigated the source of CL: Intracellular loading of lucigenin was demonstrated in cultured CNS cells, and a very similar pattern of CL as in the in vivo preparation after ischemia developed in rat brain slices after 15 min of hypoxia, which was unaffected by free CuZn-SOD (100 U/ml) but strongly attenuated by liposome-entrapped CuZn-SOD. We conclude that lucigenin-enhanced CL is a promising tool to study ROS production continuously from the in vivo brain of experimental animals and brain slices, and that the CL signal most likely derives from the intracellular production of superoxide. The production of ROS is preceded by reperfusion, is burst-like, and is dependent on the duration of the ischemic interval.

Acridines↗

PubMed1995

Protective effect of a 21-aminosteroid during experimental pneumococcal meningitis.

This study investigated whether the 21-aminosteroid U74389F, an inhibitor of lipid peroxidation, attenuates pathophysiologic changes in experimental pneumococcal meningitis. Infected rats injected intravenously with vehicle of [corrected] U74389F developed increases in regional cerebral blood flow (rCBF), intracranial pressure (ICP), brain water content, and white blood cells (WBC) in cerebrospinal fluid (CSF) within 8 h after intracisternal challenge. Pretreatment with or administration of U74389F 4 h after infection significantly reduced the increase in ICP but had no effect on rCBF increase. Moreover, U74389F pretreatment significantly reduced brain water content and CSF WBC count. In vitro, U74389F inhibited iron-dependent lipid peroxidation of astrocyte cultures and the production of tumor necrosis factor-alpha, interleukin-6, and nitric oxide by stimulated macrophages. These data suggest that U74389F modulates early pathophysiologic alterations in experimental pneumococcal meningitis.

Animals↗

PubMed1994

Methylprednisolone attenuates inflammation, increase of brain water content and intracranial pressure, but does not influence cerebral blood flow changes in experimental pneumococcal meningitis.

We investigated the effect of methylprednisolone on pathophysiological alterations in experimental pneumococcal meningitis. Untreated rats injected with pneumococcal cell wall components after hydrolization with M1 muramidase (PCW-M) developed an increase of regional cerebral blood flow (rCBF; 165.0 +/- 12.8%, baseline 100%, mean +/- S.E.M.), brain water content (79.23 +/- 0.10%), intracranial pressure (ICP; 11.9 +/- 1.0 mmHg) and white blood cell (WBC) count in the cerebrospinal fluid (CSF) (2,709 +/- 482 cells/microliters) within 8 h after intracisternal (i.c.) challenge. Pretreatment with methylprednisolone or administration of methylprednisolone 4 h after i.c. challenge significantly attenuated the increase of brain water content (78.88 +/- 0.08% and 78.82 +/- 0.05%, resp.), ICP (7.7 +/- 1.1 mmHg and 4.9 +/- 0.8 mmHg, resp.) and CSF WBC count (1,257 +/- 168 cells/microliters and 976 +/- 105 cells/microliters, resp.). However, methylprednisolone did not inhibit the increase of rCBF (163.5 +/- 13.7% and 160.9 +/- 6.8%, resp.), whereas dexamethasone significantly attenuated microvascular changes. Hypercapnia-induced reactivity of cerebral vessels tested 8 h after i.c. injection was preserved in all groups. In conclusion, we found that methylprednisolone significantly attenuated the increase of brain water content, ICP and CSF WBC count, but had no effect on microvascular changes during the early phase of experimental pneumococcal meningitis.

Animals↗

PubMed1993

Imaging of leukocyte-endothelium interaction using in vivo confocal laser scanning microscopy during the early phase of experimental pneumococcal meningitis.

Confocal laser scanning microscopy (CLSM) was used to investigate dynamic aspects of rhodamine 6G-labeled leukocytes in the pial microcirculation during the early phase of pneumococcal meningitis. Closed cranial windows were implanted into anesthetized rats without removing the dura mater. Leukocyte behavior was studied every hour after intracisternal (ic) injection. The number of adherent and extravasated leukocytes was determined during playback of videotaped images. Compared with results in controls, the number of adherent leukocytes increased significantly (P < .05) within 1 h after ic pneumococcal challenge, followed by a further increase up to 6 h after infection. In untreated infected rats, the number of extravasated leukocytes progressively increased from 3 to 6 h after infection. Leukocyte adherence to microvascular endothelium occurred in pial venules but not in arterioles. Dexamethasone pretreatment significantly (P < .05) attenuated leukocyte adherence and transendothelial passage of leukocytes.

Animals↗

PubMed1992

Transforming growth factor beta 2 inhibits cerebrovascular changes and brain edema formation in the tumor necrosis factor alpha-independent early phase of experimental pneumococcal meningitis.

Macrophages and granulocytes seem to play a key role in the pathogenesis of bacterial meningitis. Transforming growth factor beta (TGF-beta) leads to macrophage deactivation, as well as to inhibition of cytokine production and of endothelial granulocyte adhesion. We have investigated the influence of TGF-beta on regional cerebral blood flow (rCBF), intracranial pressure (ICP), and brain edema formation during the early phase of experimental meningitis. Rats which were inoculated intracisternally with live pneumococci or with pneumococcal cell wall hydrolyzed by the M1 muramidase (PCW-M) developed an increase of rCBF and ICP within 4 h postintracisternal challenge. A single intraperitoneal injection of TGF-beta 2 but not of TGF-beta 2 vehicle-control prevented the changes of rCBF. Furthermore, TGF-beta 2 significantly reduced the increase of ICP in rats inoculated with PCW-M. Likewise, the elevation of brain water content after intracisternal injection of pneumococci or PCW-M was blocked by pretreatment of rats with TGF-beta 2. TGF-beta 1 exhibited similar inhibitory effects in PCW-M-injected rats. The beneficial effects of TGF-beta 2 on the initial phase after pneumococcal inoculation seem to be tumor necrosis factor alpha- (TNF-alpha) independent since (a) intracisternal or intraperitoneal injection of neutralizing anti-TNF-alpha antibodies did not significantly influence rCBF, ICP, and brain water content in PCW-M-induced meningitis; and (b) TNF-alpha was only occasionally detected at low levels in cerebrospinal fluid at 4 h after PCW-M application.

Animals↗

PubMed1992

Antioxidants attenuate microvascular changes in the early phase of experimental pneumococcal meningitis in rats.

BACKGROUND AND PURPOSE: We tested in a rat meningitis model 1) whether pneumococcal cell wall components are capable of producing changes in regional cerebral blood flow, brain water content, and intracranial pressure similar to those we have already observed after intracisternal inoculation of live pneumococci and 2) whether antioxidants would modulate these alterations in the early phase of meningitis. METHODS: Regional cerebral blood flow as measured by laser Doppler flowmetry and intracranial pressure were monitored continuously for 4 hours after intracisternal challenge. Brain edema formation was assessed by brain water content determinations. We investigated the following groups: rats challenged intracisternally with the whole intact pneumococcal cell wall (n = 7) or the pneumococcal cell wall hydrolyzed by the M1-muramidase (n = 7); rats injected intracisternally with phosphate-buffered saline (n = 6); rats pretreated intravenously with superoxide dismutase conjugated with polyethylene glycol (10,000 units/kg) and injected intracisternally with cell wall components (n = 5) or phosphate-buffered saline (n = 6); rats injected intracisternally with phosphate-buffered saline and pretreated intravenously with polyethylene glycol (10% solution, 1.2 ml/kg, n = 5) or continuously treated with intravenous free superoxide dismutase (22,000 units/kg per hour, n = 6); and rats continuously treated intravenously with deferoxamine mesylate (10 mg/kg per hour) and injected intracisternally with cell wall components (n = 6) or phosphate-buffered saline (n = 7). RESULTS: Both pneumococcal cell wall preparations produced a significant increase in regional cerebral blood flow, intracranial pressure, and brain water content. Conjugated superoxide dismutase as well as deferoxamine prevented the increase in intracranial pressure and brain water content. In addition, the increase in regional cerebral blood flow as observed in untreated, cell wall-challenged rats (baseline, 100%; 183.1 +/- 12.3% after 4 hours, mean +/- SEM) was significantly attenuated by administration of both conjugated superoxide dismutase (136.6 +/- 14.1%) and deferoxamine (149.8 +/- 8.2%) (p < 0.05). Polyethylene glycol-conjugated superoxide dismutase alone produced an increase in regional cerebral blood flow (125.6 +/- 8.7% after 4 hours). We found that polyethylene glycol per se accounts for this action. CONCLUSIONS: These data show that pneumococcal cell wall components containing teichoic acid produce changes in regional cerebral blood flow, intracranial pressure, and brain water content and that oxygen radicals contribute to these pathophysiological alterations in the early phase of experimental pneumococcal meningitis.

Animals↗

PubMed1990

Superoxide dismutase inhibits brain oedema formation in experimental pneumococcal meningitis.

The purpose of this study was to identify mediators of brain oedema formation in experimental pneumococcal meningitis. In a rat model of pneumococcal meningitis brain water content was significantly elevated 6 hours post infection (79.69% +/- 0.24 compared to 78.94% +/- 0.16 in the control group, mean +/- SEM, p less than 0.05). Brain oedema formation was completely blocked by superoxide dismutase (132,000 U/kg i.v. per 6 hours: n = 6), pretreatment with dexamethasone (3 mg/kg i.p., n = 3), or administration of dexamethasone at two hours after pneumococcal injection (n = 5). Pretreatment with indomethacin (10 mg/kg i.v., n = 5) attenuated the brain oedema formation. These findings suggest that oxygen derived free radicals act as mediators of brain oedema formation during the early phase of experimental bacterial meningitis. Cyclooxygenase metabolites may provide one possible source for the generation of oxygen derived free radicals in bacterial meningitis.

Animals↗

PubMed1990

Microvascular changes during the early phase of experimental bacterial meningitis.

We investigated the temporal profile of the changes in regional CBF (rCBF) and intracranial pressure (ICP) during the early phase of pneumococcal meningitis in the rat. rCBF, as measured by laser-Doppler flowmetry, and ICP were continuously monitored during 6 h post infection (p.i.). Brain edema formation was assessed by brain water content determinations. Meningitis was induced by intracisternal injection of 75 microliters of 10(7) colony-forming units/ml pneumococci (n = 7). In control animals (n = 6), saline was injected. There was no change in the rCBF or ICP of controls throughout the experiment. However, there was a dramatic increase in rCBF and ICP associated with brain edema formation in untreated meningitis animals. rCBF increased to 135.3 +/- 33.8% (mean +/- SD) in the untreated animals at 1 h p.i. and reached 211.1 +/- 40.5% at 6 h p.i. (p less than 0.05 compared with controls). ICP increased from 2.9 +/- 1.4 to 10.4 +/- 4.7 mm Hg at 6 h p.i. (p less than 0.05 compared with controls). Brain water content was significantly elevated (79.69 +/- 0.24 compared with 78.94 +/- 0.16% in the control group, p less than 0.05). We investigated the effect of dexamethasone (3 mg/kg i.p.), which was given prior to the induction of meningitis (n = 3) or at 2 h after pneumococcal injection (n = 5), indomethacin (10 mg/kg i.v., n = 5), and superoxide dismutase (SOD; 132,000 U/kg i.v. per 6 h, n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗