Intraoperative computed tomography.

Intraoperative computed tomography (iCT) has gained increasing impact among modern neurosurgical techniques. Multislice CT with a sliding gantry in the OR provides excellent diagnostic image quality in the visualization of vascular lesions as well as bony structures including skull base and spine. Due to short acquisition times and a high spatial and temporal resolution, various modalities such as iCT-angiography, iCT-cerebral perfusion and the integration of intraoperative navigation with automatic re-registration after scanning can be performed. This allows a variety of applications, e.g. intraoperative angiography, intraoperative cerebral perfusion studies, update of cerebral and spinal navigation, stereotactic procedures as well as resection control in tumour surgery. Its versatility promotes its use in a multidisciplinary setting. Radiation exposure is comparable to standard CT systems outside the OR. For neurosurgical purposes, however, new hardware components (e.g. a radiolucent headholder system) had to be developed. Having a different range of applications compared to intraoperative MRI, it is an attractive modality for intraoperative imaging being comparatively easy to install and cost efficient.

Combined surgical and radiosurgical treatment of symptomatic aggressive vertebral osteomyelitis.

INTRODUCTION: The surgical treatment of vertebral osteomyelitis can be complicated by severe additional diseases or the need for extensive debridement with concomitant risks. We report a case of combined surgical and radiosurgical treatment of idiopathic vertebral osteomyelitis of L4. CASE REPORT: The patient presented with progressive enlargement of the right side of the vertebral body L4 due to chronic fibrous osteomyelitis without evidence of infection, leading to compression of nerve roots L4, L5 and the dural sac with resulting radicular paresis. During decompression of the nerve roots via a dorsal approach, massive bleeding from the inflammatory vertebral body occurred, making abortion of surgery necessary. Remnant inflammatory masses of vertebral body L4 were treated by spinal robotic radiosurgery with a high tumoricidal dose of 20 Gy without clinical and radiological signs of relapse of disease in the following three years. CONCLUSION: We describe a case of the combined surgical and radiosurgical treatment of lumbar osteomyelitis with symptomatic nerve root compression. Dorsal decompression followed by spinal radiosurgery for the anterior vertebral parts with avoidance of potentially dangerous anterior spondylectomy led to a rapid improvement of paresis and pain with persistent control of vertebral inflammation and enlargement. The described case of close cooperation of surgeons and radiosurgeons offered an effective and functionality preserving treatment in this challenging case.

Morphometric studies of the ligamentum flavum: a correlative microanatomical and MRI study of the lumbar spine.

BACKGROUND: Foraminal degenerative lumbar stenosis is traditionally considered a result of bony narrowing due to osteophytic appositions on the superior articular process. Clinical experience reveals that significant additional compression of the neural structures is due to degenerative hypertrophy of the adjacent ligamentum flavum. Therefore, microanatomical and neuroradiological investigations were performed to determine the microtopography of this ligament, especially with respect to its lateral extension. METHODS: Lumbar spine specimens of eight mid-aged human cadavers (mean age 34.5 years) were collected, and MRI studies with T1-weighted images were performed. The specially embedded specimens were sectioned horizontally at the level of the spinal ganglion (slice thickness: 2 mm). Anatomical morphometric data were correlated with identical measurements based on neuroradiological imaging and were analyzed statistically. RESULTS: The distance between midline and extraforaminal extension of the ligamentum flavum showed a mean value of 17 mm. The distance increased to 19 mm when the lateral insertion was correlated to the origin of the ligamentum flavum at the anterior margin of the lamina. The farthest lateral segment of the ligamentum flavum was determined in each case; it covered the synovial cavity of the lumbar facet joint in the direction of the extraforaminal segment of the intervertebral canal. CONCLUSIONS: Measurements from mid-aged cadavers show the extent of the ligamentum flavum including its intra- and extraforaminal parts. Due to this anatomical situation a hypertrophic ligamentum flavum may contribute significantly to nerve root compression at the level of the lateral spinal recess. This has to be kept in mind during surgical decompression, which might be incomplete unless these hypertrophied parts are completely removed.

Neuroprotective effects of a postischemic treatment with a bradykinin B2 receptor antagonist in a rat model of temporary focal cerebral ischemia.

Bradykinin, an endogenous nonapeptide produced by activation of the kallikrein-kinin system, promotes neuronal tissue damage as well as disturbances in blood-brain barrier function through activation of B2 receptors. In a rat model of focal cerebral ischemia, blockade of B2 receptors before initiation of ischemia with the B2 receptor antagonist, LF 16-0687 Ms, afforded substantial neuroprotection. In order to assess the potential clinical value of this approach, we evaluated the effect of LF 16-0687 Ms given at reperfusion following focal cerebral ischemia on local cerebral blood flow (LCBF), neurological outcome, and infarct size. Sprague-Dawley rats were subjected to MCA occlusion for 90 min by an intraluminal filament. Animals were assigned to one of four treatment arms (n = 7 each): (1) vehicle, (2) LF 16-0687 Ms (1.0 mg/kg/day), (3) LF 16-0687 Ms (3.0 mg/kg/day), or (4) LF 16-0687 Ms (10.0 mg/kg/day) given at reperfusion and repetitively over 2 days. Neurological recovery was examined daily, and infarct volume was assessed histologically on day 7 after ischemia. Physiological parameters and local CBF were not influenced by the treatment. Significant improvement of neurological outcome was observed on postischemic day 3 in animals receiving 1.0 and 3.0 mg/kg/day of LF 16-0687 Ms (P < 0.05). Inhibition of B2 receptors significantly reduced infarct volume in all treated animals predominantly in the cortex. B2 receptor blockade with LF 16-0687 Ms showed neuroprotective effectiveness even when therapy was initiated upon reperfusion, i.e. 90 min after induction of ischemia. Therefore, blockade of B2 receptors seems to be a promising therapeutic approach after focal cerebral ischemia, which deserves further experimental and clinical evaluation.

[Surgical treatment of cervical spinal canal stenosis in elderly patients]. / Degenerative HWS drückt auf das Rückenmark. Wie lange dürfen Sie mit der OP zögern?

The diagnosis is established through neurological examinations, laboratory and imaging diagnostics. Conservative treatment such as a neck brace, drug and physical therapies could bring relief. Manifest or progressing deficiency symptoms associated with sensory or motoric deficit, bladder, rectal or erectile disorder are indications for early surgery.

[Surgical treatment of lumbar spinal canal stenosis in elderly patients]. / Rückenschmerzen, Sensibilitätsstörungen, Schmerzen beim Gehen. Denken Sie an die Claudicatio spinalis?

Lumbar spinal stenosis is one of the most frequent causes of spinal surgical interventions in over 60-year olds. The exact relationship between degenerative changes and the resulting symptoms is unclear since imaging shows stenotic changes in the spines of many symptom-free patients. The concurrence of imaging findings, the symptoms described and manifestations is crucial for the indication of surgical decompression. Nevertheless, spinal claudication that is refractory to conservative therapy is the most frequent indication for surgery. The success rate two years after OP is approximately 80% in over 75-year olds. Five years after surgical intervention, an improvement in the symptoms is still recognizable in 50% of these patients.

Dose finding study of intravenous magnesium sulphate in transient focal cerebral ischemia in rats.

BACKGROUND: During many neurovascular procedures temporary occlusion of cerebral arteries is inevitable. Neuroprotective drugs may reduce the risk of cerebral infarction in this situation. Increasing evidence indicates neuroprotective properties of magnesium in cerebral ischemia. Previous experimental studies on the neuroprotective efficacy of magnesium-treatment in transient focal ischemia provide widely differing results using different magnesium doses and treatment-regimens. The present study was conducted to find the maximum protective dose of intravenous magnesium sulphate in a rat model of transient focal ischemia. METHODS: 45 male Sprague-Dawley rats were subjected to 90 minutes of middle cerebral artery occlusion (MCAO) by an intraluminal thread. Animals were randomly assigned to one of 4 treatment arms: (1) vehicle (2) MgSO(4) 1x0.75 mmol/kg (3) MgSO(4) 2x1 mmol/kg (4) MgSO(4) 1 mmol/kg+0.5 mmol/kg/h. Local cortical blood flow (LCBF) was continuously measured by laser-Doppler flowmetry. Functional deficits were quantified daily, infarct volumes were assessed histologically after 7 days. RESULTS: Magnesium serum levels below 3 mmol/l were well tolerated by the animals. Above 3 mmol/l cardiodepressive effects limited neuroprotection. Total infarct volumes in groups 3 and 4 were significantly reduced by 32% and 42%, respectively, compared to controls. Postoperative neurological recovery was significantly improved in magnesium-treated groups. CONCLUSION: Continuous magnesium-administration with stable serum concentrations between 2 and 3 mmol/l offered the best protection and was well tolerated. Serum concentrations above 3 mmol/l should not be exceeded. An elevation of magnesium serum levels could be useful for brain tissue protection during procedures which are prone to the risk of temporary vessel occlusion.

Congested residual nidus after preoperative intranidal embolization in midsize cerebral arteriovenous malformations of 3-6 cm in diameter.

BACKGROUND: Modern delicate microcatheters allow intranidal embolization of cerebral arteriovenous malformations (AVM). The aim of the current analysis was to assess effects of preoperative intranidal deployment of embolic material on surgical time and blood loss in cerebral arteriovenous malformations of 3-6 cm in diameter. METHODS: The case records of 38 cerebral AVM between 3 and 6 cm in maximum diameter were reviewed, that had been embolized intranidally with N-butyl 2-cyanoacrylate (Histacryl) and subsequently operated on. Surgical time and blood loss as well as particular intraoperative findings such as a congested nidus and thrombosis of draining veins were registered and correlated with the extent of embolization and the time interval between embolization and surgery. FINDINGS: Preoperative embolization occluded an estimated range of 10 to 90% of the nidus. Minor embolization related bleeding without clinical relevance occurred in 5 patients. Significant embolization related bleeding resulting in earlier than planned surgery occurred in another 5 patients. All embolization related haemorrhages occurred within 24 hours. Average total operating time was 343+/-106 min and average blood loss was 684+/-858 ml. Unequivocal bleeding difficulty from the nidus and a total blood loss of more than 1000 ml were encountered in 7 instances and dissection was tedious due to a bleeding AVM core in 5 other cases. A congested AVM core was the source of bleeding in 11 patients and paraventricular neovascularization in one. 6 of the 11 cases with a congested AVM core had suffered minor or substantial haemorrhage after a preoperative endovascular procedure. Intraoperative nidus congestion was noted in this series after an interval as long as 2 weeks after the last embolization. Combined management resulted in permanent morbidity in 6 of the 38 cases. In 4 of them the neurological deficit was associated with an intraoperative bleeding problem, in all due to congested nidus. Morbidity had to be correlated with major haemorrhage resulting from preoperative embolization in 2 instances. CONCLUSIONS: Intranidal embolization prior to surgical removal of AVM can lead to a congested residual nidus and intraoperative bleeding. Minor leakage after preoperative embolization is an inconsistent warning sign of nidus congestion. Nidus outflow after intranidal embolization appears to require a few weeks for normalization. Delay of surgery after embolization should be considered in cases of suspected congested residual nidus. The danger of major haemorrhage or arterial revascularization during this waiting period appears small.

Therapeutical efficacy of a novel non-peptide bradykinin B2 receptor antagonist on brain edema formation and ischemic tissue damage in focal cerebral ischemia.

OBJECTIVE: Bradykinin has been identified as a mediator of secondary brain damage in acute insults. We currently studied neuroprotective properties of a bradykinin B2 receptor antagonist (LF16-0687 Ms) in transitory focal cerebral ischemia to assess infarct formation and the development of brain edema. MATERIAL AND METHODS: 55 Rats were subjected to 90 min of MCA-occlusion. The receptor antagonist was administered at two dose levels, given from 30 min prior to ischemia over two days after ischemia. Ischemic tissue damage was quantified at day 7 after MCA-occlusion together with assessment of brain edema in separate experiments. Neurological recovery was studied daily. RESULTS: Animals receiving treatment (low dose) had a better functional recovery, particularly at days 3 and 4 (P < 0.05). Infarct formation was significantly attenuated in these animals in both total and cortical brain tissue by 50, or 80%, respectively. Postischemic brain swelling was significantly lowered, i.e. by 62%. CONCLUSIONS: Our findings provide further support for a mediator role of bradykinin in ischemic brain damage including edema formation, obviously by ligand binding to the bradykinin B2 receptor. The availability of a receptor antagonist may afford opportunity for translation of this experimental treatment into stroke patients.

Effects of LF 16-0687 Ms, a bradykinin B(2) receptor antagonist, on brain edema formation and tissue damage in a rat model of temporary focal cerebral ischemia.

Bradykinin, an endogenous nonapeptide produced by activation of the kallikrein-kinin system, promotes neuronal tissue damage as well as disturbances in blood-brain barrier function through activation of B(2) receptors. LF 16-0687 Ms, a non-peptide competitive bradykinin B(2) receptor antagonist, was recently found to decrease brain swelling in various models of traumatic brain injury. We have investigated the influence of LF 16-0687 Ms on the edema formation, neurological outcome, and infarct size in temporary focal cerebral ischemia in rats. Sprague-Dawley rats were subjected to MCA occlusion for 90 min by an intraluminal filament. Local CBF was bilaterally recorded by laser Doppler flowmetry. Study I: animals were assigned to one of three treatment arms (n=11 each): (a) vehicle, (b) LF 16-0687 Ms (12.0 mg/kg per day), or (c) LF 16-0687 Ms (36.0 mg/kg per day) given repetitively s.c. over 3 days. The neurological recovery was examined daily. The infarct volume was assessed histologically 7 days after ischemia. Study II: brain swelling and bilateral hemispheric water content were determined at 48 h post ischemia in eight rats, subjected to the low dose regimen as described above, and in eight vehicle-treated control animals. All treated animals showed tendency to exhibit improved neurological recovery throughout the observation period as compared to the vehicle-treated controls, while this improvement was only significant within the low dose group from postischemic days 3 to 4. Low dose LF 16-0687 Ms significantly attenuated the total and cortical infarct volume by 50 and 80%, respectively. Furthermore, postischemic swelling (-62%) and increase in water content of the infarcted brain hemisphere (-60.5%) was significantly inhibited. The present findings provide strong evidence for an involvement of bradykinin-mediated secondary brain damage following from focal cerebral ischemia. Accordingly, specific inhibition of bradykinin B(2) receptors by LF 16-0687 Ms attenuated postischemic brain swelling, improved the functional neurological recovery, and limited ischemic tissue damage, raising its potential for clinical evaluation in patients with acute stroke.

Anesthetic methods in rats determine outcome after experimental focal cerebral ischemia: mechanical ventilation is required to obtain controlled experimental conditions.

OBJECTIVE: Anesthetic agents, pH, blood gases and blood pressure have all been found to influence the pathophysiology of experimental stroke. In experimental research, rats are predominantly used to investigate the effects of focal cerebral ischemia. Chloral hydrate, applied intraperitoneally (i.p.), and halothane, applied via face-mask in spontaneously breathing animals or via endotracheal tube in mechanically ventilated animals are popular methods of anesthesia. We investigated the potential of these anesthetic methods to maintain physiologic conditions during focal cerebral ischemia and their influence on postischemic mortality and histological outcome. METHODS: Thirty male Sprague-Dawley rats were subjected to 90 min of middle cerebral artery occlusion by insertion of an intraluminal thread and assigned to one of three groups (n=10 each): (A) chloral hydrate i.p./spontaneously breathing; (B) halothane in 70:30 (%) N2O/O2 via face-mask/spontaneously breathing; and (C) halothane in 70:30 (%) N2O/O2 via endotracheal tube/mechanically ventilated. Physiologic parameters were measured before, during, and after ischemia. Infarct volume was histologically assessed after 7 days. RESULTS: All anesthetic techniques except mechanical ventilation via an endotracheal tube resulted in considerably fluctuating blood gases levels, hypercapnia, acidosis and low blood pressure. All spontaneously breathing animals (groups A and B) exhibited a higher postischemic mortality and significantly larger infarct volumes than group C with intubated and ventilated animals. CONCLUSIONS: Intra- and postischemic physiologic parameters such as blood pressure, pH, and blood gases critically determine outcome after focal cerebral ischemia. Although anesthesia by halothane via face-mask allowed better control of depth of anesthesia than chloral hydrate, we have found this method to be unsatisfactory due to insufficient control of ventilation and waste of anesthetic gases. Experiments with rats requiring normal physiologic parameters should be performed under conditions of controlled mechanical ventilation and sufficient analgesia.

No additional neuroprotection provided by barbiturate-induced burst suppression under mild hypothermic conditions in rats subjected to reversible focal ischemia.

OBJECT: Mild-to-moderate hypothermia is increasingly used for neuroprotection in humans. However, it is unknown whether administration of barbiturate medications in burst-suppressive doses-the gold standard of neuroprotection during neurovascular procedures-provides an additional protective effect under hypothermic conditions. The authors conducted the present study to answer this question. METHODS: Thirty-two Sprague-Dawley rats were subjected to 90 minutes of middle cerebral artery occlusion and randomly assigned to one of four treatment groups: 1) normothermic controls; 2) methohexital treatment (burst suppression); 3) induction of mild hypothermia (33 degrees C); and 4) induction of mild hypothermia plus methohexital treatment (burst suppression). Local cerebral blood flow was continuously monitored using bilateral laser Doppler flowmetry and electroencephalography. Functional deficits were quantified and recorded during daily neurological examinations. Infarct volumes were assessed histologically after 7 days. Methohexital treatment, mild hypothermia, and mild hypothermia plus methohexital treatment reduced infarct volumes by 32%, 71%, and 66%, respectively, compared with normothermic controls. Furthermore, mild hypothermia therapy provided the best functional outcome, which was not improved by additional barbiturate therapy. CONCLUSIONS: The results of this study indicate that barbiturate-induced burst suppression is not required to achieve maximum neuroprotection under mild hypothermic conditions. The magnitude of protection afforded by barbiturates alone appears to be modest compared with that provided by mild hypothermia.

Neurological impairment in rats after transient middle cerebral artery occlusion: a comparative study under various treatment paradigms.

The assessment of the functional outcome - in addition to the conventional endpoints as histomorphometry of the ischemic brain damage - for the evaluation of cerebroprotective therapies is increasingly recommended, although there is little consensus on appropriate procedures. We evaluated a battery of sensorimotor tasks in rats after transient middle cerebral artery occlusion (MCAO) to select those with the highest potential to discriminate between various degrees of neuronal damage. A total of 40 Sprague-Dawley rats were subjected to 90 min of MCAO and assigned to one of four treatment arms: (1) sham-operated controls, (2) vehicle-treated controls, (3) moderately effective neuroprotection by 2x100 mg/kg alpha-phenyl-N-tert-butyl nitrone (PBN), (4) highly effective neuroprotection by mild hypothermia (33 degrees C). Functional deficits were daily quantified using the beam balance task (1.5 cm, 2.5 cm diameter rectangular and 2.5 cm diameter cylindrical beam), the prehensile traction task, the rotarod, and a six-point neuro-score. Infarction of cerebral cortex and basal ganglia was assessed one week after ischemia. Treatment with PBN significantly reduced cortical infarction (-31%), while treatment with hypothermia resulted in a significantly smaller infarct volume of cortex (-94%) and basal ganglia (-27%). Beam balance, prehensile traction and rotarod failed to demonstrate any difference in motor performance. The six-point neuro-score showed a significant correlation with cortical infarction from day 2 and with total infarct volume from day 3. The smaller the reduction of infarct volume, the later the corresponding difference in neuro-score became apparent. Functional outcome after MCAO in rats can be assessed by a relatively simple measurement of neurological deficit. The slope of functional recovery is closely related with the degree of the morphological, particularly cortical damage. If expected treatment effects are small, an observation period of at least 3 days should be planned for the study design. The functional impairment from focal brain ischemia and its subsequent recovery could provide valuable information for future studies evaluating the neuroprotective potential of novel agents and procedures.

Neuroprotective effects of the novel brain-penetrating antioxidant U-101033E and the spin-trapping agent alpha-phenyl-N-tert-butyl nitrone (PBN).

Literature on the therapeutic efficacy of free radical scavengers suggests that drugs that are able to cross the blood-brain barrier are more effective in protecting the brain from ischemic damage. However, the exact mechanisms by which brain-penetrating antioxidants act have yet not been delineated. We compared the neuroprotective potential of the newly discovered pyrrolopyrimidine U-101033E with that of alpha-phenyl-N-tert-butyl nitrone (PBN) and investigated their influence on cerebral blood flow. Thirty male Sprague-Dawley rats were subjected to 90 min of middle cerebral artery (MCA) occlusion by an intraluminal filament. Local cerebral blood flow (LCBF) was bilaterally recorded by laser Doppler flowmetry. Neurological deficits were quantified daily. Infarct volume was assessed after 7 days. MCA occlusion reduced ipsilateral LCBF to 20-30% of baseline. After reperfusion, postischemic hyperemia was followed by a decrease in LCBF to about 70% of baseline. There was no difference in LCBF among groups. U-101033E improved neurological function and reduced infarct volume by 52% (P < 0.05). Improvement of neurological function and reduction of infarct volume (-25%) in animals treated with PBN was not significant. We conclude that U-101033E has superior neuroprotective properties compared with PBN. Neither drug improves blood flow during ischemia and 1 h of reperfusion. The mechanisms by which these brain-penetrating antioxidants act remain to be clarified.

Combination drug therapy and mild hypothermia: a promising treatment strategy for reversible, focal cerebral ischemia.

BACKGROUND AND PURPOSE: Hypothermia has been suggested to be the most potent therapeutic approach to reduce experimental ischemic brain injury identified to date, and mild hypothermia is increasingly used for neuroprotection during neurovascular surgery. We have recently demonstrated that combined administration of tirilazad mesylate and magnesium provides for an overall enhanced neuroprotective effect. The present study was designed to determine whether the efficacy of mild hypothermia (33 degrees C) can be increased by combination pharmacotherapy with tirilazad and magnesium (MgCl(2)). METHODS: Forty Sprague-Dawley rats were subjected to transient, middle cerebral artery occlusion and were randomly assigned to 1 of 4 treatment arms (n=10 each): (1) normothermia+vehicle, (2) normothermia+tirilazad+MgCl(2), (3) hypothermia+vehicle, or (4) hypothermia+tirilazad+MgCl(2). Cortical blood flow was monitored by a bilateral laser-Doppler flowmeter, and the electroencephalogram was continuously recorded. Functional deficits were quantified by daily neurological examinations. Infarct volume was assessed after 7 days. RESULTS: Tirilazad+MgCl(2), hypothermia, and hypothermia+tirilazad+MgCl(2) reduced total infarct volume by 56%, 63%, and 77%, respectively, relative to controls. In animals treated with both hypothermia and combination pharmacotherapy, cortical infarction was almost completely abolished (-99%), and infarct volume in the basal ganglia was significantly reduced by 55%. In addition, this treatment provided for the best electrophysiological recovery and functional outcome. CONCLUSIONS: The neuroprotective efficacy of hypothermia can be increased by pharmacological antagonism of excitatory amino acids and free radicals by using clinically available drugs. This treatment strategy could be of great benefit when applied during temporary artery occlusion in cerebrovascular surgery.

EEG burst suppression is not necessary for maximum barbiturate protection in transient focal cerebral ischemia in the rat.

Barbiturates have been demonstrated to reduce the cerebral metabolic rate (CMR) in a dose-dependent manner but investigations of a dose-response relationship for their neuroprotective efficacy are scant. It has been suggested that barbiturates possess other mechanism of action that may be critical to their protective effect. If so, it is conceivable that the peak effect of such mechanisms does not parallel the reduction in CMR. Thus, maximal neuroprotection may be achieved with a substantially lower dose of the drug. Thirty Sprague-Dawley rats were subjected to 2 h of middle cerebral artery occlusion while either anesthetized with (1) halothane (control) or (2) intravenous thiopental titrated to cause mild EEG suppression or (3) thiopental titrated to maintain EEG burst suppression. Cortical blood flow was recorded by continuous bilateral laser Doppler flowmetry (LDF). Infarct volume was assessed after 3 h of reperfusion. Low-dose thiopental decreased blood flow to 80% of baseline and high-dose thiopental to 70% of baseline. LDF did not indicate improvement of blood flow by thiopental in the ischemic area. Compared to controls, low-dose thiopental significantly decreased infarct volume by 28% and high-dose thiopental by 29%. The results of this study and a review of literature indicate that barbiturates provide cerebral protection but that the magnitude of this effect has been overestimated. Other mechanisms than CMR reduction seem to contribute to their beneficial effects, and high doses administered to the point of burst suppression may not be required to obtain maximal protection.

Neuroprotective efficacy of combination therapy with two different antioxidants in rats subjected to transient focal ischemia.

The vascular endothelium and parenchyma of the brain have both potential pathways to generate free radicals under pathological conditions. We evaluated the neuroprotective efficacy of two different antioxidants, a microvascularly acting 21-aminosteroid (U-74389G) and a brain-penetrating pyrrolopyrimidine (U-101033E) alone and in combination. Forty Sprague-Dawley rats were randomly assigned to one of four treatment groups: (1) vehicle-treated controls, (2) U-74389G, (3) U-101033E, (4) U-74389G+U-101033E. Drugs were administered in a dosage of 3x3 mg/kg i.v. before, during, and after ischemia. All animals were subjected to 90 min of middle cerebral artery occlusion. Local cortical blood flow (LCBF) was continuously recorded by bilateral laser Doppler flowmetry. Functional deficits were quantified by daily neurological examinations. Infarct volume was assessed after 7 days. There were no significant differences in LCBF among groups. U-101033E improved neurological function from postoperative day 4 to 7, while U-74389G did not improve neurological recovery. Animals treated with both drugs showed significantly less deficits from postoperative day 1 to 7. U-101033E and combination therapy reduced total infarct volume by 53% and 54% (P<0.05). U-74389G non-significantly reduced total infarct volume by 25%. Cortical infarct volume was significantly reduced in all treatment groups but only U-101033E and combination therapy protected the basal ganglia from infarction. In conclusion, brain-penetrating antioxidants have superior neuroprotective properties compared to microvascularly acting agents. Combination therapy, affording antioxidation plus radical scavenging in blood vessels and brain parenchyma, might yield the highest degree of neuronal protection from peroxidative damage. The neuroprotective efficacy seems to be independent of CBF.