Failure to improve the effect of thrombolysis by memantine in a rat embolic stroke model

OBJECTIVES: Partial and delayed recanalization is a regular finding after thrombolysis in stroke patients who may benefit from additional therapy with neuroprotectants. To translate this scenario into an experiment, memantine was combined with thrombolysis in an embolic stroke model and tissue outcome was assessed in terms of complete and incomplete damage. METHODS: Tissue plasminogen activator (tPA, 5 mg/kg, b.w.) was administered 1.5 or 3.5 hours after embolic middle cerebral artery (MCA) occlusion in rats. In both groups, rats were assigned to additional therapy with memantine (10 mg/kg, i.p.) or saline injection. Ischemia and eventual reperfusion were continuously monitored by laser-Doppler flowmetry. Reperfusion was defined as a lasting increase in post-thrombolytic cerebral blood flow to >60% of baseline (complete) or to a lesser degree (partial). Experiments were terminated 6 hours post-occlusion to obtain quantitative histopathology. RESULTS: tPA induced complete or partial recanalization in 54% of treated animals. Successful reperfusion reduced total ischemic lesion volume by 42% compared with non-reperfused animals (p<0.05), but increased significantly the percentage of scattered neuronal injury from 25.6 (non-reperfusion) to 36.3% (reperfusion, p<0.05). Memantine did not improve the effect of tPA-induced recanalization on infarct morphology whether applied at 1.5 or 3.5 hours post-occlusion. DISCUSSION: We conclude from our experiments that add-on therapy with memantine did not alter the effect of thrombolysis in an embolic stroke model. Recanalization appears to be a prerequisite to confer neuroprotective effects.     

Brain retraction injury

Abstract

This paper reviews the literature of the brain retraction injury during the last century. The review focused on the instrument characteristic as well as the physiopathological and histopathological damage of the brain induced by brain retraction. It was found that lesions were induced by cerebral ischemia. We conclude that a better monitoring system needs to be developed to avoid brain injury.     

Phosphodiesterase 5 inhibitor,zaprinast, selectively increases cerebral blood flow in the ischemic penumbra in the rat brain

Abstract

Background: Guanosine 3′, 5′-cyclic monophosphate (cGMP) acts as a relaxant second messenger in the cerebral vessels. cGMP-specific phosphodiesterase type 5 (PDE5) inhibitor increases intracellular cGMP levels. This study investigated the effect of the PDE5 inhibitor on the ischemic brain.

Methods: Regional cerebral blood flow (rCBF), cGMP concentration, and infarction volume were measured in the rat middle cerebral artery occlusion model. Ten minutes after ischemia, the animals received an intravenous (i.v.) infusion of vehicle (phosphate-buffered saline), PDE5 inhibitor, zaprinast (10 mg/kg), or nitric oxide donor, S-nitroso-N-acetyl-penicillamine (SNAP, 100 μg/kg). rCBF was measured continuously by laser-Doppler flowmetry in the ischemic penumbra of the ischemic and contralateral sides under continuous blood pressure monitoring. cGMP concentrations were determined using the enzyme immunoassay and infarct volumes were estimated by 2,3,5-triphenyltetrazolium chloride staining.

Results: The administration of zaprinast significantly increased rCBF in the ischemic brain compared with the pre-drug control value despite the decreased mean blood pressure, whereas it did not affect rCBF in the contralateral side. The cGMP concentration was significantly higher in the ischemic cortex compared with the contralateral side. SNAP infusion increased the cGMP concentration in the bilateral cortices to a similar extent. The volume of cerebral infarction was significantly decreased by zaprinast administration.

Conclusions: The PDE5 inhibitor zaprinast may selectively increase CBF in the ischemic brain via increased cGMP levels, thus providing a new strategy against acute cerebral infarction.     

Cerebrospinal compensation of pulsating cerebral blood volume in hydrocephalus

Abstract

Objective: The aim of the study was to develop a computational method for the assessment of brain pressure compensation of cerebrospinal arterial blood inflow. The method was verified using clinical recordings performed during infusion studies in a group of patients diagnosed with hydrocephalus.

Materials and methods: We studied 27 patients suspected of having normal pressure hydrocephalus. The infusion test was used to measure the resistance to cerebrospinal fluid outflow, and the elastance coefficient was performed together with recording of the blood flow velocity in the middle cerebral artery. From the blood flow velocity waveform, the pulsatile pattern of increasing cerebral blood volume during one heart cycle was evaluated as a time integral of the arterial blood flow velocity minus the mean arterial blood flow. Cerebrospinal 'compliance index' (C _i) was calculated as the amplitude of change in blood volume divided by the amplitude of intracranial pressure pulse waveform.

Results: Compliance index C _i decreased during the infusion test, proportionally inverse to the rise in intracranial pressure controlled by the external infusion of saline (R=?0·76; p<0·005). A relative change in compliance (from baseline to the plateau phase of the study) was positively associated with greater brain elasticity (R=0·61; p<0·005) and poorer compensatory reserve at the phase of infusion (R=0·51; p=0·009)

Conclusion: C _i decreases during the infusion study and seems to well replicate the relative changes in cerebrospinal compensatory reserve in hydrocephalus.     

Doppler ultrasonographic measurement of blood flow velocities in major cerebral arteries of the rat using triplex mode

Abstract

Objective: In patients with subarachnoid hemorrhage, delayed cerebral ischemia caused by vasospasm of major cerebral arteries is an important factor of morbidity. While Doppler ultrasonographic monitoring of blood flow velocities is a routine bedside examination in these patients, the current rodent models of vasospasm do not include this technique. In this article, we present an extended craniectomy in rats, which allows for direct angle-corrected Doppler ultrasonographic examination of major cerebral vessels.

Methods: Ultrasonographic examination employs a triplex window displaying simultaneously B-mode, colour coded vessel rendering and Doppler-assessment of blood flow velocity. The animals receive anesthesia for the measurements, which are repeated several times a week.

Results: Mean flow velocities determined by 116 measurements in 16 animals are (cm/s): truncus cerebri anterius: 8.16, arteria pericallosa: 7.49, arteries (Aa.) cerebri anteriores: 7.76, Aa. carotides: 8.76, Aa. cerebri mediae: 8.55, Aa. cerebri posteriores: 5.27, artery (A.) basilaris: 5.90.

Discussion: We describe the direct intravital detection of blood flow velocities in major cerebral vessels of the rat. The technique allows for simultaneous visualization of intracranial structures, vessel diameters and cerebral blood flow velocities. Our ongoing research focuses on determining normal values in a larger population of animals and examining the feasibility of the technique regarding the rodent model of vasospasm.     

Comparison of transcranial Doppler ultrasonography and positron emission tomography using a three-dimensional template of the middle cerebral artery

Abstract

Objective: Transcranial Doppler (TCD) measures blood flow velocities (BFV) and is an indirect method of assessing cerebral blood flow (CBF). Positron emission tomography (PET) is a direct method to measure CBF. This study evaluates the correlations between TCD and PET findings

Methods: Nine patients with a symptomatic carotid artery stenosis, who underwent CEA, were studied pre- and post-operatively on the ipsi- and contralateral sides. Measurements of the BFV, CO₂ reactivity, CBF, cerebral blood volume (CBV) and mean vascular transit time (MVTT) were performed using a three-dimensional volume of interest (VOI) for the middle cerebral artery (MCA).

Results: CBF in the MCA region, as measured with PET, shows a good correlation with BFV, as measured with TCD, with similar pattern for total, gray and white matter MCA territory (Pearson's correlation coefficients: 0.751, 0.748 and 0.748, respectively). This correlation was found in the pre-operative as well as the post-operative state. No association could be demonstrated between CO₂ reactivity and CBV or (Pearson's correlation coefficients: 0.051 and 0.166, respectively).

Conclusion: With PET, it is possible to create three-dimensional VOI of arterial territories. CBF measured in these VOI seems to correlate with BFV before and after CEA on ipsi- and contralateral sides, while CBV shows no association with pre-operative CO₂ reactivity.     

Effect of hypothermia and delayed thrombolysis in a rat embolic stroke model

Effect of hypothermia on cerebral infarcts was studied in rats embolized in the right carotid territory. Thirty-four served as normothermic controls receiving saline infusion only. In 16 rats hypothermia of 32°C was induced by cooling with a fan, followed by embolization. The rats were kept hypothermic for the following 3 h before body temperature was raised to 37°C. In 26 rats, treatment with human recombinant tissue plasminogen activator (20 mg/kg i.v. during 45 min), started 2 h after embolization. Finally, 14 rats were treated similarly with hypothermia for 3 h followed by additional rt-PA treatment starting after 2 h. Thrombolytic therapy reduced median infarct volume from 19.5% of affected hemisphere among controls to 4.6% (p = 0.006) in the treated group. Three hours of hypothermia reduced infarct volume to 1.6% (p = 0.0007). Additional rt-PA could not demonstrate further improvement in this experimental setting.     

Chronic cerebral venous hypertension model in rats

Abstract

Although cerebral venous hypertension is known as an important determinant factor for clinical manifestation and outcome in patients with dural arteriovenous malformation (AVM), the pathophysiology of that condition is not well understood. We have created a chronic rat model by cervical arteriovenous fistularization with jugular vein occlusion and examined effect of cerebral venous hypertension on cerebral blood flow regulation. This model may be suitable for investigating mechanisms of cerebrovascular alteration after venous hypertension.     

Reduction of infarct volume and mortality by thrombolysis in a rat embolic stroke model.

BACKGROUND AND PURPOSE: Thrombolytic therapy with recombinant tissue plasminogen activator was tested in a rat embolic stroke model. METHODS: The rat carotid territory was embolized with arterial-like microthrombi formed under pressure. Hemispheric cerebral blood flow before and after embolization was measured by the intraarterial Xenon-133 injection method. Fifteen minutes after embolization, 24 rats were treated with 3 mg/kg or 10 mg/kg tissue plasminogen activator, and 27 were treated with saline. Carotid angiography displayed the rate of occlusion of the cerebral arterial supply before and after treatment. Brains were fixed and evaluated neuropathologically and infarct volume was measured. RESULTS: Cerebral blood flow was reduced 70-86% after embolization. The comparison of pretreatment and posttreatment angiography showed significant (p = 0.0005) reperfusion in the treated rats. Thrombolytic therapy significantly reduced the infarct volume from 55.1% to 24.4% of embolized hemisphere volume (p = 0.007) and increased the survival rate from 0.48 to 0.96 (p = 0.0004). Fifty-three percent of the embolized rats recanalized completely after thrombolytic treatment and developed almost no infarction (median volume 2.8%), and all survived. No hemorrhagic complications were observed. CONCLUSIONS: Early thrombolytic therapy induced recanalization and reduced mortality and infarct volume after embolic stroke in this model.     

Neuroprotective effects of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), an antioxidant in middle cerebral artery occlusion induced focal cerebral ischemia in rats

Abstract

Objectives: In the present study, we have investigated the neuroprotective potential of 6hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), in middle cerebral artery occlusion (MCAO) induced focal cerebral ischemia.

Methods: Sprague–Dawley rats were subjected to 2 hours of MCAO followed by 22 or 70 hours of reperfusion. After reperfusion, rats were evaluated for neurological deficits and cerebral infarction. Brain malondialdehyde (MDA) level and in situ terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL) were also estimated.

Results: Focal cerebral ischemia produced a significant infarct volume and neurological scores as compared with sham-operated animals. Cerebral ischemia reperfusion injury was associated with an increase in lipid peroxidation in ipsilateral and contralateral hemisphere of brain along with an increase in TUNEL positive cells in ipsilateral hemisphere of brain sections indicating oxidative stress and DNA fragmentation, respectively. Trolox (10 and 30 mg/kg, i.p.) treatment significantly decreased neurological damage which was evident from the reduction in infarct volume and neurological score. Trolox (30 mg/kg) also attenuated oxidative stress and DNA fragmentation.

Discussion: Oxidative stress-induced neuronal damage is implicated in the pathophysiology of cerebral ischemia. Our study suggests that Trolox is a potent neuroprotective agent in focal cerebral ischemia and its neuroprotective effects may be attributed to the reduction of lipid peroxidation and DNA fragmentation.     

The plasticity of posterior communicating artery influences on the outcome of white matter injury induced by chronic cerebral hypoperfusion in rats

Abstract

Objective: This study was performed to identify which factors are involved in the development of white matter lesions induced by chronic cerebral hypoperfusion in rats.

Methods: Male Wistar and Sprague–Dawley (SD) rats (250–270 g) were subjected to the permanent occlusion of bilateral common carotid arteries (BCCAO). The regional cerebral blood flow (rCBF) was measured by laser Doppler flowmetry and the plasticity of the posterior communicating artery (PcomA) was visualized by transcardiac perfusion of latex solution. For the histological examination, Klüver–Barrera staining was used to evaluate white matter damage.

Results: When compared with SD rats, Wistar rats showed lower rCBF after BCCAO, as well as thinner PcomAs. Moreover, 21 days after BCCAO, Wistar rats showed marked vacuolation of white matter in the optic tract, whereas SD rats had an almost intact optic tract.

Discussion: These results suggest that the plasticity of the PcomA and the reduction of rCBF in Wistar rats are important factors in the development of BCCAO-induced white matter lesions.     

Effect of combined therapy with thrombolysis and citicoline in a rat model of embolic stroke

An approach combining reperfusion mediated by thrombolytics with pharmacological neuroprotection aimed at inhibiting the physiopathological disorders responsible for ischemia-reperfusion damage, could provide an optimal treatment of ischemic stroke. We investigate, in a rat embolic stroke model, the combination of rtPA with citicoline as compared to either alone as monotherapy, and whether the neuroprotector should be provided before or after thrombolysis to achieve a greater reduction of ischemic brain damage. One hundred and nine rats have been studied: four were sham-operated and the rest embolized in the right internal carotid artery with an autologous clot and divided among 5 groups: 1) control; 2) iv rtPA 5 mg/kg 30 min post-embolization 3) citicoline 250 mg/kg ip x3 doses, 10 min, 24 h and 48 h post-embolization; 4) citicoline combined with rtPA following the same pattern; 5) rtPA combined with citicoline, with a first dose 10 min after thrombolysis. Mortality, neurological score, volume of ischemic lesion and neuronal death (TUNEL) after 72 h and plasma levels of IL-6 and TNF-alpha, were considered to assess ischemic brain damage. Compared with controls, the use of citicoline after thrombolysis produced the greatest reduction of mortality caused by the ischemic lesion (p<0.01), infarct volume (p=0.027), number of TUNEL positive cells in striatum (p=0.014) and plasma levels of TNF-alpha at 3 h (p=0.027) and 72 h (p=0.011). rtPA induced reperfusion provided a slight non-significant reduction of infarct volume and neuronal death, but it reduced mortality due to brain damage (p<0.01) although an increase in the risk of fatal bleeding was noted. CiT as monotherapy only produced a significant reduction of neuronal death in striatum (p=0.014). The combination of CiT before rtPA did not add any benefit to rtPA alone. The superiority of the combined treatment with rtPA followed by citicoline suggests that early reperfusion should be followed by effective neuroprotection to inhibit ischemia-reperfusion injury and better protect the tissue at risk.     

Cerebral blood flow and tissue oxygen saturation in immediate and progressive ischemia in rat brain

Abstract

The aim of the present study was to investigate whether immediate ischemia is more harmful to the brain than progressive ischemia. To do so, we examined the correlation between the degree and the process of ischemia using hypobaric hypotension technique, which was used to reduce systemic blood pressure acutely or progressively below the lower threshold of CBF regulation, in rat brain. In Wistar rats (n = 21), global ischemia using bilateral carotid arteries occlusion coupled with hypobaric hypotension was induced by lowering mean arterial blood pressure (MABP) progressively to 55, 45 and 35 mmHg or immediately to 35 mmHg. Local cerebral blood flow (lCBF) by laser Doppler (LD) flowmetry and tissue hemoglobin oxygen saturation (HbSO₂) by a microspectrophotometric method were measured at 25 corresponding locations using a 'scanning' technique which employs a computer-controlled micromanipulator. Regional CBF (rCBF) and rHbSO₂ were determined by calculation of the median value from the 25 ICBF and lHbSO₂ data. In the 'progressive' group, rCBF and rHbSO₂ decreased gradually and reached 12.2 ± 15.8 LD-units and 44.9% ± 13.4% at 35 mmHg of MABP, respectively. In the 'immediate' group, both parameters dropped suddenly to 7.86 ± 10.6 LD-units (p < 0.01 vs. CBF of the progressive group) and 22.5% ± 15.5% (p < 0.001 vs. tissue HbSO₂ of the progressive group) from the control at 35 mmHg. These data suggested that cerebral ischemia is better tolerated if it is induced gradually. CBF recorded by LD-scanning technique and HbSO value by microspectrophotometric method correlated well in the ischemic condition, indicating that HbSO₂ can be preserved if CBF is decreased gradually. [Neurol Res 2001; 23: 875-880]     

Changes in hemodynamics during isoflurane and propofol anesthesia: a comparison study

Abstract

Objectives: Volatile anesthetics are thought to impair cerebral autoregulation more than i.v. anesthetics. However, few comparative studies have been carried out in humans. The aim of our study was to evaluate the differences in cerebral hemodynamic changes after introduction of isoflurane (a volatile anesthetic) and propofol (an i.v. anesthetic).

Methods: Eighteen consecutive patients submitted to laparoscopic cholecystectomy were selected. After the induction, anesthesia was maintained by isoflurane (one minimum alveolar anesthetic concentration) during the first part of the surgical operation, and then by propofol (5 mg/kg/hour i.v.). Ventilation was adjusted to maintain a constant end-tidal CO₂. Middle artery flow velocity was assessed by means of transcranial Doppler ultrasonography. Arterial blood pressure, heart rate (HR), capnometry, pulse oxymetry, inspired fraction of O₂, and body temperature, were monitored.

Results: Cerebral artery velocity, HR, and mean arterial pressure all significantly increased from baseline after the introduction of isoflurane (p<0.05); the HR and mean arterial blood pressure showed no significant difference between the isoflurane and propofol phases. Isoflurane anesthesia induced a significant increase in cerebral blood velocity. Propofol introduction led to a significant decrease in cerebral artery velocity (p<0.05).

Conclusions: Propofol but not isoflurane decreased cerebral blood velocity thus restoring cerebral autoregulation and the coupling between cerebral blood flow and cerebral metabolism.     

Neuroprotection with NBQX and thrombolysis with rt-PA in rat embolic stroke

Abstract

The efficacy of delayed thrombolysis with recombinant tissue plasminogen activator was tested in combination with the ischaemic protecting drug NBQX in an embolic stroke model. In 113 rats the carotid territory was embolized with a fibrin-rich clot formed in polyethylene tube. Hemispheric cerebral blood flow (CBF) was measured by intra-arterial ¹³³Xenon injection method before and after embolization. Two hours after embolization 67 animals were treated with tissue plasminogen activator 20 mg kg^–1 46 control animals with saline. NBQX was given to 53 animals> of which 41 animals also received thrombolytic therapy and 12 were saline controls. Carotid angiography displayed the rate of occlusion of the cerebral arterial supply before and after treatment. Brains were fixed after two days, evaluated neuropathologically, and infarct volume was measured. Embolization caused a 60-78% reduction of median CBF. The comparison of post-treatment angiography of thrombolytic treated animals to controls showed significant (p<0.01) reperfusion in thrombolytic treated animals, while NBQX alone did not enhance reperfusion. Thrombolytic therapy significantly reduced the total infarct volume from 19.5% to 4.5% of embolized hemisphere volume (p = 0.006). NBQX alone reduced total infarct volume from 19.5% to 6.5% and cortical infarct volume from 7.9% to 0.3% (p = 0.03). In thrombolytic treated animals NBQX reduced total infarct volume from 4.5% to 2.1%. The more than 50% reduction of total infarction volume caused by NBQX was not statistically significant due to the variation of infarct size in this model. Small haemorrhagic lesions in infarcts were observed in thrombolytic treated animals. The clinical outcome correlated well with infarct volume. Delayed thrombolytic therapy induced recanalization and significantly reduced infarct volume after embolic stroke. The ischaemic protecting drug NBQX significantly reduced cortical infarctions. [Neurol Res 1993; 15: 344-349]     

Three-tesla magnetic resonance imaging study of cerebral microbleeds in patients with ischemic stroke

Abstract

Objectives: The aims of this study were to analyse the distribution of cerebral microbleeds (CMBs) in patients with ischemic stroke and study the relationship between CMBs and the severity of old lacunar infarcts and cerebral white matter changes.

Methods: The study population consisted of 247 consecutive inpatients with ischemic stroke. Magnetic resonance imaging findings of these inpatients were observed. CMBs were counted respectively according to their locations, including the corticosubcortical regions, basal ganglia, thalami, brainstem and cerebellum. The number of the old lacunes and the severity of the cerebral white matter changes were also recorded. Based on the occurrence of CMBs, the patients were divided into two groups (72 patients with CMBs; 175 patients without CMBs).

Results: The most common location of CMBs in patients with ischemic stroke was the basal ganglia, followed by the corticosubcortical region, the thalami, the brainstem and the cerebellum. The severity of CMBs was closely correlated with the severity of lacunar infarcts and cerebral white matter changes, respectively.

Discussion: CMBs are closely related with cerebral microangiopathy and may be a marker of advanced stage cerebral microangiopathy.     

Thrombolytic and anticoagulation treatment in a rat embolic stroke model

OBJECTIVES: The effects of pentasaccharide (PENTA), given alone or combined with thrombolysis using recombinant tissue plasminogen activator (rt-PA), on infarct size and clinical outcome were evaluated in a rat embolic stroke model. MATERIALS AND METHODS: Ninety-two rats were embolized unilaterally and assigned to: (i). controls, (ii). rt-PA 6 mg/kg, (iii). PENTA 0.5 mg/kg, (iv). PENTA 0.5 mg/kg and rt-PA 6 mg/kg. After 2 days animals were killed, the brains removed and evaluated microscopically. RESULTS: The median infarct size measured in percentage of the affected hemisphere was 25% in the control group, 4% (P < 0.01, Mann Whitney) in group 2, 19% (n.s.) in group 3, and 10% (P < 0.05) in group 4. rt-PA, and rt-PA combined with PENTA also promoted functional recovery. CONCLUSION: The present study found no effect of 0.5 mg/kg PENTA treatment. Compared with rt-PA treatment alone, 0.5 mg/kg PENTA alone or combined with rt-PA did not significantly increase mortality or tendency for hemorrhage.     

Effects of microplasmin on recovery in a rat embolic stroke model

OBJECTIVES: The purpose of the present study was to examine the effects of microplasmin on behavioral performance and infarct volume after middle cerebral artery occlusion (MCAO) in rats. Some experiments support that microplasmin may have neuroprotective and thrombolytic properties. METHODS: Eighty rats underwent surgery and were embolized in the right carotid territory with a fibrin-rich embolus and randomly assigned into three groups: 5 mg/kg microplasmin, 10 mg/kg microplasmin or saline (control). Groups treated with microplasmin received 50% bolus injection 10 minutes after embolization and 50% continuous infusion during the following hour. Animals from all groups were trained to obtain high baseline scores in Montoya's staircase test before embolization and were retested during 7-14 days after surgery. RESULTS: When pre-maturely dead animals were excluded, no differences were observed among groups regarding infarct volumes. Furthermore, mortality was significantly lower in Group 1 than in Group 2 (p<0.05) and when performances were evaluated 7-14 days after surgery, Group 1 was significantly better than Group 2 concerning fine motor performance (p<0.05) and also achieved more normal bodyweight (p<0.05). DISCUSSION: Among surviving animals, 5 mg/kg microplasmin treatment had no effect compared to saline-treated control animals; 5 mg/kg microplasmin reduced mortality and improved both behavioral rehabilitation and bodyweight compared to 10 mg/kg microplasmin treatment, while saline-treated animals did not differ from animals treated with 10 mg/kg microplasmin. Overall, these results indicate a potential beneficial effect of 5 mg/kg microplasmin treatment, while 10 mg/kg may worsen outcomes.     

The effects of early insulin treatment combined with thrombolysis in rat embolic stroke

The therapeutic effect of insulin alone or insulin combined with 30 min delayed thrombolytic therapy was investigated in rats embolized in the right hemisphere with a fibrin clot made from autologous blood. Animals were killed seven days after embolization and the infarct volumes were measured in % of the affected hemisphere. Mortality was calculated as the number of animals dying spontaneously before the scheduled euthanasia. The median infarct volume in control animals (n = 12) was 24%. Insulin (3 IU kg(-1)) was given subcutaneously 15 min, 3 h, and 24 h after embolization (n = 12) and reduced median infarct volume to 11%. Human recombinant tissue plasminogen activator, 8 mg kg(-1), was infused intravenously during 45 min starting 30 min after embolization (n = 14), and the median infarct volume was 18% in this group. When the two treatments were combined, the median infarct volume was reduced to 11% (n = 14). The infarct volumes in the treatment groups were not significantly different from controls (p = 0.62, Kruskal Wallis test). Mortality rates increased from 0% among controls to 47% (p = 0.01) in the insulin alone and 38% (p = 0.02) in the combination therapy group. In conclusion, insulin treatment aiming at blood glucose levels around 2-4 mmol l(-1) was detrimental to clinical outcome causing significantly increased mortality.     

Influence of Repetitive Transcranial Magnetic Stimulation on Disease Severity and Oxidative Stress Markers in the Cerebrospinal Fluid Of Patients with Spinocerebellar Degeneration

Abstract

Ataxia severity, cerebellar hemispheric blood flow (CHBF), ascorbate free radical (AFR), superoxide dismutase protein, superoxide scavenging activity, and 8–hydroxy–2^´–deoxyguanosine (8–OHdG) in cerebrospinal fluid (CSF) were compared before and after an 8–week course of repetitive transcranial magnetic stimulation (rTMS) in 20 patients with spinocerebellar degenerations (SCD). SCD patients showed higher AFR, 8–OHdG, and superoxide scavenging activity than 19 controls. In SCD patients, AFR and ataxia severity declined, and CHBF increased after rTMS. As the SCD patients showed negative correlations between ataxia severity and CHBF or superoxide scavenging activity, the therapeutic mechanism of rTMS may involve decreased oxidative stress and increased CHBF.