摘要:

Background and Purpose—Hyperglycemia at the time of ischemic stroke is associated with increased mortality and morbidity. Animal studies suggest that infarct expansion may be responsible. The influence of persisting hyperglycemia after stroke has not previously been examined. We measured the blood glucose profile after acute ischemic stroke and correlated it with infarct volume changes using T2- and diffusion-weighted MRI.Methods—We recruited 25 subjects within 24 hours of ischemic stroke symptoms. Continuous glucose monitoring was performed with a glucose monitoring device (CGMS), and 4-hour capillary glucose levels (BGL) were measured for 72 hours after admission. MRI and clinical assessments were performed at acute (median, 15 hours), subacute (median, 5 days), and outcome (median, 85 days) time points.Results—Mean CGMS glucose and mean BGL glucose correlated with infarct volume change between acute and subacute diffusion-weighted MRI (r≥0.60,P<0.01), acute and outcome MRI (r=0.56,P=0.01), outcome National Institutes of Health Stroke Scale (NIHSS;r≥0.53,P<0.02), and outcome modified Rankin Scale (mRS;r≥0.53,P=0.02). Acute and final infarct volume change and outcome NIHSS and mRS were significantly higher in patients with mean CGMS or mean BGL glucose ≥7 mmol/L. Multiple regression analysis indicated that both mean CGMS and BGL glucose levels ≥7 mmol/L were independently associated with increased final infarct volume change.Conclusions—Persistent hyperglycemia on serial glucose monitoring is an independent determinant of infarct expansion and is associated with worse functional outcome. There is an urgent need to study normalization of blood glucose after stroke.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background and Purpose—Hyperglycemia has a deleterious effect on brain ischemia. However, the effect of hyperglycemia in intracerebral hemorrhage (ICH) is not well known. We investigated the effect of hyperglycemia on the development of brain edema and perihematomal cell death in ICH.Methods—Hyperglycemia was induced by intraperitoneal injection of streptozotocin (60 mg/kg) in adult Sprague-Dawley male rats. ICH was induced by stereotaxic infusion of 0.23 U of collagenase into the left striatum. Seventy-two hours after ICH, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining was performed for perihematomal cell death. We also measured brain water content to evaluate edema formation.Results—The serum glucose level of the hyperglycemic group was 394.0±180.3 mg/dL (n=31), and that of the normoglycemic group was 97.5±27.4 mg/dL (n=31). The size of hemorrhage was similar between groups, without any significant difference (n=8 in each group). The brain water content of hyperglycemic rats (n=17) increased in both lesioned (81.0±0.5%) and nonlesioned hemispheres (78.7±0.6%) compared with the normoglycemic group (n=17; lesioned: 78.9±0.8%; nonlesioned: 77.3±1.1%). In the hyperglycemic group, more TUNEL-positive cells were found in the perihematomal regions (n=6).Conclusions—Hyperglycemia caused more profound brain edema and perihematomal cell death in experimental ICH.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background and Purpose—A major limitation of intracerebral hemorrhage (ICH) research is the lack of reproducible animal models. The present study was conducted to validate in the mouse the double-injection method of ICH initially developed in the rat. We investigated the effect of intrastriatal injection of blood or cerebrospinal fluid (CSF) on cerebral blood flow (CBF), neurological score, hematoma volume, and brain swelling.Methods—Male C57BL/6 mice were anesthetized with halothane/nitrous oxide delivered by face mask. Rectal and cranial temperatures were regulated at 37°C to 37.5°C. Mice were placed in a stereotactic frame, and a 30-gauge stainless steel cannula was introduced through a burr hole into the left striatum. Each mouse received a 5-&mgr;L injection of either whole blood or CSF (over 3 minutes), followed 7 minutes later by 10 &mgr;L injected over 5 minutes. The injection cannula was slowly withdrawn 10 minutes after the second injection. Control mice had only cannula insertion. CBF was studied by laser Doppler perfusion imaging. Neurological status was evaluated on days 1 and 2. After 2 days, hematoma volume and brain swelling were calculated.Results—Physiological values were stable. Mice with ICH but not those with CSF or cannula alone had a marked, persistent neurological deficit and a highly reproducible hematoma, whose mean±SEM volume was 2.0±0.2 mm3compared with a lesion size of 0.2±0.1 mm3in mice with CSF. Residual swelling of the ipsilateral hemisphere at 48 hours was 5.7% in the hematoma and 1.5% in the CSF groups. Relative CBF in the neocortex ipsilateral to the injection site declined by ∼45% to 60% during the first 20 minutes after cannula insertion/injection in all groups but began to renormalize at ∼25 to 30 minutes in the CSF and cannula-only groups; in the hematoma group, cortical hypoperfusion of ∼35% to 50% persisted during the 90-minute measurement period.Conclusions—The present ICH model in mice produces a consistent neurological deficit, hypoperfusion, hematoma volume, and brain swelling. This model closely mimics human hypertensive basal ganglionic ICH and should be useful for the evaluation of pharmaceutical therapies. Laser Doppler perfusion imaging is a useful new technique to quantify relative CBF changes and can be used for studies of dynamic changes of CBF in this in vivo model of ICH in mice.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background and Purpose—NXY-059 has substantial protective effects when administered immediately after the onset of ischemia in a primate model of stroke. This study examined the efficacy of this drug when administered 4 hours after onset, a more clinically relevant time point.Methods—Before surgery, marmosets were trained and tested on a number of neurological tests, which assessed general neurological function, motor ability, and spatial awareness. Four hours after permanent middle cerebral artery occlusion (pMCAO), marmosets received a bolus of saline (n=13) or NXY-059 (n=13), and osmotic minipumps were implanted, providing 48-hour saline or drug (85 &mgr;mol/kg per hour) infusion. The monkeys were retested 3 and 10 weeks after surgery. Finally, infarct size was evaluated with histological analysis.Results—The unbound plasma NXY-059 concentration was 200±9 &mgr;mol/L after 24-hour infusion, a concentration well tolerated in stroke patients. Drug treatment ameliorated the long-term motor impairment produced by pMCAO; the marmosets were better at using their contralesional, stroke-affected arm than controls at both 3 and 10 weeks. Saline-treated animals had a debilitating spatial neglect at 3 weeks with residual signs evident at 10 weeks. NXY-059 treatment substantially attenuated neglect at 3 weeks, with no deficit being seen at 10 weeks. NXY-059 reduced the overall infarct size by 28% (saline, 324±46 mm3; NXY-059, 234±30 mm3) with protection to the cortex, white matter, and subcortical structures.Conclusions—NXY-059 is an effective neuroprotective agent when administered 4 hours after pMCAO in a primate species, attenuating both motor and spatial neglect. The compound also substantially lessened the volume of cerebral damage.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background and Purpose—Permanent middle cerebral artery occlusion (MCAO) with the use of the suture technique causes hypothalamic damage with subsequent hyperthermia, which can confound neuroprotective drug studies. In the present study the neuroprotective effects of dizocilpine (MK-801) were compared in different permanent MCAO models with and without hypothalamic damage and hyperthermia.Methods—Sixty Sprague-Dawley rats were treated with MK-801 or placebo, beginning 15 minutes before MCAO, and assigned to the following groups: suture MCAO (group I), macrosphere MCAO without hypothalamic damage (group II), or macrosphere MCAO with intentionally induced hypothalamic infarction (group III). Body temperature was measured at 3, 6, and 24 hours. Lesion size was determined after 24 hours (2,3,5-triphenyltetrazolium chloride staining).Results—Hypothalamic damage was present in animals in group I and was intentionally induced in group III with the use of a modified macrosphere MCAO technique. Body temperature was significantly increased 3, 6, and 24 hours after MCAO in these 2 groups of animals. Hypothalamic damage and subsequent hyperthermia could be avoided effectively by limiting the number of macrospheres (group II). MK-801 provided a highly significant neuroprotective effect in group II but not in groups I and III.Conclusions—Hypothalamic damage with subsequent hyperthermia masked the neuroprotective effect of MK-801. This side effect can be avoided by using the macrosphere MCAO technique with a limited number of spheres. This model therefore may be more appropriate to study the effects of neuroprotective drugs in permanent focal cerebral ischemia than the suture method.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background and Purpose—The fetus is well known to be able to survive prolonged exposure to asphyxia with minimal injury compared with older animals. We and others have observed a rapid suppression of EEG intensity with the onset of asphyxia, suggesting active inhibition that may be a major neuroprotective adaptation to asphyxia. Adenosine is a key regulator of cerebral metabolism in the fetus.Methods—We therefore tested the hypothesis that infusion of the specific adenosine A1receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), given before 10 minutes of profound asphyxia in near-term fetal sheep, would prevent neural inhibition and lead to increased brain damage.Results—DPCPX treatment was associated with a transient rise and delayed fall in EEG activity in response to cord occlusion (n=8) in contrast with a rapid and sustained suppression of EEG activity in controls (n=8). DPCPX was also associated with an earlier and greater increase in cortical impedance, reflecting earlier onset of primary cytotoxic edema, and a significantly smaller reduction in calculated cortical heat production after the start of cord occlusion. After reperfusion, DPCPX-treated fetuses but not controls developed delayed onset of seizures, which continued for 24 hours, and sustained greater selective hippocampal, striatal, and parasagittal neuronal loss after 72-hour recovery.Conclusions—These data support the hypothesis that endogenous activation of the adenosine A1receptor during severe asphyxia mediates the initial suppression of neural activity and is an important mechanism that protects the fetal brain.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background and Purpose—We have recently demonstrated that pretreatment with magnesium (calcium and glutamate antagonist) and tirilazad (antioxidant) in combination with intraischemic mild hypothermia (33°C) (MTH) offers superior neuroprotective efficacy in a rat model of focal transient cerebral ischemia. In the present study, we investigated the time window of this treatment strategy with a posttreatment regimen to define its role for stroke patients.Methods—We subjected 48 Sprague-Dawley rats to 90 minutes of middle cerebral artery occlusion by an intraluminal filament. Bilateral regional cerebral blood flow was continuously recorded by laser Doppler flowmetry. Combination therapy with MTH was started at 0, 1, 3, and 5 hours after induction of ischemia. Drugs were given in 1-hour intervals, and hypothermia was maintained for 2 hours. Neurological deficits were assessed daily. Infarct size was planimetrically determined on postoperative day 7.Results—Combination therapy with MTH significantly reduced infarct volume compared with normothermic controls by −74%, −49%, and −45% when applied at 0, 1, and 3 hours after induction of ischemia. Furthermore, these treatment groups showed less neurological deficits on postischemic days 1 and 2 (P<0.05). Onset of treatment 5 hours after middle cerebral artery occlusion failed to significantly reduce infarct formation and neurological deficits.Conclusions—The therapeutic window of the new combination therapy is at least 3 hours after onset of ischemia, comparable to that of moderate hypothermia (30°C), a grade of hypothermia associated with higher risks of severe side effects.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background and Purpose—Middle cerebral artery occlusion (MCAO) by an intraluminal filament is a widely accepted animal model of focal cerebral ischemia. In this procedure, cutting of the external carotid artery (ECA) is a prerequisite for thread insertion. However, the implications of ECA transsection have not yet been described.Methods—After 90 minutes of filament MCAO or sham surgery, rats were evaluated for up to 14 days in terms of body weight development, core temperature, and motor performance. Repeated in vivo MRI of the head and neck was performed for quantification of brain edema and infarct volume. The temporal muscles were histologically analyzed postmortem.Results—In 47% of all rats, ischemic tissue damage to the ipsilateral ECA area, including temporal, lingual, and pharyngeal musculature, was detectable by MRI. Histology of temporal muscles confirmed acute ischemic myopathy. Animals with ECA territory ischemia (ECA-I) showed delayed body weight development and poorer recovery of motor function. There was no difference in the extent of brain edema or final cerebral lesion size between ECA-I–affected and unaffected rats.Conclusions—Filament MCAO was complicated by the consequences of ECA ischemia in approximately half of all rats. Impaired mastication and swallowing functions restricted ingestion and resulted in postsurgical body weight loss and worse motor performance. Impaired cerebral microperfusion resulting from dehydration and reduced spontaneous motor activity resulting from reduced food and water uptake might have contributed to poorer neurological recovery in ECA ischemic rats. Thus, adverse effects caused by extracerebral ischemia with potential impact on outcome have to be considered in this stroke model.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background and Purpose—Cell transplantation has been used to reduce behavioral deficit in cerebral ischemia. However, there is no report about cell transplantation in experimental intracerebral hemorrhage (ICH). We hypothesize that intravenously transplanted human neural stem cells (NSCs) can migrate and differentiate into neurons or glial cells, thereby improving functional outcome in ICH.Methods—Experimental ICH was induced by intrastriatal administration of bacterial collagenase in adult rats. One day after surgery, the rats were randomly divided into 2 groups to receive intravenously either immortalizedLac z–positive human NSCs (5×106cells in 500 &mgr;L, n=12) or the same amount of saline (n=13). The animals were evaluated for 8 weeks with modified limb placing and rotarod tests. Transplanted NSCs were detected by X-gal histochemistry or &bgr;-gal immunohistochemistry with double labeling of GFAP, NeuN, neurofilament, or CNPase.Results—Intravenously transplanted NSCs migrated selectively to the perihematomal areas and differentiated into neurons (≈10% of &bgr;-gal+cells) and astrocytes (≈75%). The NSC-transplanted group showed better functional performance on rotarod test after 2 weeks and on modified limb placing test after 5 weeks compared with the control group (P<0.05), and these effects persisted for up to 8 weeks. There was no difference in the final hemispheric area between the 2 groups.Conclusions—Intravenously transplanted NSCs can enter the rat brain with ICH, survive, migrate, and improve functional recovery. Transplantation of human NSCs can be used to restore neurological deficits in experimental ICH.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—This article reviews the anatomy, connections, and functions of the thalamic nuclei, their vascular supply, and the clinical syndromes that result from thalamic infarction.Summary of Review—Thalamic nuclei are composed of 5 major functional classes: reticular and intralaminar nuclei that subserve arousal and nociception; sensory nuclei in all major domains; effector nuclei concerned with motor function and aspects of language; associative nuclei that participate in high-level cognitive functions; and limbic nuclei concerned with mood and motivation. Vascular lesions destroy these nuclei in different combinations and produce sensorimotor and behavioral syndromes depending on which nuclei are involved. Tuberothalamic territory strokes produce impairments of arousal and orientation, learning and memory, personality, and executive function; superimposition of temporally unrelated information; and emotional facial paresis. Paramedian infarcts cause decreased arousal, particularly if the lesion is bilateral, and impaired learning and memory. Autobiographical memory impairment and executive failure result from lesions in either of these vascular territories. Language deficits result from left paramedian lesions and from left tuberothalamic lesions that include the ventrolateral nucleus. Right thalamic lesions in both these vascular territories produce visual-spatial deficits, including hemispatial neglect. Inferolateral territory strokes produce contralateral hemisensory loss, hemiparesis and hemiataxia, and pain syndromes that are more common after right thalamic lesions. Posterior choroidal lesions result in visual field deficits, variable sensory loss, weakness, dystonia, tremors, and occasionally amnesia and language impairment.Conclusions—These vascular syndromes reflect the reciprocal cerebral cortical-thalamic connections that have been interrupted and provide insights into the functional properties of the thalamus.

ISSN:0039-2499    

出版商:OVID    

年代:2003

数据来源: OVID