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1.
J Neurosurg Spine ; 6(2): 165-8, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17330586

ABSTRACT

The authors present a rare case of cervical myelopathy caused by dropped head syndrome. This 68-year-old woman presented with her head hanging forward. After 1 month, she was admitted to the medical service because of head drop progression. Examination of biopsy specimens from her cervical paraspinal muscles showed nonspecific myopathic features without inflammation, and isolated neck extensor myopathy was diagnosed. The patient's condition did not respond to the administration of corticosteroids. During follow up as an outpatient, the patient's head drop continued to gradually progress. At 1 year after onset, she developed bilateral weakness of the upper and lower extremities, clumsiness of the hands, and gait disturbance. A radiograph of the cervical spine obtained in a standing position showed a pronounced kyphotic deformity and instability at the level of C4-5. Magnetic resonance imaging demonstrated spinal cord compression at C-3 and C-4. The patient underwent a C3-4 laminectomy and occipitocervicothoracic fixation. Gait and hand coordination gradually improved, and she was able to walk with no support 1 month postoperatively. Surgical fixation was beneficial in this patient with dropped head syndrome, myelopathy, and cervical instability.


Subject(s)
Muscle Weakness/complications , Neck Muscles , Spinal Cord Compression/etiology , Aged , Arm , Bone Nails , Cervical Vertebrae/diagnostic imaging , Cervical Vertebrae/pathology , Cervical Vertebrae/surgery , Female , Head Movements , Humans , Joint Instability/complications , Joint Instability/surgery , Kyphosis/complications , Kyphosis/diagnostic imaging , Laminectomy , Leg , Magnetic Resonance Imaging , Muscle Weakness/etiology , Muscle Weakness/physiopathology , Radiography , Spinal Cord Compression/complications , Spinal Cord Compression/diagnosis , Spinal Cord Compression/surgery , Spinal Diseases/complications , Spinal Diseases/surgery , Syndrome , Thoracic Vertebrae/surgery , Treatment Outcome
2.
J Cereb Blood Flow Metab ; 27(1): 196-204, 2007 Jan.
Article in English | MEDLINE | ID: mdl-16685257

ABSTRACT

There is increasing interest in using algorithms combining multiple magnetic resonance imaging (MRI) modalities to predict tissue infarction in acute human stroke. We developed and tested a voxel-based generalized linear model (GLM) algorithm to predict tissue infarction in an animal stroke model in order to directly compare predicted outcome with the tissue's histologic outcome, and to evaluate the potential for assessing therapeutic efficacy using these multiparametric algorithms. With acute MRI acquired after unilateral embolic stroke in rats (n=8), a GLM was developed and used to predict infarction on a voxel-wise basis for saline (n=6) and recombinant tissue plasminogen activator (rt-PA) treatment (n=7) arms of a trial of delayed thrombolytic therapy in rats. Pretreatment predicted outcome compared with post-treatment histology was highly accurate in saline-treated rats (0.92+/-0.05). Accuracy was significantly reduced (P=0.04) in rt-PA-treated animals (0.86+/-0.08), although no significant difference was detected when comparing histologic lesion volumes. Animals that reperfused had significantly lower (P<0.01) GLM-predicted infarction risk (0.73+/-0.03) than nonreperfused animals (0.81+/-0.05), possibly reflecting less severe initial ischemic injury and therefore tissue likely more amenable to therapy. Our results show that acute MRI-based algorithms can predict tissue infarction with high accuracy in animals not receiving thrombolytic therapy. Furthermore, alterations in disease progression due to treatment were more sensitively monitored with our voxel-based analysis techniques than with volumetric approaches. Our study shows that predictive algorithms are promising metrics for diagnosis, prognosis and therapeutic evaluation after acute stroke that can translate readily from preclinical to clinical settings.


Subject(s)
Infarction, Middle Cerebral Artery/pathology , Stroke/pathology , Algorithms , Animals , Brain Ischemia/pathology , Linear Models , Magnetic Resonance Imaging , Male , Models, Neurological , Plasminogen Activators/therapeutic use , Predictive Value of Tests , Rats , Rats, Sprague-Dawley , Recombinant Proteins/therapeutic use
3.
J Cereb Blood Flow Metab ; 25(6): 722-9, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15716855

ABSTRACT

Previous studies have shown that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) protect the brain against ischemic injury by upregulating endothelial nitric oxide synthase (eNOS). Here, we tested the hypothesis that statins provide additional beneficial effects by also upregulating endogenous tissue plasminogen activator (tPA) and enhancing clot lysis in a mouse model of embolic focal ischemia. Heterologous blood clots (0.2 mm) were injected into the distal internal carotid artery to occlude blood flow in the middle cerebral artery territory after long-term (14 days) simvastatin, atorvastatin or vehicle treatment. Ischemic lesion volume, neurologic deficits, as well as residual blood clots were measured at 22 h. Reverse transcription-polymerase chain reaction assessed mRNA levels of eNOS, tPA, and the endogenous plasminogen activator inhibitor PAI-1. Ischemic lesion volumes and neurologic deficits were significantly reduced in wild-type mice by both simvastatin and atorvastatin. Statins increased eNOS and tPA mRNA levels but did not change mRNA levels of PAI-1. In eNOS knockout mice, atorvastatin reduced the volume of ischemic tissue and improved neurologic outcomes after arterial occlusion by blood clot emboli. In contrast, statins did not have protective effects in tPA knockout mice after embolic focal ischemia, but only in a filament model where focal ischemia was achieved via mechanical occlusion. These results suggest that statins protect against stroke by multiple mechanisms involving both eNOS and tPA. The involvement of each pathway may be revealed depending on the choice of experimental stroke model.


Subject(s)
Brain Ischemia/drug therapy , Brain Ischemia/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Nitric Oxide Synthase/metabolism , Simvastatin/pharmacology , Tissue Plasminogen Activator/metabolism , Animals , Atorvastatin , Disease Models, Animal , Heptanoic Acids/pharmacology , Intracranial Embolism/drug therapy , Intracranial Embolism/metabolism , Male , Mice , Mice, Inbred Strains , Mice, Knockout , Neuroprotective Agents/pharmacology , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase Type II , Nitric Oxide Synthase Type III , Pyrroles/pharmacology , Stroke/drug therapy , Stroke/metabolism , Tissue Plasminogen Activator/genetics
4.
J Cereb Blood Flow Metab ; 23(8): 895-9, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12902833

ABSTRACT

Thrombolytic stroke therapy with tissue plasminogen activator (tPA) is limited by serious risks of intracerebral hemorrhage. In this study, the authors show that a novel antiactin-targeted immunoliposome significantly reduced tPA-induced hemorrhage in an established rat model of embolic focal stroke. Spontaneously hypertensive rats were subjected to focal ischemia using homologous blood clot emboli. Delayed administration of tPA (10 mg/kg, 6 hours after ischemia) induced intracerebral hemorrhage at 24 hours. In control rats treated with tPA plus vehicle, hemorrhage volumes were 9.0 +/- 2.4 uL (n = 7). In rats treated with tPA plus antiactin immunoliposomes, hemorrhage volumes were significantly reduced to 4.8 +/- 2.7 uL (n = 8, P < 0.05). No significant effects were seen when rats were treated with tPA plus a nontargeted liposome (7.8 +/- 2.1 uL, n = 9). Fluorescent immunohistochemistry showed that rhodamine-labeled targeted liposomes colocalized with vascular structures in ischemic brain that stained positive for endothelial barrier antigen, a marker of cerebral endothelial cells. These data suggest that immunoliposomes may ameliorate vascular membrane damage and reduce hemorrhagic transformation after thrombolytic therapy in cerebral ischemia.


Subject(s)
Actins/immunology , Cerebral Hemorrhage/therapy , Intracranial Embolism/drug therapy , Liposomes , Tissue Plasminogen Activator/adverse effects , Animals , Cerebral Hemorrhage/chemically induced , Cerebral Hemorrhage/immunology , Disease Models, Animal , Immunohistochemistry , Male , Rats , Rats, Inbred SHR
5.
Stroke ; 33(11): 2711-7, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12411666

ABSTRACT

BACKGROUND AND PURPOSE: Most experimental models of cerebral ischemia use mechanical methods of occlusion and reperfusion. However, differences between mechanical reperfusion versus clot thrombolysis may influence reperfusion injury profiles. In this study we compared blood flow recovery, blood-brain barrier (BBB) permeability, and matrix metalloproteinase-9 (MMP-9) expression in cortex after mechanical versus thrombolytic reperfusion in rat focal ischemia. METHODS: Male spontaneously hypertensive rats were used. Mechanical ischemia/reperfusion was achieved with the use of an intraluminal filament to occlude the middle cerebral artery for 2 hours. Thrombolytic reperfusion was achieved by administering tissue plasminogen activator at 2 hours after embolic focal ischemia. Regional cortical blood flow was monitored by laser-Doppler flowmetry. BBB permeability in cortex was measured by Evans blue dye leakage. Cortical MMP-9 levels were assessed with zymography and immunohistochemistry. RESULTS: Blood flow recovery during mechanical reperfusion was complete in both central and peripheral areas of ischemic cortex. However, after thrombolysis, reperfusion was incomplete, with moderate recovery in the periphery only. BBB permeability was mainly increased in the central regions of the ischemic cortex after mechanical reperfusion but was increased in both central and peripheral areas after thrombolysis. Overall, MMP-9 levels were higher after embolic versus mechanical ischemia/reperfusion, even though ischemic injury was similar in both models at 24 hours. CONCLUSIONS: There are significant differences in the profiles of blood flow recovery, BBB leakage, and MMP-9 upregulation in mechanical versus thrombolytic reperfusion after focal ischemia.


Subject(s)
Blood-Brain Barrier , Brain Ischemia/enzymology , Intracranial Embolism/enzymology , Matrix Metalloproteinase 9/biosynthesis , Reperfusion Injury/enzymology , Animals , Blood Flow Velocity/drug effects , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/physiology , Brain Ischemia/pathology , Cerebral Cortex/blood supply , Cerebral Cortex/enzymology , Cerebral Cortex/pathology , Cerebrovascular Circulation/drug effects , Disease Models, Animal , Evans Blue , Fibrinolytic Agents/therapeutic use , Immunohistochemistry , Intracranial Embolism/drug therapy , Intracranial Embolism/pathology , Male , Rats , Rats, Inbred SHR , Reperfusion Injury/pathology , Tissue Plasminogen Activator/therapeutic use , Up-Regulation/drug effects
6.
J Cereb Blood Flow Metab ; 22(7): 861-8, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12142571

ABSTRACT

Recent studies suggest that normobaric hyperoxia can be beneficial, if administered during transient stroke. However, increased oxygenation theoretically may increase oxygen free-radical injury, particularly during reperfusion. In the present study, the authors assessed the benefit and risks of hyperoxia during focal cerebral ischemia and reperfusion. Rats were subjected to hyperoxia (Fio2 100%) or normoxia (Fio2 30%) during 2-hour filament occlusion and 1-hour reperfusion of the middle cerebral artery. At 24 hours, the hyperoxia group showed 70% (total) and 92% (cortical) reduction in infarct volumes as compared to the normoxia group. Levels of oxidative stress were evaluated using three indirect methods. First, since oxygen free radicals increase blood-brain barrier (BBB) damage, Evan's blue dye extravasation was quantified to assess BBB damage. Second, the expression of heme oxygenase-1 (HO-1), a heat shock protein inducible by oxidative stress, was assessed using Western blot techniques. Third, an immunoblot technique ("OxyBlot") was used to assess levels of protein carbonyl formation as a marker of oxidative stress-induced protein denaturation. At 24 hours, Evan's blue dye extravasation per average lesion volume was similar between groups. There were no significant differences in HO-1 induction and protein carbonyl formation between groups, in the ipsilateral or contralateral hemispheres, at 6 hours and at 24 hours. These results indicate that hyperoxia treatment during focal cerebral ischemia-reperfusion is neuroprotective, and does not increase oxidative stress.


Subject(s)
Ischemic Attack, Transient/therapy , Oxygen/administration & dosage , Reperfusion , Animals , Arteries , Blood-Brain Barrier , Cerebral Infarction/pathology , Disease Models, Animal , Heme Oxygenase (Decyclizing)/metabolism , Heme Oxygenase-1 , Hyperoxia , Ischemic Attack, Transient/etiology , Ischemic Attack, Transient/pathology , Kinetics , Male , Middle Cerebral Artery/surgery , Nerve Tissue Proteins/chemistry , Oxidative Stress , Oxygen/blood , Oxygen/therapeutic use , Protein Denaturation , Rats , Rats, Sprague-Dawley
7.
Stroke ; 33(7): 1882-8, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12105370

ABSTRACT

BACKGROUND AND PURPOSE: Apoptotic-like pathways may contribute to brain cell death after intracerebral hemorrhage. In this study, we used a simplified in vitro model of hemoglobin neurotoxicity to map the caspase cascades involved and to document the role of oxidative stress. METHODS: Primary neuronal cultures were obtained from rat cerebral cortex and exposed to hemoglobin to induce cell death. Cytotoxicity was assessed via measurements of mitochondrial viability (MTT assay) and lactate dehydrogenase (LDH assay). Activation of caspase-3, -8, and -9 was measured by Western blot and enzyme activity assays. Various caspase inhibitors (zVADfmk, zDEVDfmk, zIETDfmk, and zLEHDfmk) were tested for neuroprotective efficacy. The role of oxidative stress was assessed with the use of U83836E as a potent scavenger of free radicals. RESULTS: Exposure of primary cortical neurons to hemoglobin induced a dose- and time-dependent cytotoxicity. Western blots showed upregulation of cleaved caspase-3. Enzyme assays showed an increase in caspase-9-like and caspase-3-like activity. However, caspase inhibition did not result in neuroprotection. In contrast, the free radical scavenger U83836E significantly reduced hemoglobin-induced neuronal death. Combination treatment with both U83836E and the broad spectrum caspase inhibitor zVADfmk did not yield additional protection. CONCLUSIONS: Upstream and downstream caspases were upregulated after hemoglobin-induced neurotoxicity in vitro, but only an antioxidant approach with a potent free radical scavenger significantly improved neuronal survival. These data suggest that in addition to the activation of caspase cascades, parallel pathways of oxidative stress may predominate in this model of hemoglobin neurotoxicity.


Subject(s)
Caspases/metabolism , Cerebral Cortex/drug effects , Hemoglobins/toxicity , Neurons/drug effects , Animals , Antioxidants/pharmacology , Blotting, Western , Caspase 3 , Caspase 8 , Caspase 9 , Caspase Inhibitors , Cell Death/drug effects , Cell Survival/drug effects , Cells, Cultured , Cerebral Cortex/cytology , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Free Radical Scavengers/pharmacology , In Vitro Techniques , L-Lactate Dehydrogenase/metabolism , Mitochondria/drug effects , Mitochondria/metabolism , Neurons/cytology , Neuroprotective Agents/pharmacology , Oxidative Stress/drug effects , Rats , Rats, Sprague-Dawley , Up-Regulation
8.
Stroke ; 33(3): 831-6, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11872911

ABSTRACT

BACKGROUND AND PURPOSE: Thrombolytic therapy with tissue plasminogen activator (tPA) for acute ischemic stroke remains complicated by risks of hemorrhagic transformation. In this study we used a previously established quantitative rat model of tPA-associated hemorrhage to test the hypothesis that matrix metalloproteinases (MMPs) are involved. METHODS: Spontaneously hypertensive rats were subjected to embolic focal ischemia by placing homologous blood clots into the middle cerebral artery. Three groups of rats were studied: (1) untreated controls that received saline at 6 hours after ischemia; (2) rats that received tPA alone (10 mg/kg at 6 hours after ischemia); and (3) rats that received tPA plus the broad-spectrum MMP inhibitor BB-94 (50 mg/kg of BB-94 before ischemia and at 3 and 6 hours after ischemia plus tPA at 6 hours). Gelatin zymography was used to quantify MMP levels. A hemoglobin spectrophotometry method was used to quantify cerebral hemorrhage. Ischemic lesions were measured at 24 hours with tetrazolium staining. RESULTS: At 6, 12, and 24 hours, pro-MMP-9 and cleaved MMP-9 were upregulated in ischemic brain. At 12 hours, tPA-treated rats showed significantly higher levels of pro-MMP-9 and cleaved MMP-9 than untreated controls. By 24 hours, all rats showed evidence of hemorrhagic transformation in the ischemic territory. Rats treated with BB-94 and tPA showed significantly reduced hemorrhage volumes compared with those that received tPA alone. There was no effect on infarct size. CONCLUSIONS: These results indicate that (1) tPA treatment increases levels of MMP-9 after embolic focal cerebral ischemia, (2) MMPs are involved in the mechanism of tPA-associated hemorrhage, and (3) combination therapies with MMP inhibitors may be useful for decreasing the risk and severity of this dreaded complication of thrombolytic therapy.


Subject(s)
Brain Ischemia/physiopathology , Cerebral Hemorrhage/etiology , Cerebral Hemorrhage/physiopathology , Matrix Metalloproteinases/metabolism , Phenylalanine/analogs & derivatives , Thrombolytic Therapy/adverse effects , Animals , Blood Flow Velocity/drug effects , Brain/drug effects , Brain/enzymology , Brain/pathology , Brain Ischemia/etiology , Cerebrovascular Circulation/drug effects , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Intracranial Embolism/complications , Intracranial Embolism/drug therapy , Intracranial Embolism/physiopathology , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Matrix Metalloproteinase Inhibitors , Phenylalanine/pharmacology , Rats , Rats, Inbred SHR , Sodium, Dietary , Survival Rate , Thiophenes/pharmacology , Tissue Plasminogen Activator/adverse effects
9.
J Cereb Blood Flow Metab ; 22(4): 444-52, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11919515

ABSTRACT

The authors provide the first in vitro and in vivo evidence that perturbations in mitogen-activated protein kinase (MAPK) signal-transduction pathways are involved in the pathophysiology of traumatic brain injury. In primary rat cortical cultures, mechanical trauma induced a rapid and selective phosphorylation of the extracellular signal-regulated kinase (ERK) and p38 kinase, whereas there was no detectable change in the c-jun N-terminal kinase (JNK) pathway. Treatment with PD98059, which inhibits MAPK/ERK 1/2, the upstream activator of ERK, significantly increased cell survival in vitro. The p38 kinase and JNK inhibitor SB203580 had no protective effect. Similar results were obtained in vivo using a controlled cortical impact model of traumatic injury in mouse brain. Rapid and selective upregulation occurred in ERK and p38 pathways with no detectable changes in JNK. Confocal immunohistochemistry showed that phospho-ERK colocalized with the neuronal nuclei marker but not the astrocytic marker glial fibrillary acidic protein. Inhibition of the ERK pathway with PD98059 resulted in a significant reduction of cortical lesion volumes 7 days after trauma. The p38 kinase and JNK inhibitor SB203580 had no detectable beneficial effect. These data indicate that critical perturbations in MAPK pathways mediate cerebral damage after acute injury, and further suggest that ERK is a novel therapeutic target in traumatic brain injury.


Subject(s)
Brain Injuries/metabolism , MAP Kinase Signaling System/physiology , Mitogen-Activated Protein Kinases/metabolism , Neurons/metabolism , Animals , Brain/metabolism , Brain/pathology , Brain Injuries/enzymology , Cell Survival , Cells, Cultured , Enzyme Inhibitors/pharmacology , Flavonoids/pharmacology , Imidazoles/pharmacology , In Vitro Techniques , Male , Mice , Mice, Inbred C57BL , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Neurons/drug effects , Neurons/physiology , Pyridines/pharmacology , Rats
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