Hahn Young Kim

Involvement of Matrix Metalloproteinase in Neuroblast Cell Migration from the Subventricular Zone after Stroke

After brain injury, neuroblast cells from the subventricular zone (SVZ) expand and migrate toward damaged tissue. The mechanisms that mediate these neurogenic and migratory responses remain to be fully dissected. Here, we show that bromodeoxyuridine-labeled and doublecortin-positive cells from the SVZ colocalize with the extracellular protease matrix metalloproteinase-9 (MMP-9) during the 2 week recovery period after transient focal cerebral ischemia in mice. Treatment with the broad spectrum MMP inhibitor GM6001 significantly decreases the migration of doublecortin-positive cells that extend from the SVZ into the striatum. These data suggest that MMPs are involved in endogenous mechanisms of neurogenic migration as the brain seeks to heal itself after injury.

Baicalein and 12/15-Lipoxygenase in the Ischemic Brain

Background and Purpose— The natural product baicalein is a specific inhibitor of 12/15-lipoxygenase, but it also has antioxidant properties. The current study was designed to test if the neuroprotective properties of baicalein are related to its lipoxygenase inhibition. Methods— The presence of 12/15-lipoxygenase in the ischemic mouse brain was demonstrated by immunohistochemistry. A mouse model of transient middle cerebral artery occlusion was used to study lipoxygenase-dependent protection of the ischemic brain by baicalein. Rat primary neurons were subjected to oxidative stress in the presence or absence of baicalein. Results— In a mouse model of transient middle cerebral artery occlusion, 12/15-lipoxygenase is increased in the peri-infarct area surrounding the primary infarction, predominantly in neurons. Oxidative toxicity in primary rat neurons is reduced by baicalein. C57Bl6J mice are protected against transient focal ischemia by intraperitoneal injection of baicalein, and a similar degree of protection is seen in 12/15-lipoxygenase knockout mice compared with wild-type mice. In contrast, the 12/15-LOX knockout mice are not further protected by baicalein. Conclusion— Baicalein protects against ischemia/reperfusion injury by inhibiting the 12/15-lipoxygenase pathway to neuronal cell death.

Normobaric hyperoxia extends the reperfusion window in focal cerebral ischemia

A major limitation in thrombolysis for acute ischemic stroke is the restricted time window for safe and effective therapy. Any method that can extend the reperfusion time window would be important. In this study, we show that normobaric hyperoxia extends the time window for effective reperfusion from 1 to 3 hours in rats subjected to focal cerebral ischemia. Normobaric hyperoxia did not increase cellular markers of superoxide generation or brain levels of matrix metalloproteinase‐9. Normobaric hyperoxia may be a clinically feasible adjunct method for significantly increasing the time window for effective thrombolytic therapy in acute ischemic stroke. Ann Neurol 2005;57:571–575

Ischemic Stroke in Cancer Patients With and Without Conventional Mechanisms. A Multicenter Study in Korea

Background and Methods— To assess the precise mechanisms of stroke in cancer patients, we analyzed the data for cancer patients with acute ischemic stroke registered from 6 centers in South Korea. Clinical features, risk factors, diffusion-weighted imaging lesion patterns, and laboratory findings including d-dimer levels were compared between patients with conventional stroke mechanisms (CSMs) and cryptogenic group. Results— A total of 161 patients were included in this study: 97 (60.2%) patients in the CSM group and 64 (39.8%) in the cryptogenic group. Patients in the CSM group were older and vascular risk factors were more prevalent than in the cryptogenic group. Diffusion-weighted imaging patterns of multiple lesions involving multiple arterial territories were observed more frequently in the cryptogenic group than in the CSM group. In addition, levels of the d-dimer were higher in the cryptogenic group than in the CSM group (11.5±14.6 versus 3.6±10.3 &mgr;g/dL). In multivariate analysis, the diffusion-weighted imaging lesion pattern of multiple vascular territories (odds ratio, 11.2; 95% CI, 3.74 to 33.3), and d-dimer levels of >1.11 &mgr;g/dL (odds ratio, 10.6; 95% CI, 3.29 to 33.8) were associated independently with the cryptogenic group. Conclusions— Stroke outside of CSM occurred in a large number in cancer patients. In stroke patients with cancer, d-dimer levels and diffusion-weighted imaging lesion patterns may be helpful in early identification of non-CSMs (especially coagulopathy associated with cancer) and possibly in guiding preventive strategies for stroke.

Stroke awareness decreases prehospital delay after acute ischemic stroke in korea

BackgroundDelayed arrival at hospital is one of the major obstacles in enhancing the rate of thrombolysis therapy in patients with acute ischemic stroke. Our study aimed to investigate factors associated with prehospital delay after acute ischemic stroke in Korea.MethodsA prospective, multicenter study was conducted at 14 tertiary hospitals in Korea from March 2009 to July 2009. We interviewed 500 consecutive patients with acute ischemic stroke who arrived within 48 hours. Univariate and multivariate analyses were performed to evaluate factors influencing prehospital delay.ResultsAmong the 500 patients (median 67 years, 62% men), the median time interval from symptom onset to arrival was 474 minutes (interquartile range, 170-1313). Early arrival within 3 hours of symptom onset was significantly associated with the following factors: high National Institutes of Health Stroke Scale (NIHSS) score, previous stroke, atrial fibrillation, use of ambulance, knowledge about thrombolysis and awareness of the patient/bystander that the initial symptom was a stroke. Multivariable logistic regression analysis indicated that awareness of the patient/bystander that the initial symptom was a stroke (OR 4.438, 95% CI 2.669-7.381), knowledge about thrombolysis (OR 2.002, 95% CI 1.104-3.633) and use of ambulance (OR 1.961, 95% CI 1.176-3.270) were significantly associated with early arrival.ConclusionsIn Korea, stroke awareness not only on the part of patients, but also of bystanders, had a great impact on early arrival at hospital. To increase the rate of thrombolysis therapy and the incidence of favorable outcomes, extensive general public education including how to recognize stroke symptoms would be important.

Efficacy and Safety of Combination Antiplatelet Therapies in Patients With Symptomatic Intracranial Atherosclerotic Stenosis

Background and Purpose— An optimal strategy for management of symptomatic intracranial atherosclerotic stenosis (ICAS) has not yet been established. We compared the efficacy of 2 combinations of antiplatelets, aspirin plus cilostazol (cilostazol group) verus aspirin plus clopidogrel (clopidogrel group), on the progression of ICAS, which is known to be associated with clinical stroke recurrence. Methods— In this investigator-initiated double-blind trial, 457 patients with acute symptomatic stenosis in the M1 segment of the middle cerebral artery or the basilar artery were randomly allocated into either a cilostazol group or a clopidogrel group. After 7 months of treatment, follow-up MR angiogram and MRI were performed. The primary end point was the progression of ICAS in comparison with stenosis on the baseline MR angiogram. Secondary end points included the occurrence of new ischemic lesions on MRI, composite of cardiovascular events, and major bleeding complications. Results— Cardiovascular events occurred in 15 of 232 patients (6.4%) in the cilostazol group and 10 of 225 (4.4%) in the clopidogrel group (P=0.312). Cilostazol did not reduce the progression of symptomatic ICAS (20 of 202) compared to clopidogrel (32 of 207) (odds ratio, 0.61; P=0.092), although favorable changes in serum lipoproteins were observed in the cilostazol group. There were no significant differences between the 2 groups with respect to new ischemic lesions (18.7% versus 12.0%; P=0.078) and major hemorrhagic complications (0.9% versus 2.6%; P=0.163). Conclusions— This trial failed to show significant difference in preventing progression of ICAS and new ischemic lesions between the 2 combination antiplatelet therapies in the patients with symptomatic ICAS. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00130039.

Synergistic Memory Impairment Through the Interaction of Chronic Cerebral Hypoperfusion and Amlyloid Toxicity in a Rat Model

Background and Purpose— Vascular pathology and Alzheimer disease (AD) pathology have been shown to coexist in the brains of dementia patients. We investigated how cognitive impairment could be exacerbated in a rat model of combined injury through the interaction of chronic cerebral hypoperfusion and amyloid beta (A&bgr;) toxicity. Methods— In Wistar rats, chronic cerebral hypoperfusion was modeled by permanent occlusion of bilateral common carotid arteries (BCCAo). Further, AD pathology was modeled by bilateral intracerebroventricular A&bgr; (A&bgr; toxicity) using a nonphysiological A&bgr; peptide (A&bgr; 25 to 35). The experimental animals were divided into 4 groups, including sham, single injury (A&bgr; toxicity or BCCAo), and combined injury (BCCAo-A&bgr; toxicity) groups (n=7 per group) . Cerebral blood flow and metabolism were measured using small animal positron emission tomography. A Morris water maze task, novel object location and recognition tests, and histological investigation, including neuronal cell death, apoptosis, neuroinflammation, and AD-related pathology, were performed. Results— Spatial memory impairment was synergistically exacerbated in the BCCAo–A&bgr; toxicity group as compared to the BCCAo or A&bgr; toxicity groups (P<0.05). Compared to the sham group, neuroinflammation with microglial or astroglial activation was increased both in multiple white matter lesions and the hippocampus in other experimental groups. AD-related pathology was enhanced in the BCCAo–A&bgr; toxicity group compared to the A&bgr; toxicity group. Conclusion— Our experimental results support a clinical hypothesis of the deleterious interaction between chronic cerebral hypoperfusion and A&bgr; toxicity. Chronic cerebral hypoperfusion-induced perturbation in the equilibrium of AD-related pathology may exacerbate cognitive impairment in a rat model of combined injury.

Ischemic Stroke and Cancer: Stroke Severely Impacts Cancer Patients, While Cancer Increases the Number of Strokes

Background Cancer and ischemic stroke are two of the most common causes of death among the elderly, and associations between them have been reported. However, the main pathomechanisms of stroke in cancer patients are not well known, and can only be established based on accurate knowledge of the characteristics of cancer-related strokes. We review herein recent studies concerning the clinical, laboratory, and radiological features of patients with cancer-related stroke. Main Contents This review covers the epidemiology, underlying mechanisms, and acute and preventive treatments for cancer-related stroke. First, the characteristics of stroke (clinical and radiological features) and systemic cancer (type and extent) in patients with cancer-specific stroke are discussed. Second, the role of laboratory tests in the early identification of patients with cancer-specific stroke is discussed. Specifically, serum D-dimer levels (as a marker of a hypercoagulable state) and embolic signals on transcranial Doppler (suggestive of embolic origin) may provide clues regarding changes in the levels of coagulopathy related to cancer and anticoagulation. Finally, strategies for stroke treatment in cancer patients are discussed, emphasizing the importance of preventive strategies (i.e., the use of anticoagulants) over acute revascularization therapy in cancer-related stroke. Conclusion Recent studies have revealed that the characteristics of cancer-related stroke are distinct from those of conventional stroke. Our understanding of the characteristics of cancer-related stroke is essential to the correct management of these patients. The studies presented in this review highlight the importance of a personalized approach in treating stroke patients with cancer.

Alternations of Septal-hippocampal System in the Adult Wistar Rat with Spatial Memory Impairments Induced by Chronic Cerebral Hypoperfusion

In the current investigation, the status of the septo-hippocampal cholinergic pathway and hippocampal mitogen-activated protein kinase (MAPK) signaling was examined in male Wistar rats with chronic cerebral hypoperfusion, which showed cognitive deficits based on assessment on a version of the Morris water maze. Chronic cerebral hypoperfusion was induced by bilateral common artery occlusion and maintained for 12 weeks until behavioral testing. Chronic cerebral hypoperfusion was shown to induce memory impairments and microglial activation in regions of white matter, including the fimbria of hippocampus. Choline acetyltransferase expression of the basal forebrain and expression of hippocampal MAPKs was decreased in rats with BCCAo compared to control rats. The results of this study suggest that cognitive decline induced by chronic cerebral hypoperfusion could be related to dysfunction of the basal forebrain cholinergic system and reduction of hippocampal MAPK activities.

Symptomatic Hemorrhagic Transformation and Its Predictors in Acute Ischemic Stroke with Atrial Fibrillation

Background and Purpose: Patients with acute cardioembolic stroke frequently show hemorrhagic transformation (HTr). We attempted to identify predictors of symptomatic HTr in acute ischemic stroke with atrial fibrillation (AF). Methods: Of the consecutive acute ischemic stroke patients with AF at 12 hospitals in Korea, patients with posterior circulation stroke or thrombolytic therapy were excluded. Immediate anticoagulation was recommended to all patients, except those with: (1) large infarcts, 50% or more of the middle cerebral artery territory, (2) significant HTr on initial imaging, or (3) other safety concerns. Symptomatic HTr was defined as cerebral hemorrhage temporally related to neurological deterioration. Results: Of the 389 included patients (mean age 71 years), 260 (67%) were treated with anticoagulation within 1 week from the onset. Symptomatic HTr occurred in 4.6%. Large infarct (OR 6.38, 95% CI 1.16–35.14), previous hemorrhagic stroke (OR 10.67, 1.77–64.25), and low platelet count (OR per 104 increase 0.87, 0.79–0.97) were independent predictors of symptomatic HTr. hsCRP values tended to be higher in patients with symptomatic HTr (p = 0.055). Conclusions: Caution is needed in anticoagulation treatment of acute cardioembolic stroke patients with a large infarct, previous hemorrhagic stroke, low platelet count, or a high hsCRP level.