Toshiya Katsumata

Long-term measurement of cerebral blood flow and metabolism in a rat chronic hypoperfusion model

1. Rat bilateral common carotid artery occlusion (BCAO) was used as a chronic cerebral hypoperfusion model. We observed autoradiographically the long‐term changes in regional cerebral blood flow (rCBF) and regional cerebral glucose utilization (rCGU) after 2 days and 1, 4 and 8 weeks of BCAO and in controls. Regions evaluated included the cerebral cortex, white matter and basal ganglia. Pathological changes were also observed with Klüver–Barrera and haematoxylin–eosin staining.

Effects of long-term administration of HMG-CoA reductase inhibitor, atorvastatin, on stroke events and local cerebral blood flow in stroke-prone spontaneously hypertensive rats.

The objective of this study was to determine whether the long-term administration of an HMG-CoA reductase inhibitor, atorvastatin, confers protective effects against stroke events in stroke-prone spontaneously hypertensive rats (SHRSPs). Atorvastatin (2 mg/kg, 20 mg/kg) or vehicle was orally administered to 8-week-old SHRSPs for 11 weeks. The survival ratio and stroke incidence were calculated, and plasma lipids and plasma levels of asymmetric dimethylarginine (ADMA), a circulating endogenous competitive inhibitor of NO synthase, were measured after sacrifice. The effect of atorvastatin on local cerebral blood flow (l-CBF) was also determined in 13-week-old SHRSPs after treatment with 20 mg/kg atorvastatin daily for 5 weeks. The survival ratios at 19 weeks of age were 15, 30, and 50% in the vehicle, low-dose (2 mg/kg), and high-dose groups (20 mg/kg), respectively. The survival ratio was significantly higher in the high-dose group than in the vehicle group. The incidence of stroke was significantly lower in the high-dose group than in the vehicle group. The levels of ADMA were 0.81+/-0.18 (mean+/-S.D.), 0.62+/-0.09, and 0.61+/-0.06 micromol/l in the vehicle, low-dose, and high-dose groups, respectively. Atorvastatin administration significantly reduced the ADMA levels without affecting the levels of plasma lipids. The level of l-CBF tended to be higher in the treated group, but not to a significant extent. Thus, atorvastatin was determined to confer a protective effect against hypertension-based stroke. The data suggest that the efficacy of the statin for stroke protection may be partially involved in the improvement of endothelial function via NO production and reduction of ADMA. Statins may confer useful protection against not only atherosclerosis-based stroke, but also hypertension-based stroke.

Effect of long-term administration of ethyl eicosapentate (EPA-E) on local cerebral blood flow and glucose utilization in stroke-prone spontaneously hypertensive rats (SHRSP).

The objective of this study was to determine the effect of ethyl eicosopentate (EPA-E) on local cerebral blood flow (1-CBF) and local glucose utilization (1-CGU) in specific regions of the brain in stroke-prone spontaneously hypertensive rats (SHRSP). EPA-E (100 mg/kg body weight) or saline was orally administered to 8-week-old SHRSP. L-CBF and 1-CGU in the EPA-E-treated, saline-treated, and 8-week-old control rats were measured autoradiographically using 14C-iodoantipyrine and 14C-deoxyglucose (Sakuradas and Sokoloffs methods). The 1-CBF of the saline-treated group decreased significantly with age in all areas measured. EPA-E treatment alleviated the age-dependent decrease in 1-CBF in all areas, especially those in the basal ganglia. The 1-CGU of the saline-treated group did not change with age, however EPA-E treatment increased 1-CGU in all areas measured, though the changes were not significant. EPA-E ameliorated the decrease in cerebral blood flow and improved glucose metabolism in SHRSP suffering from severe hypertension. These results suggest that EPA-E may be useful in the prevention of stroke.

Delayed administration of ethyl eicosapentate improves local cerebral blood flow and metabolism without affecting infarct volumes in the rat focal ischemic model

The objective of this study was to assess whether delayed administration of ethyl eicosapentate has a favorable effect on cerebral blood flow and metabolism in rats suffering from cerebral infarction. Adult male Sprague-Dawley rats weighing 250-300 g were used. Left middle cerebral artery occlusion was induced for 2 h. After 24-h reperfusion, rats were treated with ethyl eicosapentate (100 mg kg(-1); ethyl eicosapentate treated) or saline (saline treated) by gavage, once a day for 4 weeks. After 4 weeks, local cerebral blood flow and local cerebral glucose utilization were measured autoradiographically, and infarction size was measured. In the ischemic side, the local cerebral blood flow and local cerebral glucose utilization values in the parietal cortex and the lateral caudoputamen, which constituted the ischemic core, were equivalent to zero in both groups. The peri-infarcted areas, i.e., the frontal cortex and medial caudoputamen, were significantly higher in the ethyl eicosapentate treated group than the saline treated group. In the non-ischemic side, ethyl eicosapentate treated group had a tendency to improve local cerebral blood flow and local cerebral glucose utilization values in a medial caudoputamen. These results suggest that ethyl eicosapentate treatment may be beneficial for maintaining cerebral circulation and metabolism except for infarction area after cerebral infarction.

Low Serum n-3 Polyunsaturated Fatty Acid/n-6 Polyunsaturated Fatty Acid Ratio Predicts Neurological Deterioration in Japanese Patients with Acute Ischemic Stroke

Background: Epidemiological and clinical trials have shown that n-3 polyunsaturated fatty acids (PUFAs) reduce the incidence of coronary heart disease or stroke. However, the association between PUFAs and acute-phase stroke has not yet been thoroughly studied. We investigated the impact of serum PUFAs on early neurological deterioration (END) in patients with acute ischemic stroke. Methods: In this retrospective study, we enrolled 281 Japanese patients (mean age: 75 ± 13 years; 165 males) with acute ischemic stroke diagnosed within 24 h of onset. General blood examinations, including PUFAs (n-3 PUFAs: eicosapentaenoic acid, EPA, and docosahexaenoic acid, DHA, and n-6 PUFAs: arachidonic acid, AA), were performed on admission. Other risk factors and comorbidities were also examined. END was defined as a ≥2-point increase in the National Institutes of Health Stroke Scale (NIHSS) score within a 72-hour period. Statistical significance between the END and non-END group was assessed using Wilcoxon rank sum tests or Students t tests for categorical variables. Multiple logistic regression analyses were performed to identify predictors of END. Results: END was observed in 75 patients (26.7%). Diabetes mellitus (p = 0.003), high-sensitivity C-reactive protein (hs-CRP) level (p < 0.001), prior stroke (p = 0.035), ischemic heart disease (p = 0.029), EPA/AA ratio (p = 0.003), DHA/AA ratio (p = 0.002), EPA+DHA/AA ratio (p = 0.002), diagnosis of small vessel disease (p = 0.004) and admission NIHSS score (p < 0.001) were significantly associated with END. We used separate multiple logistic regression analyses for the EPA/AA, DHA/AA and EPA+DHA/AA ratios, because EPA and DHA are considered covariant factors (r = 0.544; p < 0.0001). Multiple logistic regression analyses showed that END was positively associated with diabetes mellitus, hs-CRP level and NIHSS score on admission, and negatively associated with the EPA/AA ratio (odds ratio, OR: 0.18; 95% confidence interval, CI: 0.05-0.58; p = 0.003), DHA/AA ratio (OR: 0.045; 95% CI: 0.006-0.30; p = 0.001), EPA+DHA/AA ratio (OR: 0.45; 95% CI: 0.26-0.74; p = 0.002) and diagnosis of small vessel disease. Conclusions: Our data suggest that a low serum n-3 PUFA/n-6 PUFA ratio on admission may predict neurological deterioration in Japanese patients with acute ischemic stroke. Large-scale prospective studies are further required to clarify the role of PUFAs in the acute phase of ischemic stroke.

Neuroprotective effect of NS-7, a novel Na+ and Ca2+ channel blocker, in a focal ischemic model in the rat.

NS-7 is a novel, voltage-dependent Na(+) and Ca(2+) channel blocker. This study evaluated the in vivo neuroprotective effect of NS-7 in a rat transient focal ischemic model when administered during occlusion. Left middle cerebral artery occlusion was induced in adult male Sprague-Dawley rats for 120 min using an intraluminal thread method. The rats received a single intravenous injection of NS-7 or saline (control group) just after the onset of ischemia, and at 30, 60 and 120 min after ischemia. Their brains were removed after 48 h reperfusion, sectioned, and stained with hematoxylin and eosin. Animals were evaluated by neurological examination at 120 min ischemia and 48 h reperfusion. Infarcted cortex and striatum were measured quantitatively and infarction volumes were calculated. Cortical infarction volumes were 128+/-74 (NS-7) and 214+/-64 mm(3) (control) immediately after the ischemia group, 155+/-48 (NS-7) and 225+/-12 mm(3) (control) after the 30 min group, 160+/-54 (NS-7) and 225+/-48 mm(3) (control) after the 60 min group, and 176+/-43 (NS-7) and 223+/-38 mm(3) (control) after the 120 min group. Cortices in NS-7-treated groups were significantly less infarcted than in control groups at all treatment times. There was no significant difference in the striatal infarction volume between the treatment and control groups. Neurological examination showed that hemiparesis and abnormal posture of the NS-7 groups were significantly more improved at 48 h reperfusion than those of the control groups without posture examination in the 120 min group. These observations suggest that NS-7 may be a new potential therapeutic agent for the acute phase of cerebral infarction.

Correlation between insulin resistance and white matter lesions among non-diabetic patients with ischemic stroke

Abstract Objective: We investigated whether a correlation exists between insulin resistance and the severity of cerebral white matter lesions among non-diabetic patients with ischemic stroke. Methods: The subjects were 105 consecutive patients without diabetes who were hospitalized due to non-cardioembolic stroke. The insulin resistance was evaluated by a homeostasis model assessment of insulin resistance (HOMA-IR). The degrees of periventricular hyperintensity (PVH) and deep and subcortical white matter hyperintensity (DSWMH) were evaluated by the brain MRI. The HOMA-IR values ≥2·5 were indicative of the insulin resistance. Results: The presence of PVH and DSWMH were 86·7 and 83·8%, respectively. The ratio of insulin resistance increased with higher grades of PVH and DSWMH. The HOMA-IR level in grade 3 PVH was significantly higher than those in grades 0 and 1. The HOMA-IR level in grade 3 DSWMH was significantly higher than those in grades 0–2. Multiple linear regression analysis showed that HOMA-IR was significantly associated with PVH or DSWMH. Conclusion: It was found that insulin resistance correlated with white matter lesions among non-diabetic patients with non-cardiogenic ischemic stroke.

Carotid Hemodynamic Parameters Are Useful for Discriminating Between Atherothrombotic Infarction and Lacunar Infarction

Using ultrasound, we investigated whether carotid parameters differed among subtypes of ischemic stroke and evaluated the usefulness of these parameters in discriminating among subtypes. Patients with ischemic stroke admitted to Nippon Medical School Hospital were consecutively recruited and grouped into 3 subtypes based on the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification: cardioembolism (group CE), large-artery atherosclerosis (group LAA), and small-vessel occlusion (group SVO). All subjects underwent carotid ultrasonography to determine maximum intima-media thickness (IMT), maximum systolic velocity (Vmax), minimum diastolic velocity (Vmin), mean velocity, and pulsatility index (PI). Carotid parameters that differed among subtypes were statistically identified. A total of 138 patients were enrolled. Intergroup comparisons revealed that the Vmin of the affected side was significantly lower in group LAA than in group SVO (mean±SD, 0.12±0.05 m/s vs 0.15±0.05 m/s; P=.02) and the Vmin of the mean of both sides was lower in group LAA than in group SVO (0.12±0.04 vs 0.16±0.05; P=.03). Multivariate analysis showed that the PI of the affected side was a useful adjunct to discriminate between groups SVO and LAA (odds ratio=2.94; P=.03, group SVO as control). Receiver operating characteristic curve analysis found that the Vmin of the affected side was the most useful parameter for discriminating between group SVO and group LAA. The PI and the Vmin of the affected side were found to differ among stroke subtypes, and thus these may be useful parameters for discriminating among ischemic stroke subtypes.

Recurrent strokes in a young adult patient with Fabry's disease

Sirs, Fabry’s disease is an X-linked disorder resulting from a deficiency of lysosomal a–galactosidase A (a–Gal A) (Desnick et al., 2001). Systemic accumulation of glycosphingolipids, predominantly globotriaosylceramide, results in diverse clinical manifestations. Several investigators have reported that strokes were a frequent complication of Fabry’s disease in relatively young patients (Grewal, 1994; Mitsias and Levine, 1996; Utsumi et al., 1997). In this report we describe recurrent strokes during a 2-month period in a young man with Fabry’s disease. A 24-year-old man was admitted to the hospital because of weakness of his right hand and dysarthria. In childhood he had experienced occasional mild pain in the extremities when he had a fever. He was diagnosed with mitral valve prolapse at the age of 21 years. On admission, he was alert. His temperature was 37.5 C, and the pulse rate was 60/min. Blood pressure was 124/ 72 mmHg. Physical examination disclosed no abnormalities except for angiokeratoma over the extremities, chest, abdomen, and back. He had no signs of left ventricular hypertrophy and no proteinuria. Neurologic examination confirmed weakness of the right hand and dysarthria. T2-weighted magnetic resonance images (MRI) revealed an area of high signal intensity in the pons (Fig. 1a and b). He was diagnosed with brainstem infarction in the territory of the basilar artery, and was treated with intravenous heparin sodium (10 000 U/day), ozagrel sodium (160 mg/day), and glycerin (400 ml/day). Given the occurrence of stroke in a relatively young patient with angiokeratoma, activities of several lysosomal enzymes were examined to rule out lysosomal diseases. No activity of aGal A could be detected in plasma or leukocytes; he was diagnosed with Fabry’s disease. The patient’s brother had very low aGal A activity, whilst their mother had moderate reduction of aGal A activity. Accordingly, his brother also was diagnosed with Fabry’s disease, similarly manifest as angiokeratoma over extremities from childhood, and echocardiographically detected mitral valve prolapse. His mother was diagnosed as an asymptomatic carrier. Sequencing of cDNA disclosed a C-to-T transition at cDNA number 334 in exon 2 of the aGal A gene, resulting in L

Extracranial carotid plaque is increasing in Japanese ischemic stroke patients

Objective –  The objectives of this study were to investigate the prevalence of extracranial carotid plaque and the association between risk factors and carotid plaque in Japanese patients with ischemic stroke.