Hiroshi Nakane

AMPA receptor antagonist, YM90K, reduces infarct volume in thrombotic distal middle cerebral artery occlusion in spontaneously hypertensive rats

We examined the effects of a potent and selective antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtype of glutamate receptor, YM90K, on brain infarction using a newly developed stroke model of thrombotic distal middle cerebral artery occlusion. Male spontaneously hypertensive rats (5-7 months old) were subjected to photochemically-induced distal middle cerebral artery occlusion as previously described [Stroke 26 (1996) 333-336]. Intravenous infusion of YM90K (n = 8) (5 mg/kg per h for 1 h) or the same amount of vehicle (n = 8) (alkaline saline) was started 5 min after distal middle cerebral artery occlusion. Penumbral cerebral blood flow was determined with laser-Doppler flowmetry. Three days after the ischemic insult, brains were stained with 2,3,5-triphenyltetrazolium chloride and infarct volumes were determined. One hour infusion of YM90K significantly reduced infarct volume by 34% (93 +/- 23 mm3 in control group vs. 61 +/- 25 mm3 in YM90K-treated group, P = 0.017). There were no significant differences in the degrees of cerebral blood flow reduction after distal middle cerebral artery occlusion between the YM90K treated and control groups. YM90K reduces infarct volume in experimental ischemia produced by photothrombotic distal middle cerebral artery occlusion in rats. The present results demonstrated beneficial effects of AMPA receptor blockade on acute ischemic stroke.

Modulation of ischemia-evoked release of excitatory and inhibitory amino acids by adenosine A1 receptor agonist.

Adenosine has been reported to have beneficial effects against ischemic brain damage, although the mechanisms are not fully clarified. To examine the role of adenosine on the ischemia-evoked release of neurotransmitters, we applied a highly selective agonist for adenosine A1 receptor, 2-chloro-N6-cyclopentyladenosine (CCPA), into the ischemic brain using in vivo brain dialysis, which directly delivered the agonist to the local brain area. Concentrations of extracellular amino acids (glutamate, aspartate, gamma-aminobutyric acid (GABA) and taurine) and regional blood flow in the striatum of spontaneously hypertensive rats (SHRs) were monitored during cerebral ischemia elicited by bilateral carotid artery occlusion for 40 min and recirculation. Striatal blood flow and basal levels of amino acids were not affected by direct perfusion of CCPA (10 microM or 100 microM). During ischemia, concentrations of glutamate, aspartate, GABA and taurine increased up to 37-, 30-, 96- and 31-fold, respectively, when vehicle alone was administered. Administration of CCPA did not affect the changes in regional blood flow during ischemia and reperfusion. Perfusion of CCPA (100 microM), however, significantly attenuated the ischemia-evoked release of aspartate (by 70%) and glutamate (by 73%). The ischemia-induced increase of GABA tended to be decreased by CCPA, although it was not statistically significant. In contrast, both low and high concentrations of CCPA had little effect on the release of taurine during ischemia. These results suggest that stimulation of adenosine A1 receptors selectively attenuated the ischemia-evoked release of excitatory amino acids, but not of inhibitory amino acids without affecting blood flow. This modulation of the release of amino acids by adenosine A1 receptor agonists may play a protective role against ischemic neuronal damage.

Cerebral blood flow and metabolism in hypertensive patients with cerebral infarction.

The authors investigated, by positron emission tomography, the effect of long-standing hypertension on cerebral blood flow (CBF) and oxygen metabolism in patients with chronic atherothrombotic brain infarction. In the nonbrain infarct (non-BI) group (n=13, mean age: sixty-two years), the regional CBF (rCBF) was decreased significantly with a rise in the mean arterial blood pressure (MABP) in the cerebral cortexes (r=-0.575) and the deep gray matter (r=-0.451), whereas the regional cerebral metabolic rate for oxygen (rCMRO2) remained unchanged. In the brain infarct (BI) group (n=22, mean age: fifty-eight years), however, the rCBF as well as the rCMRO2 were reduced even in the normotensive patients and thus did not correlate with the MABP. These results suggest that long-standing hypertension per se causes a reduction in the rCBF but not in the oxygen metabolism with a compensatory increase in the oxygen extraction fraction. On the other hand, patients with brain infarction, even normotensives, show a diffuse decrease in cerebral circulation and metabolism, which is probably due to the more severe sclerotic changes that take place in the cerebral vessels.

Brain infarction caused by syphilitic aortic aneurysm : A case report

Neurosyphilis often develops brain infarction. Recently, the authors experienced a case of brain infarction caused by syphilitic aneurysm on the thoracic aorta, and its clinical signif icance is reported. A seventy-eight-year-old woman with strongly positive serologic tests for syphilis suddenly developed global aphasia and right hemiplegia. Brain computed tomography (CT) showed a large brain infarction in the left middle cerebral artery territory. A huge aneurysm of the ascending aorta eroded the sternum and the second and third ribs. The left common carotid artery was completely compressed by the aneurysm, and blood flow was not demonstrated on enhanced CT. A cerebrospinal fluid examination revealed normal cell counts, and the titer of a syphilis test was very low. She did not have any arrhythmia, ischemic heart disease, or valvular heart disease as an embolic source. Brain infarction may be developed by pressure of an aortic aneurysm on the left common carotid artery. They recommend consideration of syphilis as an etiology of brain infarction when luetic patients are seen in old age.

FLOW VOLUME AND CROSS-SECTIONAL AREA OF THE EXTRACRANIAL VERTEBRAL ARTERIES AND ITS RELATION TO VASCULAR LESIONS OR ANATOMICAL VARIATIONS IN THE POSTERIOR CIRCULATION

We examined whether the time-averaged maximum velocity (TAMV), flow volume (FV) or cross-sectional area (CA) in the vertebral arteries (VA) as determined by ultrasonography was related to vascular lesions or variations in the intracranial part of the posterior circulation. Three hundred nine patients without severe stenosis in the carotid circulation (159 males, 150 females, mean age of 69.1 years) underwent both colour duplex ultrasonography and magnetic resonance angiography (MRA) and were thus analyzed. According to the MRA findings, the patients were divided as follows; 22 patients with severe stenosis in the bilateral PCA or VA or basilar artery (V group) and 287 patients without (N group). The N group was then further divided as follows; 144 patients with no (P0 group); 89 with one (P1) and 54 with both posterior communicating arteries (P2) detected on MRA. TAMV, FV and CA were compared among these groups. Both TAMV and FV of V group were significantly lower than those of N group (35.3 vs. 42.6 cm/sec in TAMV, 98.2 vs. 135.3 mL/min in FV, p < 0.001 and 0.0001, respectively). The FVs and CAs in the P0 through P2 groups were all significantly different according to the number of posterior communicating arteries (149.3 vs. 128.0 vs. 109.8 mL/min, 22.5 vs. 20.2 vs. 16.5 mm2, both p < 0.001) while TAMVs in these groups did not differ substantially. The FV in both VAs were thus found to be related to the vascular lesions or variations in the posterior circulation.

Cerebral Blood Flow Threshold and Regional Heterogeneity of Heat Shock Protein 72 Induction Following Transient Forebrain Ischemia in Rats

Heat shock proteins (HSPs) induced by brain ischemia may play an important role in neuroprotection from neuronal degeneration. In this study, we examined the cerebral blood flow (CBF) threshold to produce regional differences in HSP72 induction after transient forebrain ischemia in spontaneously hypertensive rats (SHRs). Female SHRs were subjected to 20 min of cerebral ischemia induced by bilateral carotid artery occlusion. The CBF was measured by laser Doppler flowmetry. At forty-eight hours after cerebral ischemia and reperfusion, the rats were decapitated and the brains were removed. Specific areas (hippocampal CA1, CA2-3, dentate gyrus, dorsolateral and ventromedial striatum, and parietal cortex) were thereafter dissected from the brain. The amounts of HSP72 in these samples were determined using Western blot analysis. In the hippocampus, HSP72 was induced when the CBF decreased to less than 18–25% of the resting level. The mean values of HSP72 produced in the CA1 area, CA2-3 area, and the dentate gyrus following ischemia and reperfusion treatment were 4.44 ± 1.43 (±SD) ng/μg prtein, 3.51 ± 0.72 ng/μg protein and 3.77 ± 1.05 ng/μg protein, respectively. In the parietal cortex, the amount of HSP72 induction was less pronounced (2.55 ± 0.40 ng/μg protein), while HSP72 was hardly detected at all in the striatum, even under conditions of very severe CBF reduction and reperfusion. We demonstrated the existence of both a CBF threshold (i.e., approximately 20% of the resting level) for HSP72 induction and regional heterogeneity for the induction of HSP72 protein.

Fulminant bilateral cerebral infarction caused by paradoxical embolism in a patient with protein S Ala525Val substitution

We report a 42‐year‐old woman who developed sudden fulminant cerebral infarction in the bilateral middle cerebral artery territories, causing status epilepticus and a decreased level of consciousness. Investigation showed thrombus in the right soleus vein and a patent foramen ovale, but no obvious embolic source, such as atrial fibrillation or a carotid or cerebral artery atherosclerotic lesion. Blood coagulation tests showed decreased levels of free protein S (25%) and total protein S (52%), and decreased protein S activity (15%). The patient was diagnosed with cerebral infarction as a result of paradoxical embolism, and type I protein S deficiency. DNA sequencing identified a novel point mutation in the PROS1 gene, leading to the amino acid substitution, Ala525Val. It should be noted that this protein S mutation can cause thrombophilia and cerebral infarction.

Age-Related Changes in the DNA and RNA Content of the Brain in Spontaneously Hypertensive Rats

To elucidate the effects of aging accompanied with hypertension on brain nucleic acid, we measured both the DNA and RNA contents of six specific brain regions in adult (5–6 months old) and aged (18–22 months old) female spontaneously hypertensive rats (SHRs). Although no statistical difference was observed in the RNA content, the DNA content did tend to increase in the hippocampal CA1 of aged SHR (4.24 ± 0.55 ng/μg protein, mean ± SD, n = 6) in comparison to that of adult SHR (3.21 ± 0.71 ng/μg protein, n = 4). Hence, aged SHRs showed a significant decrease in the RNA to DNA ratio in the CA1 subfield of the hippocampus (3.79 ± 0.61) compared to adult SHR (5.27 ± 0.81). On the other hand, no other regions, except for the dorsolateral region of the striatum, showed any difference in the RNA/DNA ratio between aged and adult SHR. We therefore conclude that subtle changes in the nucleic acid occur in vulnerable regions of the brain in aged SHRs.