Search PubMed⌕ Search

Biomedical subjects

S Nogawa

Publications and source records attributed to S Nogawa.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cyclooxygenase-2 immunoreactivity in the human brain following cerebral ischemia.

The prostaglandin synthesizing enzyme cyclooxygenase-2 (COX-2) is up-regulated in the brain of rodents during cerebral ischemia and contributes to ischemic brain injury. This study sought to determine whether COX-2 is also up-regulated in the human brain in the acute stages of cerebral ischemic infarction. Paraffin-embedded sections from patients who died 1-2 days following infarction in the middle cerebral artery territory were processed for COX-2 immunohistochemistry. COX-2 immunoreactivity was observed in infiltrating neutrophils, in vascular cells and in neurons located at the border of the infarct. The data suggest that COX-2 up-regulation is also relevant to cerebral ischemia in humans and raise the possibility that COX-2 reaction products participate in the mechanisms of ischemic injury also in the human brain.

Aged↗
PubMed1999

Inhibition of cyclic AMP-dependent protein kinase in the acute phase of focal cerebral ischemia in the rat.

Binding of cyclic AMP to the regulatory subunit of cyclic AMP-dependent protein kinase is an essential step in cyclic AMP-mediated intracellular signal transduction. In the present study, the binding capacity of cyclic AMP-dependent protein kinase for cyclic AMP was examined by autoradiography with local cerebral blood flow in focal cerebral ischemia in the rat, which was induced by occlusion of the middle cerebral artery using the intraluminal suture method. The binding capacity of cyclic AMP-dependent protein kinase and local cerebral blood flow were assessed by the in vitro [3H]cyclic AMP binding and the [14C]iodoantipyrine methods, respectively. At 3 h of occlusion, a significant reduction in the binding of cyclic AMP-dependent protein kinase to cyclic AMP was already noted in the lateral region of the caudate-putamen and the parietal cortex. Between three and five hours of occlusion, the area with reduced cyclic AMP binding was significantly expanded to the peri-ischemic regions including the frontal cortex and the medial region of the caudate-putamen. The threshold in local cerebral blood flow for reduced cyclic AMP binding was clearly noted at 5 h of ischemia, and was 45 ml/100 g per min in the cerebral cortices, and 38 ml/100 g per min in the caudate-putamen, respectively. No threshold was noted at 3 h of ischemia, since cyclic AMP binding showed a large variation ranging from reduced to normal values even when local cerebral blood flow was below 20 ml/100 g per min. Recirculation for 3.5 h following 1.5 h of ischemia restored the normal cyclic AMP binding in the cerebral cortices, but failed to normalize cyclic AMP binding in the caudate-putamen despite good recovery of local cerebral blood flow. Western blot analysis suggested that this reduction in cyclic AMP binding was not due to loss or degradation of the subunit protein of cyclic AMP-dependent protein kinase, and may therefore have resulted from conformational changes in the protein. A significant increase in cyclic AMP binding was noted after recirculation in the non-ischemic regions such as the frontal and the cingulate cortices on the occluded side and in the contralateral cortices. These data indicate that cyclic AMP-mediated signal transduction in the brain tissue may be very susceptible to ischemic stress, and the region of disrupted signal transduction may expand progressively from the ischemic core to peri-ischemic regions in the acute phase of ischemia. Such impairment of signal transduction may not be restored in the caudate-putamen even when cerebral circulation is fully recovered after short-term ischemia, suggesting that a regional vulnerability to ischemic stress may also exist in cyclic AMP-mediated signal transduction. A significant increase in cyclic AMP binding after recirculation in regions outside of ischemic area may be closely related with the protective mechanisms of brain tissue, since cyclic AMP has been reported to exert various neuroprotective actions.

Animals↗
PubMed1999

Role of the ryanodine receptor in ischemic brain damage--localized reduction of ryanodine receptor binding during ischemia in hippocampus CA1.

1. The ryanodine receptor has recently been shown to play a pivotal role in the regulation of intracellular Ca2+ concentration via Ca(2+)-induced Ca2+ release (CICR). Effects of ischemia on CICR in the brain tissue, however, remain largely unknown since only a few reports have been published on this subject. In this paper we report on work in this area by our group and review related progress in this field. 2. We examined alterations of ryanodine receptor binding and local cerebral blood flow (LCBF) at 15 min, 30 min, and 2 hr after occlusion of the right common carotid artery in the gerbil brain. A quantitative autoradiographic method permitted simultaneous measurement of these parameters in the same brain. The LCBF was significantly reduced in most of the cerebral regions on the occluded side during each time period of ischemia. In contrast, only in the hippocampus CA1 on the occluded side was a significant reduction in ryanodine binding found at 15 min, 30 min and 2 hr after the occlusion. 3. These findings suggest that suppression of ryanodine binding in the hippocampus CA1 may be attributable to a regionally specific perturbation of CICR and that this perturbation may be closely associated with the pathophysiological mechanism that leads to be selective ischemic vulnerability of this region. 4. Other recent studies have also reported an important role for ryanodine receptors in neuronal injury such as the delayed neuronal death in the hippocampus CA1. These data suggest that derangement of CICR is likely to be involved in acute neuronal necrosis as well as in delayed neuronal death in ischemia. 5. Further studies on clarifying the role of CICR in ischemic brain damage are needed in order to develop new therapeutic strategies for stroke patients.

Animals↗
PubMed1999

Temporal profile and cellular localization of interleukin-6 protein after focal cerebral ischemia in rats.

Although interleukin-6 (IL-6) has various neuroprotective effects against cerebral ischemia, the topographic distribution and cellular source of IL-6 after cerebral ischemia remain unclear. In the current study, the localization of IL-6 protein was immunohistochemically examined in rats after 3.5, 12, 24, and 48 hours of reperfusion after 1.5 hours of middle cerebral artery occlusion. Middle cerebral artery occlusion was induced by the intraluminal suture method. The specificity of the anti-IL-6 antibody used in the current study was confirmed by Western blot analysis and an immunoabsorption test. To identify the cellular source, lectin histochemical study and immunohistochemical study with microtubule-associated protein-2, ED1, and glial fibrillary acidic protein also were carried out. The sham group did not show any clear IL-6 immunoreactivity. After 3.5 hours of reperfusion, IL-6 immunoreactivity was first detected on the reperfused side, and it was upregulated, especially in the periinfarct region, after 24 hours of reperfusion. Also, IL-6 was expressed after 3.5 hours of reperfusion in the contralateral cerebral cortex and bilateral hippocampi. Double staining showed that the cells containing IL-6 were neurons and round-type microglia, not astrocytes. The current findings suggest that IL-6 expression in ischemically threatened neurons and reactive microglia is closely associated with brain tissue neuroprotective mechanisms against cerebral ischemia.

Animals↗
PubMed1999

[Alteration of cAMP-mediated signal transduction in cerebral ischemia--binding activity of PKA and phosphorylation of CREB].

Binding of cAMP to the regulatory subunit of cAMP-dependent protein kinase (PKA) is an essential step for cAMP-mediated signal transduction including phosphorylation of cAMP response element binding protein (CREB). In the present study, binding activity of PKA with cAMP and CREB phosphorylation were examined in rat focal brain ischemia induced by occlusion of the middle cerebral artery for 1.5 hours followed by various time of recirculation. Binding activity of PKA with cAMP was progressively inhibited during the acute phase of ischemia from the ischemic core to peri-ischemia area. Phosphorylated CREB-positive cells in the ischemic core revealed a significant, but transient increase in number at 3.5 hours of recirculation, followed by a rapid decrease below the control level during the subsequent period. On the other hand, in the peri-ischemia area, the number of phosphorylated CREB-positive cells showed a more marked increase as compared to that in the ischemic core, and the increase continued until 48 hours of recirculation with a tendency for gradual decline. Persistent enhancement of CREB phosphorylation may thus be closely related to the neuronal viability and neuroprotective mechanisms, whereas rapid disappearance of CREB phosphorylation following ischemic insult may clearly precede neuronal death.

Animals↗
PubMed1998

Interaction between inducible nitric oxide synthase and cyclooxygenase-2 after cerebral ischemia.

Focal cerebral ischemia is associated with expression of both inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), enzymes whose reaction products contribute to the evolution of ischemic brain injury. We tested the hypothesis that, after cerebral ischemia, nitric oxide (NO) produced by iNOS enhances COX-2 activity, thereby increasing the toxic potential of this enzyme. Cerebral ischemia was produced by middle cerebral artery occlusion in rats or mice. Twenty-four hours after ischemia in rats, iNOS-immunoreactive neutrophils were observed in close proximity (<20 micrometer) to COX-2-positive cells at the periphery of the infarct. In the olfactory bulb, only COX-2 positive cells were observed. Cerebral ischemia increased the concentration of the COX-2 reaction product prostaglandin E2 (PGE2) in the ischemic area and in the ipsilateral olfactory bulb. The iNOS inhibitor aminoguanidine reduced PGE2 concentration in the infarct, where both iNOS and COX-2 were expressed, but not in the olfactory bulb, where only COX-2 was expressed. Postischemic PGE2 accumulation was reduced significantly in iNOS null mice compared with wild-type controls (C57BL/6 or SV129). The data provide evidence that NO produced by iNOS influences COX-2 activity after focal cerebral ischemia. Pro-inflammatory prostanoids and reactive oxygen species produced by COX-2 may be a previously unrecognized factor by which NO contributes to ischemic brain injury. The pathogenic effect of the interaction between NO, or a derived specie, and COX-2 is likely to play a role also in other brain diseases associated with inflammation.

Animals↗
PubMed1997

Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage.

Cyclo-oxygenase-2 (COX-2), a rate-limiting enzyme for prostanoid synthesis, is induced during inflammation and participates in inflammation-mediated cytotoxicity. Cerebral ischemia is followed by an inflammatory reaction that plays a role in the evolution of the tissue damage. We studied whether COX-2 is induced after cerebral ischemia and if so, whether such expression contributes to ischemic brain damage. The middle cerebral artery was occluded in rats, and the ischemic area was sampled for analysis 3-96 hr later. COX-2 mRNA was determined by the competitive reverse-transcription PCR. COX-2 mRNA was upregulated in the ischemic hemisphere, but not contralaterally, beginning 6 hr after ischemia. The upregulation reached a maximum at 12 hr, at which time a fivefold induction of the message occurred. Twenty-four hours after ischemia, the concentration of prostaglandin E2 was elevated in the injured brain by 292 +/- 57% (n = 6). COX-2 immunoreactivity was observed in neurons at the medial edge of the ischemic area. Administration of the COX-2 inhibitor NS-398 attenuated the elevation in prostaglandin E2 in the postischemic brain and reduced the volume of the infarct by 29 +/- 6% (p < 0.05). Thus, cerebral ischemia leads to upregulation of COX-2 message, protein, and reaction products in the injured hemisphere. The data implicate COX-2 in the mechanisms of delayed neuronal death at the infarct border and provide the rationale for neuroprotective strategies employing COX-2 inhibitors.

Animals↗
PubMed1997

Familial idiopathic brain calcification with autosomal dominant inheritance.

We report a family with brain calcification, predominantly in the basal ganglia, and no evident cause such as abnormal calcium or phosphorus metabolism. The proband, a 48-year-old man, had intellectual decline, parkinsonism, and mild cerebellar ataxia. He had bilateral and symmetric calcification of the basal ganglia, thalamus, dentate nucleus, cerebral cortex, subcortical white matter, and hippocampus on CT. Calcified areas showed low- or high-intensity signals on MRI T1-weighted images, and low-intensity signals on MRI T2-weighted images. Two sons and both parents, all asymptomatic, also showed calcification of the basal ganglia, suggesting an autosomal dominant inheritance. Familial idiopathic brain calcification is a rare disorder with less than 20 previously reported families. Twelve families with autosomal dominant inheritance showed a relatively homogeneous clinical picture, which may represent a distinct clinical entity. Mental deterioration, parkinsonism, and cerebellar ataxia appear in adult life and progress gradually. CT imaging, rather than MRI, is a simple and useful means to screen family members for this condition.

Brain Diseases↗
PubMed1996

Alteration of ryanodine receptor in the hippocampus CA1 after hemispheric cerebral ischemia.

Alterations in ryanodine binding and local cerebral blood flow (LCBF) were examined at 30 minutes and 2 hours post-ischemia in the gerbil brain in order to evaluate the influence of cerebral ischemia on the intracellular channels of Ca2+-induced Ca2+ release (CICR). Severe hemispheric cerebral ischemia was induced by occluding the right common carotid artery. LCBF was measured at the end of the experiment using [14C]iodoantipyrine method, and the ryanodine binding was evaluated in vitro using [3H]ryanodine as a specific ligand for CICR channels. An autoradiographic method developed in our laboratory enabled us to determine both parameters within the same brain. A group of gerbils who underwent a sham procedure served as controls. LCBF was found to be significantly reduced in most of the cerebral regions on the occluded side at both 30 minutes as well as 2 hours post-ischemia. In contrast, a significant reduction in ryanodine binding was noted only in the hippocampus CA1 on the occluded side at 30 minutes and 2 hours after the occlusion. These findings suggest that regionally specific changes of CICR may be the cause of decreased ryanodine binding in the hippocampus CA1, and that these changes may be related to the pathophysiological mechanisms that cause this region to be particularly vulnerable to ischemia.

Animals↗
PubMed1996

Flow threshold for reduction of cyclic AMP binding in the hippocampus CA1 and other brain regions during stroke development in gerbils.

The flow threshold for alterations of the in vitro [3H]cyclic AMP (cAMP) binding, an indicator of the total amount of particulate cAMP-dependent protein kinase, was evaluated in the gerbil brain after 30 min, 2 h, and 6 h of unilateral common carotid artery occlusion, respectively. The autoradiographic method developed in our laboratory enabled us to measure the [3H]cAMP binding and local CBF in each region of the same brain. The ischemic flow thresholds for reduction of the cAMP binding in the hippocampus CA1 were 18, 34, and 49 ml 100 g-1 min-1 after 30-min, 2-h, and 6-h ischemia, respectively. These values were higher than those in other regions such as the hippocampus CA, and temporal cerebral cortex in each duration of ischemia. These findings indicate that (a) the ischemic flow threshold for perturbation of the cAMP system may be higher in the hippocampus CA1 than in other brain regions, suggesting that the hippocampus CA1 could be especially vulnerable to acute ischemic stress; and (b) the level of the aforementioned threshold may increase progressively during the time course of ischemia in particular regions such as the hippocampus CA1 and CA3, suggesting that the duration of ischemia exerts a definite influence on the viability of the ischemic neuronal cells in these regions.

Animals↗
PubMed1996

Myasthenia-like syndrome induced by overdosage of cibenzoline.

A case of cibenzoline-induced myasthenia-like syndrome is reported. A 67-year-old woman with renal failure and no previous disorder of neuromuscular junction complained of fatigue during climbing up a flight of stairs and experiencing heavy eyelids after administration of 100 mg/day of cibenzoline. Repetitive nerve stimulation tests revealed decrement at 5-10 Hz. After reduction of the dosage, myasthenia-like signs and symptoms disappeared. The peak cibenzoline concentration was still high even after the dose reduction (666.4 ng/ml). In conclusion, cibenzoline, at a high plasma level, may induce myasthenia-like syndrome without any disorder of the neuromuscular junction.

Aged↗
PubMed1995

Chronic transection of post-ganglionic parasympathetic and nasociliary nerves does not affect local cerebral blood flow in the rat.

The role of post-ganglionic parasympathetic nerve fibers from the sphenopalatine ganglion and nasociliary nerve fibers from the trigeminal ganglion in the regulation of basal cerebral blood flow (CBF) was examined using rats, which had been divided into three groups; a sham group, a denervation group and a denervation+NG-monomethyl-L-arginine (L-NMMA) group. In the denervation and denervation+L-NMMA groups, unilateral chronic transection of the above nerve fibers had been performed at the ethmoidal foramen (EF) for 2 weeks. In the sham group, the above nerve fibers were only exposed at EF and not severed 2 weeks before the CBF measurement. Local CBF was measured by the [14C]iodoantipyrine autoradiographic method after intravenous administration of saline in the sham and denervation groups or L-NMMA (30 mg/kg) in the denervation+L-NMMA group. No significant difference in CBF was noted on each side in any of the regions between the sham and denervation groups. L-NMMA induced a significant reduction in local CBF on either side in each brain region. Neither the animals which were administered saline nor those with L-NMMA showed any side-to-side differences in local CBF in any of the brain regions examined. These findings suggest that the perivascular nerve fibers running through the EF, which are known to contain substantial nitric oxide synthase (NOS), may not play a pivotal role in the regulation of basal CBF. The reduction in CBF induced by the acute administration of L-NMMA was not affected by the chronic denervation of the above NOS-containing perivascular nerves.

Animals↗
PubMed1995

Flow threshold for enhanced phorbol ester binding in the ischemic gerbil brain.

The correlation between regional phorbol ester binding and cerebral blood flow (CBF) was evaluated in the gerbil brain after 2-hour unilateral common carotid artery occlusion. [3H]phorbol 12,13-dibutyrate (PDBu) was used as a specific ligand for estimating the translocation of protein kinase C (PKC), and CBF was determined by the [14C]iodoantipyrine method. A quantitative autoradiographic method permitted concurrent measurement of these two parameters in the same brain. In the ischemia group of the animals, statistically significant, inverse correlations were noted between the CBF and PDBu binding in the hippocampus (CA1 and CA3 regions and dentate gyrus), the caudate-putamen and lateral nuclei of the thalamus. In these regions, the PDBu binding increased progressively as CBF fell below 35-40 ml/100 g/min. On the other hand, the PDBu binding in the cerebral cortices did not show any significant changes even when CBF was decreased to below 35 ml/100 g/min. The above data suggest that (1) the translocation of PKC to the cell membrane may be regionally specific in response to ischemia, and may remain in the regions particularly vulnerable to ischemia such as the hippocampus, caudate-putamen and lateral nuclei of the thalamus in the early ischemic phase; (2) the threshold of CBF below which PKC begins to translocate to the cell membrane in the above regions, may be 35-40 ml/100 g/min in 2-hour ischemia.

Animals↗
PubMed1995

Levodopa-induced local cerebral blood flow changes in Parkinson's disease and related disorders.

Local cerebral blood flow (CBF) in the steady state and after intravenous administration of levodopa (1 mg/kg) was measured by xenon-enhanced computed tomography in patients with Parkinson's disease (PD, n = 16), progressive supranuclear palsy (PSP, n = 6), olivopontocerebellar atrophy (OPCA, n = 5), and arteriosclerotic parkinsonism (AP, n = 7). Three patterns of local CBF changes following levodopa were observed: (1) diffuse CBF increases, especially in striatum and thalamus, as found in patients with PD; (2) no significant changes in CBF, as in patients with OPCA and AP; and (3) CBF reductions in basal ganglia and thalamus, as seen in patients with PSP. The CBF increases after levodopa in PD may be secondary to metabolic activation of the nigrostriatal dopaminergic system. The poor CBF responses in patients with OPCA, AP, and PSP appeared to reflect degeneration of the dopaminergic neurons and dopamine receptors to various degrees. The CBF increases, especially in striatum and thalamus, tended to be greater (not significant) among responders to oral levodopa therapy. Levodopa-induced CBF measurements may be useful for the differential diagnosis of parkinsonian syndromes of various etiologies, but are not necessarily sufficient for predicting outcomes of long-term levodopa therapy.

Adult↗
PubMed1995

Effects of intravenous arginine administration on cerebral circulation in the rat.

The present study was designed to determine the effects of intravenous infusion of L-arginine (ARG), an endogenous precursor of nitric oxide (NO), on the cerebral circulation in the rat. Systemic arterial blood pressure (ABP) was continuously recorded, and local cerebral blood flow (LCBF) was measured by the iodo[14C]antipyrine method at a point of time as follows: In Saline group (n = 12); at 3 min after an intravenous injection of saline. In NG-monomethyl-L-arginine (L-NMMA) group (n = 7); at 3 min after an injection of L-NMMA (30 mg/kg/30 sec). In L-NMMA+L-ARG group (n = 7); at 3 min after an infusion of L-ARG free base (300 mg/kg/1 min) 3 min after prior injection of L-NMMA (30 mg/kg/30 sec). In L-ARG-1 group (n = 7); during an infusion of L-ARG free base (300 mg/kg/1 min). In L-ARG-2 group (n = 8); at 3 min after an administration of L-ARG free base (300 mg/kg/1 min). In D-ARG group (n = 5); at 3 min after an infusion of D-ARG free base (300 mg/kg/1 min). (1) The diffuse reduction in LCBF and increase in ABP induced by L-NMMA were almost completely reversed by excess L-ARG. (2) During the administration of L-ARG, a sustained decrease in ABP was observed, but LCBF revealed no significant change. (3) At 3 min after the infusion of L-ARG, LCBF was significantly decreased in several regions, while ABP recovered. (4) The infusion of D-ARG also induced a transient decrease in ABP, but did not alter LCBF. The effect of L-ARG on ABP may not be entirely due to an increase in substrate availability for NO synthase, since the D-enantiomer also had some vasodilatory property. Regarding the therapeutic application of L-ARG, further investigations on its actions should be performed under various conditions.

Animals↗
PubMed1994

Alteration of inositol 1,4,5-trisphosphate receptor after six-hour hemispheric ischemia in the gerbil brain.

In order to evaluate the influence of cerebral ischemia on the inositol 1,4,5-trisphosphate receptor, the alterations of inositol 1,4,5-trisphosphate receptor binding sites and local cerebral blood flow were examined 6 h after occlusion of the right common carotid artery in the gerbil brain. The autoradiographic method developed in our laboratory enabled us to measure both parameters within the same brain. Animals attaining ischemic scores of more than 5, as assessed 1 h after occlusion, were utilized. The local cerebral blood flow was measured 6 h after occlusion by the [14C]iodoantipyrine method. The inositol 1,4,5-trisphosphate binding sites were evaluated in vitro using [3H]inositol 1,4,5-trisphosphate as a specific ligand. The local cerebral blood flow fell below 15 ml/100 g per min in most of the cerebral regions on the occluded side. In contrast, a significant reduction in inositol 1,4,5-trisphosphate binding sites was noted only in the hippocampus CA1 on the occluded side. Inositol 1,4,5-trisphosphate binding tended to decrease when the values of local cerebral blood flow were below 20 ml/100 g per min in this region. On the other hand, the inositol 1,4,5-trisphosphate receptor immunoreactivity in the brain examined with a monoclonal antibody against inositol 1,4,5-trisphosphate receptor protein did not reveal any differences between the ischemia and sham groups on both sides, suggesting that the inositol 1,4,5-trisphosphate receptors may not undergo significant morphological degradation. These findings indicate that the suppression of inositol 1,4,5-trisphosphate binding in the hippocampus CA1 may be attributable to a regionally specific perturbation of the inositol 1,4,5-trisphosphate metabolism in this region.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗