Ryo Inoue

Long-term outcomes of pediatric moyamoya disease treated by encephalo-duro-arterio-synangiosis.

To investigate the efficacy of encephalo-duro-arterio-synangiosis (EDAS) for the treatment of pediatric moyamoya disease, we analyzed 11 patients who were followed up for more than 100 months. Among 22 sides in 11 patients, we performed EDAS on 16 sides in 10 pa- tients, encephalo-duro-arterio-myo-synangiosis (EDAMS) on 5 sides in 4 patients and encephalo-myo-synangiosis (EMS) on 1 side. Of the 11 patients, 8 patients showed normal development and had no neurological deficit. The remaining 3 patients showed mild to moderate neurological deficits, but in these cases, pre- and perioperative insults were considered to be attributable to the morbidities. Of 13 sides treated by EDAS, well-developed neovascularization was observed in 12. However, well-developed neovascularization was observed in only 3 out of 6 sides treated by EMS or EDAMS. These data might indicate that EDAS is a therapeutic alternative for the surgical treatment of pediatric moyamoya disease.

A rosette-forming glioneuronal tumor of the spinal cord: the first case of a rosette-forming glioneuronal tumor originating from the spinal cord.

Rosette-forming glioneuronal tumors of the fourth ventricle are rare brain tumors, and only 19 such lesions have been previously reported. This report presents the first case of a rosette-forming glioneuronal tumors arising from the spinal cord. A 44-year-old woman presented with a 15-year history of dissociated sensory disturbance of the lower extremities that gradually spread through her upper extremities. She also experienced continuing motor disturbance. Magnetic resonance imaging demonstrated a mass in the cervicothoracic spinal cord that suggested an intramedullary spinal tumor. A total gross resection of the tumor was performed. As is typical of rosette-forming glioneuronal tumors of the fourth ventricle, this spinal cord example manifested neurocytic and astrocytic components. Neurocytic rosettes were detected in the neurocytic component, and the center of rosettes showed positive immunostaining for synaptophysin. The astrocytic component showed characteristic features of a pilocytic astrocytoma, as is often the case in the fourth ventricle examples.

Neuroprotective effect of donepezil, a nicotinic acetylcholine-receptor activator, on cerebral infarction in rats.

This study evaluated the potential effect of donepezil, which is known as an acetylcholinesterase inhibitor used for treatment of Alzheimers disease, against cerebral infarction induced by permanent left middle cerebral artery (MCA) occlusion. Donepezil was given orally in various regimens, prior to MCA occlusion in rats. Pretreatment with a single oral dose of donepezil (12 mg/kg), 2 h before ischemia, significantly attenuated cerebral infarction volume (165.5 +/- 105.3 vs. 377.1 +/- 48.5 mm(3); P < 0.05). These neuroprotective effects were prevented by coinjection with mecamylamine, a nicotinic acetylcholine-receptor (nAChR) antagonist, indicating that protection was mediated by nAChR activation.

A genotype of the polymorphic DNA repair gene MGMT is associated with de novo glioblastoma

Abstract Glioblastoma is one of the most malignant tumors in humans. This tumor is thought to develop as a result of the accumulation of genetic abnormalities, mainly focused on the loss of heterozygosity on chromosome 10. O6-methylguanine-DNA methyltransferase (MGMT), which is one of the most important DNA repair proteins, has also been reported that enzymatic activity, as well as the methylation status of the promoter region of the MGMT gene, contributes to the therapeutic response of alkylating agents. We previously found three allelic variants in the MGMT gene and assayed the characteristics of these polymorphic proteins. We designed a case-control study to investigate the role of MGMT genotypic risk factors for primary brain tumors. We compared the distributions of MGMT genotypes in primary brain tumors and normal controls. The frequencies of MGMT genotypes in examined primary brain tumors were not different from normal subjects. However, the combined heterozygote of V1 and a wild allele (V1/W) was frequently detected in de novo glioblastoma group with significant difference. Interestingly, among glial tumors, the V1/W genotype was dominantly detected in the patients with de novo glioblastoma. This study suggests that the V1/W genotype of the MGMT gene may contribute to the de novo occurrence of glioblastoma.

IκBαM suppresses angiogenesis and tumorigenesis promoted by a constitutively active mutant EGFR in human glioma cells

Abstract Human glioma cell lines (G36ΔEGFR and IN500ΔEGFR) have been shown to display an enhanced tumorigenic phenotype, when transfected with a constitutively active form of the epidermal growth factor receptor (ΔEGFR). These cells were transfected with a mutant IκBα (IκBαM) that is resistant to phosphorylation and degradation, and hence blocks NF-κB activity. Recently, EGFR has been shown to increase the activity of NF-κB and to induce angiogenesis. In this report, we asked if IκBαM gene transfer into human glioma cell lines would inhibit tumorigenicity and angiogenesis in glioma. IκBαM inhibited in vitro and in vivo expression of vascular endothelial growth factor (VEGF) and interleukin 8 (IL-8). Human glioma xenografts treated with IκBαM gene transfer exhibited significantly decreased angiogenesis both in an orthotopic and in an ectopic model. The decreased expression of VEGF and IL-8 directly correlated with decreased tumorigenicity, and tumor vascularization. Taken in combination, these results provide strong evidence of IκBαMs role in regulating glioma angiogenesis even in the presence of constitutive EGFR activation.

Significance of leptin expression in invasive potential of pituitary adenomas

We immunohistochemically examined the expression of leptin in pituitary adenomas to investigate the correlation between the invasiveness of tumours and leptin expression. The subjects consisted of 79 patients with pituitary adenoma and were classified into the following groups: (1) non-functioning adenomas; (2) GH-secreting adenomas; (3) prolactinomas; (4) ACTH-secreting adenomas; (5) others (LH, FSH or TSH-secreting adenomas). Thereafter all cases were subdivided according to the size of tumour and the presence of invasion to the surrounding tissue. Among non-functioning adenomas, there was no significant difference between invasive and non-invasive non-functioning adenoma. In functioning adenomas, a significant difference in leptin expression was noted in intrasellar non-invasive adenomas compared to other adenomas. There was also a significant difference in leptin expression between non-invasive and invasive adenomas regardless of size. These results suggest that leptin has a role in the invasive potential of functioning adenomas.

Attempted Gene Therapy for Intractable Pain: Dexamethasone-Mediated Exogenous Control of β-Endorphin Secretion in Genetically Modified Cells and Intrathecal Transplantation

For optimal neural transplantation using gene engineering, it might be important to control the expression of the transfected gene extrinsically as required. This strategy could be very useful for the treatment of intractable pain that responds to opioids. For this purpose, we established a genetically modified embryonal carcinoma cell line (P19) in which the expression of beta-endorphin (beta-EP) could be controlled by the addition of dexamethasone. To obtain extrinsic control, we transfected the cells with pMAMneo containing mouse MMTV-LTR as a promoter and cDNA of the artificial beta-EP. The upregulation of beta-EP, through the activation of MMTV by the administration of dexamethasone, was confirmed in vitro. Then we transplanted these cells into the subarachonoid space in rats and evaluated the analgesic potential of these cells in vivo by hot plate test and formalin test. In the rats that received beta-EP-producing cells, we observed prominent analgesic effects after the transplantation for a month. The administration of naloxone blocked these effects. Intraperitoneal injection of 100 mg/kg dexamethasone further enhanced these effects by up to two times. These data indicate obvious analgesic effects of the cells after the transplantation and the possible exogenous upregulation of transfected beta-EP gene expression in vivo. The application of this technique might provide a new therapeutic approach to various neurological diseases.

Immediate plasticity in the motor pathways after spinal cord hemisection: implications for transcranial magnetic motor-evoked potentials.

The present study evaluates motor functional recovery after C2 spinal cord hemisection with or without contralateral brachial root transection, which causes a condition that is similar to the crossed phrenic phenomenon on rats. Descending motor pathways, including the reticulospinal extrapyramidal tract and corticospinal pyramidal tracts, were evaluated by transcranial magnetic motor-evoked potentials (mMEPs) and direct cortical electrical motor-evoked potentials (eMEP), respectively. All MEPs recorded from the left forelimb were abolished immediately after the left C2 hemisection. Left mMEPs recovered dramatically immediately after contralateral right brachial root transection. Corticospinal eMEPs never recovered, regardless of transection. The facilitation of mMEPs in animals that had undergone combined contralateral root transection was well correlated with open-field behavioral motor performance. Both electrophysiological and neurological facilitations were significantly attenuated by the selective serotonin synthesis inhibitor para-chlorophenylalanine (p-CPA). These results suggest that serotonergic reticulospinal fibers located contralateral to hemisection contribute to the behavioral and electrophysiological improvement that immediately follows spinal cord injury (SCI).

Neuroprotective effect of geranylgeranylacetone, a noninvasive heat shock protein inducer, on cerebral infarction in rats

The present study evaluated the neuroprotective effect of geranylgeranylacetone (GGA), which is known as an antiulcer agent and more recently as a heat shock protein (HSP) inducer, against cerebral infarction induced by permanent left middle cerebral artery (MCA) occlusion. GGA was given orally in various regimens prior to MCA occlusion in rats. Pretreatment with a single oral GGA dose (800 mg/kg) 48 h before ischemia significantly attenuated cerebral infarction volume (81.7+/-18.4 mm3 versus 369.1+/-70.2 mm3; P<.01). A significant increase in HSP70 immunoreactivity was found in the neocortex in GGA-treated animals with or without ischemia. Pretreatment with a single oral dose of GGA provides an important tool for exploring the mechanisms of neuroprotection against cerebral ischemic neuronal damage.

A single oral dose of geranylgeranylacetone attenuates kainic acid-induced seizures and neuronal cell death in rat hippocampus

The present study evaluated the potential effect of geranylgeranylacetone (GGA), which is known as an antiulcer agent, against kainic acid (KA)-induced neurotoxicity. Pretreatment with a single oral GGA dose (800 mg/kg, 2 days before KA) significantly attenuated KA-induced seizures and cell death in rat hippocampus. These effects of GGA were prevented by the coinjection of MK801, a noncompetitive N-methyl-D-aspartate glutamate receptor antagonist, which indicates that the protection was indeed mediated by glutamate receptor activation.