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Biomedical subjects

Isao Date

Publications and source records attributed to Isao Date.

64 records · Page 4Linked to original sources
PubMed2003

Inhibition of excitatory neuronal cell death by cell-permeable calcineurin autoinhibitory peptide.

In glutamate-mediated excitatory neuronal cell death, immunosuppressants (FK506, Cys-A) are powerful agents that protect neurons from apoptosis. Immunosuppressants inhibit two types of enzyme, calcium/calmodulin-dependent protein phosphatase (calcineurin: CaN), and peptidyl-prolyl cis-trans-isomerase (PPIase) activity such as the FKBP family. In this study, we used a protein transduction approach to determine the functional role of CaN and to produce a potential therapeutic agent for glutamate-mediated neuronal cell death. We created a novel cell-permeable CaN autoinhibitory peptide using the 11 arginine protein transduction domain. This peptide was highly efficient at transducing into primary culture neurons, potently inhibited CaN phosphatase activities, and inhibited glutamate-mediated neuronal cell death. These results showed that CaN plays an important role in excitatory neuronal cell death and cell-permeable CaN autoinhibitory peptide could be a new drug to protect neurons from excitatory neuronal death.

Active Transport, Cell Nucleus↗
PubMed2003

Time course of the diameter of the major cerebral arteries after subarachnoid hemorrhage using corrosion cast technique.

In this report, we examined whether corrosion cast method is also applicable for the measurement and estimation of the rat major arteries in which subarachnoid hemorrhage (SAH) is produced. Additionally, we have examined the diameters of the rat major arteries following SAH. A total of 0.3 ml autologous blood was injected into the cisterna magna of male Sprague-Dawley rats for the SAH model. A perfusion of a semi-polymerized casting medium was performed, 10 min, 30 min, 1 h, 4 h, 8 h, 1 day, 2 days, 3 days, 5 days, and 7 days after SAH. The brains were corroded in a 10% NaOH solution. The BA and the other major arteries were then measured using scanning electron microscopy (SEM). Macroscopic observation and hematoxylin-eosin (HE) staining were also performed. Using the corrosion cast method, the biphasic contractile response was observed in the BA; 8.3% and 11.6% contractions were observed 30 min and 1 day after SAH, respectively. In addition, there was almost no smooth muscle or adventitial thickening in the chronic stage. In contrast, the dilative response was observed in the internal carotid artery and middle cerebral artery 10 min after SAH. Macroscopic findings and HE staining revealed that the extensive basal subarachnoid hematoma had almost disappeared by day 2. These results indicate that in this model, the minimal spasm, which occurs one day after SAH, can be explained by the small capacity of the rat subarachnoid space and the rapid cerebrospinal fluid washout around major vessels at the cerebral base. Moreover, the present data also show the compensatory dilatation in the ICA and MCA in the early stage after SAH.

Animals↗
PubMed2003

Glioblastoma with metastasis to the spleen--case report.

A 47-year-old woman presented with headache and left homonymous hemianopsia. T1-weighted magnetic resonance (MR) imaging with contrast medium showed a mass lesion with ring-like enhancement in the right temporo-occipital lobe. The patient underwent surgery, focal irradiation, and chemotherapy. The histological diagnosis was glioblastoma. Four months after the operation, the patient again developed headache and left homonymous hemianopsia in addition to vomiting and mild left hemiparesis. MR imaging showed recurrence of the tumor and hydrocephalus. The patient underwent a second craniotomy and placement of a ventriculoperitoneal shunt. Intraoperative findings revealed that the transverse-sigmoid sinus was occluded by tumor invasion. The patient died of intraventricular dissemination 2 months after the second operation. Autopsy revealed metastases in the spleen and lungs. Glioblastoma with metastases to the spleen is very rare. The prognosis for patients is poor. Excessive therapy should not be used for patients with extracranial metastases from glioblastoma.

Brain Neoplasms↗
PubMed2003

Stereotactic transplantation of a dopamine-producing capsule into the striatum for treatment of Parkinson disease: a preclinical primate study.

OBJECT: The PC12 cells are well known for their ability to secrete dopamine and levodopa. In multiple animal mode encapsulated PC12 cells have been shown to ameliorate parkinsonian symptoms when transplanted into the striatum; technique is expected to be effective clinically as well. The present study was performed using nonhuman primates to ensure that the transplantation of encapsulated PC12 cells is likely to be both safe and effective in human clinical trials. METHODS: Unencapsulated or encapsulated PC12 cells were implanted into the brains of Japanese monkeys (Macaca fuscata). Histological and immunocytochemical analyses were performed 1, 2, 4, and 8 weeks posttransplantation on the unencapsulated cells and 2, 4, and 8 weeks after transplantation on the encapsulated cells. The survival of the PC12 cells inside the capsule was determined by measuring the amounts of dopamine and levodopa released from the capsules a removal from the striatum. Magnetic resonance imaging was performed in both unencapsulated and encapsulated PC12 cell-grafted groups. Due to the immunological reaction of the host brain no unencapsulated PC12 cells remained in the grafted area 8 weeks after transplantation. On the contrary, encapsulated PC12 cells retrieved from the host brain continued to release dopamine and levodopa even 8 weeks after implantation. The host's reaction to the PC12-loaded capsule was much weaker than that to the unencapsulated PC12 cells. CONCLUSIONS: These results suggest that the transplantation of encapsulated PC12 cells could be a safe and effective treatment modality for Parkinson disease in human patients.

Animals↗
PubMed2003

Reduction of infarct volume and apoptosis by grafting of encapsulated basic fibroblast growth factor-secreting cells in a model of middle cerebral artery occlusion in rats.

OBJECT: This study was conducted to evaluate the effects of grafting encapsulated basic fibroblast growth factor (bFGF)-secreting cells in rat brains subjected to ischemic injury. METHODS: Two cell lines were used for encapsulated grafting in this experiment, namely, a bFGF-secreting cell line established by genetic manipulation of baby hamster kidney (BHK) cells, and a naive BHK cell line. Forty-seven Sprague-Dawley rats were used in this experiment. The animals were divided into the following three groups: those receiving grafts of encapsulated bFGF-secreting cells (BHK-bFGF group); those with grafts of encapsulated naive BHK cells (naive BHK group); and those with no grafts (control group). The authors implanted encapsulated cells into the right striatum of host rats in the BHK-bFGF and naive BHK groups. Six days after grafting, the host and control animals underwent permanent right middle cerebral artery occlusion (MCAO) with an intraluminal suture procedure. The infarct volume was evaluated using 2,3,5-triphenyltetrazolium chloride staining and computerized image analysis 24 hours after MCAO. Fragmentations of DNA in the host brains were analyzed using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling 12 hours after MCAO. The authors found that the infarct volume in the BHK-bFGF group was reduced by approximately 30% compared with that in the naive BHK and control groups. In the ischemic penumbral area, the number of apoptotic cells in the BHK-bFGF group was significantly decreased compared with that in the other groups. CONCLUSIONS: The grafting of encapsulated BHK bFGF-secreting cells protected the brain from ischemic injury. Encapsulation and grafting of genetically engineered cells such as bFGF-secreting cells is thus thought to be a useful method for protection against cerebral ischemia.

Animals↗
PubMed2002

Neuroprotective and restorative effects of intrastriatal grafting of encapsulated GDNF-producing cells in a rat model of Parkinson's disease.

Glial cell line-derived neurotrophic factor (GDNF) has been shown to possess potent neurotrophic effects on dopaminergic (DA) neurons. We attempted the transplantation of encapsulated GDNF-producing cells to generate a stable supply of GDNF in the brain to promote neuroprotective and restorative effects for DA neurons. We established baby hamster kidney (BHK) cells and introduced GDNF cDNA to produce human GDNF (BHK-GDNF). These BHK-GDNF cells, or nontransfected BHK cells (BHK-Control), were encapsulated into hollow fibers, and the polymer encapsulated cells were unilaterally implanted into the striatum of adult rats, either before or after the administration of 6-hydroxydopamine into the same striatum. The encapsulated BHK-GDNF cells produced GDNF continuously in the striatum for up to 6 months. The rats that received a BHK-GDNF capsule showed a significant decrease in rotational behaviour compared to those that received a BHK-control capsule. Preservation of the nigrostriatal pathway was significantly greater in those that received a BHK-GDNF capsule than in those that received a BHK-control capsule. This indicates that encapsulated GDNF-producing cells can supply GDNF in a stable fashion and have protective and restorative effects on host DA neurons. Our results support a role for this grafting technique in the treatment of Parkinson's disease.

Animals↗
PubMed2002

[Intracerebral grafting of cell line or patient-derived neural stem cells for the treatment of neurological disorders].

Due to the development of molecular biology techniques, several types of neurotransmitter or neurotrophic factor secreting cell line can be established. These cell lines were grafted into the brain of animal models of Parkinson's disease and cerebral ischemia after encapsulating into the hollow fiber consisted of semipermeable membrane. Immunological reaction and tumor formation were prevented and functional effects were observed histologically, chemically and behaviorally. Current issues regarding encapsulated cell grafting are: delivery of neurotransmitter and neurotrophic factor simultaneously from one capsule, usage of human-derived cell lines and control of secretion from outside. There are two possible approaches regarding the usage of patient's own neural stem cells for regenerative therapy. Neural stem cells are collected from the subventricular zone of the lateral ventricle and these cells are differentiated into dopaminergic neurons using tyrosine hydroxylase induction cocktail (TH cocktail). Then, these neurons are grafted into the striatum of the patient. Another method is to inject TH cocktail into the patient's striatum in order to induce differentiation of dopaminergic neurons from the neural stem cells in vivo.

Animals↗
PubMed2001

Single administration of GDNF into the striatum induced protection and repair of the nigrostriatal dopaminergic system in the intrastriatal 6-hydroxydopamine injection model of hemiparkinsonism.

Purpose: Neurotrophic factor delivery into the brain is a promising approach in the treatment of Parkinson's disease. Glial cell line-derived neurotrophic factor (GDNF) is one of the most potent neurotrophic factors for dopaminergic neurons. Although multiple injections of GDNF into the brain are commonly performed in experimental studies, the present study investigates the efficacy of using a single injection of GDNF, which may be useful in elinically applying this treatment. Methods: Unilateral 6-hydroxydoparnine (6-OHDA) administration into the striatum was perforrned in Sprague-Dawley rats to create a partial lesion of the nigrostriatal DA system. These parkinsonian model rats received a single injection of human recombinant GDNF into the same portion of the striatum either 24 h before or 4 weeks after 6-OHDA treatrnent. Results: GDNF injected into the striatum before 6-OHDA administration potently protected the dopaminergic system, as shown by the numbers of mesencephalic dopaminergie neuron cell bodies and dopaminergic nerve terminal densities in the striatum. Dopaminergic neuron cell bodies and fiber densities were also significantly restored when GDNF was given after 6-OHDA administration, although the degree of restoration was lower than in the protective experiment. ODNF administration ameliorated apomorphine-induced rotational behavior in animals receiving it either before or after 6-OHDA treatment. However, the degree of improvement was less prominent when GDNF was iniected after 6-OHDA. Conclusion: Intracerebral GDNF adininistration exerts both protective and regenerative effects on the nigrostriatal dopaminergic system, a finding which may have implications for the development of new treatment strategies for Parkinson's disease.

Journal Article↗