Biomedical subjects

M Shinoda

Publications and source records attributed to M Shinoda.

At least 73 records · Page 4Linked to original sources

PubMed1997

Types of potassium channels involved in coronary reactive hyperemia depend on duration of preceding ischemia in rat hearts.

This study was undertaken to clarify factors other than nitric oxide involved in reactive hyperemia after a short (30 sec) and a long (300 sec) coronary global no-flow ischemia in isolated rat hearts perfused at a constant pressure (90 mmHg) with special focuses on the contribution of various K channels including large and small conductance Ca-activated K (KCa) channels as well as ATP-sensitive K (KATP) channels. Reactive hyperemia was induced following 30 sec and 300 sec of no-flow ischemia of the heart. Coronary reactive hyperemia was observed even after the inhibition of nitric oxide synthase by N(omega)-nitro-L-arginine methylester (L-NAME). Selected K channel blockers, none of which affected the basal flow, were used to evaluate contribution of K channels to this L-NAME-resistant reactive hyperemia. After 30-sec ischemia, tetraethylammonium (TEA: a non-selective K channel blocker), glibenclamide (Gli: a KATP channel blocker) and alpha,beta-methylene adenosine 5'-diphosphonate (AOPCP: an inhibitor of ecto 5'-nucleotidase) all suppressed both peak flow/basal flow (%PF) and repayment of flow debt (%RFD). After 300-sec ischemia, TEA and charybdotoxin (ChTX: a large conductance KCa channel blocker) decreased %PF and %RFD; AOPCP decreased both %RFD and duration, 4-aminopyridine (a voltage-dependent K channel blocker) decreased only duration. Neither apamin (a small conductance KCa channel blocker) nor indomethacin (a cyclooxygenase inhibitor) affected the both types of reactive hyperemia. These findings suggest that opening of KATP channel contributes to coronary vasodilation in reactive hyperemia after short 30-sec ischemia, and that opening of KCa, but not KATP, channel contributes to it after long 300-sec ischemia. These results also suggest that adenosine may partly be involved in both types of reactive hyperemia.

4-Aminopyridine↗

PubMed1997

Effect of a novel prolyl endopeptidase inhibitor, JTP-4819, on spatial memory and central cholinergic neurons in aged rats.

The effects of a novel prolyl endopeptidase inhibitor (PEP), (S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)- 1-pyrrolidinecar-boxamide (JTP-4819), on performance of the Morris water maze task and on central cholinergic function were investigated in aged rats. Spatial memory (escape latency, path length, and swimming speed to the platform) was impaired in aged rats performing the Morris water maze task when compared to young rats. Administration of JTP-4819 (1 mg/kg, p.o.) for 14 days improved this memory deficit in aged rats, as shown by the decrease in escape latency and path length. In addition, when JTP-4819 (at doses of 1 and 3 mg/kg, p.o.) was administered for 3 wk, it reversed the age-related increase of ChAT activity in the cerebral cortex and the decrease of 3H-choline uptake in the hippocampus. These data suggest that JTP-4819 ameliorates age-related impairment of spatial memory and partly reverses central cholinergic dysfunction, possibly due to the enhancement of neuropeptide function by inhibition of PEP mediated degradation of substance P, arginine-vasopressin, and thyrotropin-releasing hormone.

Acetylcholine↗

PubMed1997

A novel prolyl endopeptidase inhibitor, JTP-4819, with potential for treating Alzheimer's disease.

The pharmacological actions of JTP-4819, a new prolyl endopeptidase (PEP) inhibitor targeted for the treatment of Alzheimer's disease, are reviewed with respect to its effects on PEP activity, brain neurotransmitters, and memory-related behaviour in rats. JTP-4819 was shown to be a very potent and specific inhibitor of PEP. At nanomolar concentration, JTP-4819 inhibited the degradation of substance P, arginine-vasopressin, and thyrotropin-releasing hormone by PEP in supernatants of the rat cerebral cortex and hippocampus. Repeated administration of JTP-4819 reversed the aging-induced decrease in brain substance P-like and thyrotropin-releasing hormone-like immunoreactivity, suggesting that this drug may be able to improve the imbalance of peptidergic neuronal systems that develops with senescense by inhibiting PEP activity. JTP-4819 increased acetylcholine release from the frontal cortex and hippocampus, regions closely associated with memory, in both young and aged rats. In addition, it improved performance in several memory and learning-related tests (e.g., the Morris water maze task in aged or MCA-occluded rats and the passive avoidance test). This memory-enhancing effect of JTP-4819 may result from prevention of the metabolic degradation of brain neuropeptides by PEP as well as from the enhancement of acetylcholine release. Taken together, these unique and potent pharmacological actions of JTP-4819 suggest that it may have the potential to be used for treating Alzheimer's disease.

Alzheimer Disease↗

PubMed1997

Changes in distribution of cystatin C, apolipoprotein E and ferritin in rat hypothalamus after hypophysectomy.

To clarify the mechanism underlying the process of degeneration of injured CNS neurons, we have immunohistochemically examined the distribution of cystatin C, apolipoprotein E, IgG, transferrin and ferritin in the hypophysectomized rat hypothalamus. Stainings for ferritin revealed that reactive microglial cells massed in the paraventricular and supraoptic nuclei 14 days after hypophysectomy, when the degeneration of vasopressin neuronal cell bodies was apparent. Cystatin C-positive magnocellular neurons first appeared at 4 days and the number of intensely-stained cells increased rapidly up to the 7th day of hypophysectomy, followed by a decrease thereafter. Most of such cystatin C-positive neurons were simultaneously stained with anti-vasopressin serum. Accumulation of apolipoprotein E in extracellular spaces was obvious in the both hypothalamic magnocellular nuclei at 7 days. Several apolipoprotein E-positive cells were localized in the supraoptic nucleus, although the number of apolipoprotein E-positive cells was much smaller than that of cystatin C-positive cells. The experiments performed with the transferrin and IgG antibodies showed undetectable levels of such molecules in and around the degenerating magnocellular neurons during whole experimental periods. These findings suggest the importance of cystatin C and apolipoprotein E in the process of degeneration and/or regeneration of magnocellular neurons after hypophysectomy.

Animals↗

PubMed1997

Mucosal chemokine activity in Helicobacter pylori infection.

We examined secretion, mRNA expression, and histologic localization of interleukin-8 (IL-*) and growth-related gene product-alpha (GRO alpha) in the Helicobacter pylori-infected gastric antral mucosa. Antral biopsies were obtained from an area of endoscopically intact mucosa. Significantly higher levels of IL-8 and GRO alpha were secreted in organ cultures from patients with H. pylori infection, and their elevation was prominent in patients with duodenal ulcer. There was a significant association between these alpha-chemokine levels and histologic grades of activity, inflammation, and H. pylori density. In fresh antral biopsies, IL-8 and GRO alpha mRNA expression was detected more frequently in H. pylori-infected patients compared with those without infection. Immunofluorescence microscopy showed localization of IL-8 and GRO alpha proteins in gastric epithelial cells and infiltrating CD68+ macrophages. In the chemotaxis assay, a significant positive correlation was found between neutrophil migration induced by the organ culture supernatants and their contents of IL-8 and GRO alpha. After H. pylori eradication, a significant decrease was observed in IL-8 and GRO alpha levels detected in organ cultures. In conclusion, mucosal alpha-chemokine activity correlates well with histologic severity of H. pylori-associated antral gastritis and can be used to predict the effects of H. pylori eradication therapy.

Adult↗

PubMed1997

Viscoelastic properties of the pig temporomandibular joint articular soft tissues of the condyle and disc.

It has been suggested that a sustained loading condition such as clenching could compress the temporomandibular joint (TMJ) articular soft tissues. However, there is still no clear understanding of how the TM joint articular tissues respond under compression. To answer this question, we performed in vitro indentation tests on fresh articular discs and cartilage-bone systems of the condyles of 10 Yorkshire pigs (aged 7 months) using a self-developed indentation tester. The indenter was 5 mm in diameter and was controlled by means of a computer-aided feedback mechanism. Bilateral condyles from the same mandible were uniformly prepared; one was used for measurements under sustained compression (SC) and the other for measurements under intermittent compression (IC). The displacements of the indenter induced by a SC of 10, 20, and 30 Newtons (N, units of force) for 10 min and by an IC, also of 10, 20, and 30 N, with one-second duration and two-second intervals for 10 min were measured by means of a displacement sensor with a resolution of 0.001 mm. From these data, the indentation curves of the articular discs and the cartilage-bone systems were calculated. Both the disc and the articular cartilage showed characteristic displacement vs. time curves-namely, an instantaneous deformation upon load application, followed by a time-dependent creep phase of asymptotically increasing deformation under constant load. However, the indentation curves of the two tissues were not identical: The deformation of the articular cartilage was dose-dependent, but that of the disc was not. Moreover, the articular cartilage deformed significantly less under IC than under SC. This difference was not found in the disc. It can be concluded that both the disc and the articular cartilage of the pig temporomandibular joint have viscoelastic properties against compression; however, the disc is stiffer than the articular cartilage.

Analysis of Variance↗

PubMed1997

Immunological aspects of kaolin-induced hydrocephalus.

Adult female Sprague Dawley rats were administrated 0.1 ml Kaolin (250 mg/ml) into cisterna magna. One, 4 and 8 weeks later, brains were analyzed using antibodies against MHC class I (OX18), MHC class II (OX6), CD4 (OX38), CD8 (OX8), OX42, ED1, NF, GFAP, AChE and TH. Remarkably high numbers of T lymphocytes, and OX42- and ED1-positive macrophages were found aggregated in subarachnoid spaces, and in the third and fourth ventricles. Marked aggregations of ED1-positive reactive microglial cells were also found in paraventricular structures, medial septum, retrosplenic cortex and commissural structures. However, no such cells were found in hippocampus. ED1-positive areas were also positive for round cells with a rim of MHC I fluorescent cytoplasm as well as for OX42-positive cells and MHC II positive microglial cells. At week 1, in ventro-frontal areas of cortex, CD8-positive cells and MHC I positive astroglial fibers were detected. At week 1, MHC I positive ramified microglial cells were also recognized in almost the entire brain. These positive cells gradually decreased with time and finally remained rounded with a rim of fluorescent cytoplasm. In addition, ED1 positive partly ramified microglial cells could be recognized in corpus callosum, probably representing cells in transition between ramified and reactive microglia. CD8+ cells entered ventral brain structures, and were found in the horizontal diagonal band at week 4, and had disappeared at week 8. Finally in cortex, ED1 positive microglial cells could be identified only in the retrosplenic cortex, and there were also "dark shrunken neurons" in light microscopic stainings. However, there was only a moderate GFAP positive gliosis. In conclusion, kaolin-induced hydrocephalus leads to immune reactions in several defined areas such as cholinergic systems, corpus callosum, circumventricular organs, pontine cerebellar peduncles and the vestibular nucleus.

Animals↗

PubMed1997

[A carcinoma arising from benign pleomorphic adenoma of the trachea].

A 69-year-old female complained of husky voice and dyspnea. Bronchofiberscopic examination revealed a tumor at the left side of the trachea, which obstructed approximately 80% of the tracheal lumen. Benign pleomorphic adenoma was diagnosed by biopsy. The tumor was removed by circumferenctial resection of the trachea with partial sternotomy adding to the 3 th intercostal transverse resection. Historical finding of the resected specimen revealed a carcinoma arising from benign pleomorphic adenoma of the trachea and residue of malignancy at the margin of the trachea and esophagus. Additional radiotherapy was performed (60 Gy). The postoperative course was uneventful for 4 months and one year.

Adenocarcinoma↗

PubMed1997

Mucosal interleukin-8 is involved in neutrophil migration and binding to extracellular matrix in inflammatory bowel disease.

OBJECTIVES: In this study, our purpose was to determine whether locally generated interleukin-8 (IL-8) is involved in neutrophil migration and binding to extracellular matrix, using the colonic mucosal specimens obtained from patients with inflammatory bowel disease (IBD). METHODS: Levels of IL-8 secreted in the organ cultures were measured by enzyme-linked immunosorbent assay. Chemotactic activity and binding capacity of neutrophils were induced by the organ culture supernatants. RESULTS: Significantly higher levels of IL-8 were secreted in patients with IBD, and its elevation was more prominent in patients with active ulcerative colitis. The organ culture supernatants induced higher chemotactic activity and binding capacity of neutrophils in patients with IBD, especially in those with active ulcerative colitis, compared with controls. These effects were inhibited significantly when the supernatants were submitted to preincubation with neutralizing anti-IL-8 antibody. CONCLUSIONS: Increased mucosal generation of IL-8 may attract neutrophils from the circulation into the inflammatory site and induce binding of neutrophils in the interstitial tissue, contributing to accumulation and activation of neutrophils in the affected mucosa with IBD.

Adolescent↗

PubMed1996

MUC1-specific targeting immunotherapy with bispecific antibodies: inhibition of xenografted human bile duct carcinoma growth.

For the purpose of establishing a new adoptive immunotherapy for bile duct carcinoma (BDC), we synthesized two bispecific antibodies (BsAbs), MUC1 x CD3 BsAb constructed with MUSE11 (anti-MUC1 tumor antigen) and OKT-3 (anti-CD3), and MUC1 x CD28 BsAb constructed with MUSE11 and 15E8 (anti-CD28) antibodies. These two BsAbs reacted well with both MUC1-positive target tumor cells and effector lymphokine-activated killer (LAK) cells. Investigation of in vitro cytotoxicity [3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazolium bromide assay] revealed that the MUC1 x CD3 BsAb could antigen-specifically enhance the cytotoxicity of LAK cells. Addition of the two BsAbs (MUC1 x CD3 BsAb plus MUC1 x CD28 BsAb) in vitro resulted in a 60% cytotoxicity, similar to that obtained with BsAb (MUC1 x CD3) alone. Interleukin 12-induced LAK cells demonstrated far greater cytotoxicity (50%) than their interleukin 2-induced counterparts (LAK cells), and this was also enhanced by the BsAbs. When 2 x 10(7) LAK cells sensitized with both kinds of BsAbs were administered four times i.v. to BDC-grafted severe combined immunodeficient mice (tumor size 5 mm in diameter), inhibition of tumor growth was observed. Thus, BsAb-LAK therapy for control of BDC warrants clinical trials.

Animals↗

PubMed1996

Structure-activity relationships of (E)-3-(1,4-benzoquinonyl)-2-[(3-pyridyl)-alkyl]-2-propenoic acid derivatives that inhibit both 5-lipoxygenase and thromboxane A2 synthetase.

As part of our research for the development of novel antiinflammatory drug candidates, we have designed and synthesized a series of (E)-3-(1,4-benzoquinonyl)-2-[(3-pyridyl)alkyl]-2-propenoic acid derivatives as dual inhibitors of 5-lipoxygenase (5-LO) and thromboxane (TX) A2 synthetase. In order to increase the absorption after oral administration, we introduced a carboxylic acid moiety into the 1,4-benzoquinone skeleton, which has 5-LO-inhibitory character. Introduction of a 3-pyridylalkyl group at the double bond of the 1,4-benzoquinonyl propenoic acid moiety afforded good to moderate inhibitory activities against the production of leukotriene (LT) B4 and TXA2 while not significantly inhibiting that of prostaglandin E2 by glycogen-induced peritoneal cells of rat (in vitro). The length of the methylene chain of the 3-pyridylalkyl group influenced the inhibition of LTB4 and TXB2 production. An increase of lipophilicity by introducing a more lipophilic alkoxy group did not markedly increase the inhibitory activity on LTB4 production. The position of alkoxy group on the 1,4-benzoquinone skeleton played an important role in TXA2 synthetase inhibition. Compounds such as 20c (E6700) with an appropriate alkoxy group and proper length of methylene side chain, together with a polar substituent (carboxylic acid), showed good inhibition of both 5-LO and TXA2 synthetase and possess a variety of pharmacologically beneficial effects.

Animals↗

PubMed1996

Pharmacological studies of a novel prolyl endopeptidase inhibitor, JTP-4819, in rats with middle cerebral artery occlusion.

We studied behavioral and pharmacological effects of a novel prolyl endopeptidase inhibitor, (S)-2-[[(S)-2-(hydroxyacetyl)- 1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)-1-pyrrolidine-car boxamide (JTP-4819), in rats with middle cerebral artery occlusion. Administration of JTP-4819 (0.1 and 1 mg/kg p.o for 7 days) significantly prolonged passive avoidance latency, while the latency of rats with middle cerebral artery occlusion receiving the vehicle was significantly shorter than that of sham-operated rats. The prolonged escape latency in the Morris water maze task in rats with middle cerebral artery occlusion was also significantly reduced by administration of JTP-4819 (0.3 and 1 mg/kg p.o.). Interestingly, administration of JTP-4819 (0.3-3 mg/kg p.o. for 15 days) restored the decreased cortical thyrotropin-releasing hormone (TRH)-like immunoreactivity content of rats with middle cerebral artery occlusion but did not affect the cortical and hippocampal substance P- or arginine vasopressin-like immunoreactivity content. These results suggest that JTP-4819 ameliorates memory impairment due to middle cerebral artery occlusion by restoring the cortical TRH content.

Animals↗

PubMed1996

Interactions of neurotrophic factors GDNF and NT-3, but not BDNF, with the immune system following fetal spinal cord transplantation.

Glial cell line-derived neurotrophic factor (GDNF) is known to stimulate survival of dopaminergic and spinal cord motor neurons. However, little is known of the possible immune sequelae of GDNF exposure, or that of other putative trophic factors. To address these questions we utilized in oculo grafts of spinal cord, wherein we could induce different levels of immune responses via allogeneic vs. syngeneic combinations. Adult female Sprague-Dawley and Fisher rats were used as hosts for allogeneic and syngeneic grafts, respectively. Embryonic age 14-15-day-old fetuses were taken from pregnant dams of each strain, and cervical spinal cords were removed and dissected. Pieces of the spinal cord were transplanted into the anterior chamber of the eye within each strain. At 5-day intervals, 0.5 microgram of GDNF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) or cytochrome c (CC) was injected into the anterior chamber of the eye and the sizes of the transplants were measured for the Sprague-Dawley rats. The same injections and measurements, but only for GDNF and CC, were carried out using Fisher rats. As expected, GDNF increased transplant survival and growth in both the Sprague-Dawley and Fisher animals. At day 41-42, all rats were sacrificed. Cameral graft appearance was evaluated by cresyl violet and immunohistochemically using antibodies against neurofilament (NF), calcitonin gene-related peptide (CGRP) and glial fibrillary acidic protein (GFAP). To monitor immune responses, the following monoclonal antibodies were used: OX38 against CD4, OX18 against MHC class I (MHCI), OX8 against CD8, OX6 against MHC class II (MHCII), OX42 against CD11b, R73 against alpha and beta T cell receptor (TcR), and ED1. In the Sprague-Dawley grafts, significantly higher amounts of CD8+, T lymphocyte+, MHCI+ and MHCII+ antigen-presenting cells (APC) were observed in GDNF-treated transplants. These markers were also increased in NT-3-treated groups. There were two types of OX-42+ cells, one was the ordinary ramified microglial cell, the other appeared to be a phagocytic cell, looking like the interstitial proliferating variety. Interestingly, the phagocytic OX-42+ cells had the same distribution as ED1+ and MHCII+ cells. In contrast, there were few immunoreactive cells after GDNF treatment in the inbred Fisher animals, similar to the CC control group. These results suggest that GDNF and to some extent NT-3, can activate the immune system in allogeneic graft combinations, but that these trophic factors do not produce overt rejection, and do not per se induce immune responses.

Animals↗

PubMed1996

Microglial cell responses to fetal ventral mesencephalic tissue grafting and to active and adoptive immunizations.

Microglia express cytokines, major histocompatibility (MHC) loci, and several other immunologically important constituents. The aim of this study was to detect immunological responses of microglial cells following allogeneic dopaminergic transplantation using active and adoptive immunizations. Adult inbred Fisher 344 (F344 RT1) rats were unilaterally dopamine (DA) depleted in striatum by injection of 6-hydroxydopamine. The degree of degeneration was assessed by recording the rotational response to apomorphine. Fetal ventral mesencephalic tissue containing DA neuroblasts from Wistar-Furth (WF, RT1u) rat donors (9-12 mm CRL) were later implanted in striatum on the lesioned side. Lymph nodes and spleen cells were collected aseptically, resuspended, and diluted for isovolumetric injections. Animals selected for active immunization were injected intraperitoneally with varying amounts of WF lymphocytes. Animals selected for adoptive immunization (transferred immunity) were intraperitoneally injected with 10(8) F344 lymphocytes prepared from animals actively immunized 3 weeks previously. Monoclonal antibodies against CD4 (OX38), CD8 (OX8), CD11b (OX42), MHC class I (OX18), monomorphic MHC class II (OX-6), and ED1 and polyclonal antibodies against tyrosine hydroxylase (TH) were used for immunohistochemistry. We found that the degree of ED1-positive cell proliferation was well correlated to the immunization patterns. Groups that were actively immunized with or without prior adoptive immunization had a larger amount of reactive microglial proliferation. ED1 immunohistochemistry revealed patterns of immunolabeling of engrafted areas: 8-12 weeks after grafting in nonimmunized and adoptively immunized groups reactive microglial proliferation occurred only at the graft periphery. Active and adoptive + active immunization led to ED1-IR within the grafts themselves. At early stages nonimmunized groups had an ED1 pattern which was partially inside the grafts. At early time points nonimmunized groups contained ameboid microglial cells within the grafts which disappeared at later stages and were absent in the immunized groups. ED1-positive ameboid microglial cells within the grafts may be of graft origin and constitute a part of a continued normal development of the fetal tissue.

Animals↗

PubMed1996

Effect of a novel prolyl endopeptidase inhibitor, JTP-4819, on neuropeptide metabolism in the rat brain.

The effect of a novel prolyl endopeptidase (PEP) inhibitor, (S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl] carbonyl]-N-(phenylmethyl)-1-pyrrolidine-carboxamide (JTP-4819), on neuropeptide metabolism was investigated in the rat brain. JTP-4819 exhibited a strong in vitro inhibitory effect on cortical and hippocampal PEP activity, with the IC50 values being approximately 0.58 +/- 0.02 and 0.61 +/- 0.06 nM, respectively. JTP-4819 also inhibited the in vitro degradation of substance P (SP), arginine-vasopressin (AVP), and thyrotropin-releasing hormone (TRH) by rat brain supernatants, with the IC50 values being respectively 3.4, 2.1, and 1.4 nM in the cerebral cortex and 3.3, 2.8, and 1.9 nM in the hippocampus. Oral administration of JTP-4819 at doses of 1 and 3 mg/kg increased SP-like immunoreactivity (LI) and AVP-LI in the cerebral cortex. JTP-4819 also increased hippocampal SP-LI and AVP-LI at doses of 1 and 3 mg/kg, as well as hippocampal TRH-LI at a dose of 3 mg/kg. These findings suggest that JTP-4819 inhibited the degradation of SP, AVP, and TRH in the rat brain secondary to the inhibition of PEP, and thus increased cortical and hippocampal SP-LI and AVP-LI as well as hippocampal TRH-LI.

Administration, Oral↗

PubMed1996

Differential immune responses to fetal intracameral spinal cord and cortex cerebri grafts.

While the central nervous system (CNS) has been characterized as an immunologically privileged site, there are also several reports describing immunological reactions within the CNS. A certain degree of immunological privilege has also been ascribed to the anterior chamber of the eye. We have used the intraocular transplantation model to study immunological reactions in transplants of embryonic neural tissue. Outbred Sprague-Dawley rats and inbred Fisher rats were used. Pieces of rat parietal cortex or the cervical spinal cord were prepared from embryonic day 14 and implanted into the eye chambers of adult rats of the same strain. Following intraocular maturation, grafts were analysed using antibodies against: major histocompatibility complex (MHC) class I, MHC class II; rat antigens CD4, CD8, CD11b; T-cell receptor; rat antigen ED1; and glial fibrillary acidic protein. Using this set of markers for immunological reactions, transplants were scored on a blind basis. We found no significant differences in immunological scores between transplants obtained from different litters of fetuses of the outbred animals. Grafting in the outbred strain led to increased numbers of immunologically reactive cells in the grafts. This was not seen in grafts in the inbred strain. Spinal cord transplants led to a significantly higher degree of cytotoxic immunity-related cells expressing MHC class II as well as CD4-positive cells. There was a positive correlation between ED1 negativity and well-developed ramified microglia. From these results we conclude also that well-developed intraocular CNS tissue grafts do contain cellular evidence of immunological events and that different areas of the CNS may provoke different degrees of response. Reactive microglial proliferation appears to be one of the most sensitive ways to monitor the immunological condition of grafted CNS tissue.

Animals↗

PubMed1996

Neurovascular developmental interaction: a specific form of vascular maldevelopment in the malformed brain. I. An experimental study and proposal of a new teratological concept.

The process of the development of the intracranial vessels was studied by means of immunohistochemical analysis of factor VIII in normal and exencephalic chick fetuses. The results revealed that the development of blood vessels in exencephalic brain was far advanced beyond the norm, with intense immunoreactivity to factor VIII on postincubation day 16 exceeding that on day 21 in normal controls. Compared with results regarding the direction of the overgrowth in the neuronal maturation process in the previous study using the chick exencephaly model, the findings of overmatured blood vessels were compatible with NSE- and somatostatin-positive elements that appeared especially in the overgrowth foci. The results of the present study suggested the pathogenic development of the "area cerebrovasculosa" in the neural placode as a phenomenon consequent upon hypervascularization in response to neuronal overgrowth, as seen in human cases of exencephaly or anencephaly. We emphasize the significance of this specific phenomenon in the development of the fetal central nervous system, namely neurovascular developmental interaction.

Animals↗

PubMed1996

Synthesis and evaluation of an 18F-labeled dopa prodrug as a PET tracer for studying brain dopamine metabolism.

In the quantitative studies of presynaptic dopamine metabolism by PET with 6-[18F]fluoro-L-dopa (6-[18F]FDOPA), metabolic analysis in the plasma is required to determine the precise input function because of susceptibility of the compound to peripheral metabolism. In this study, we prepared 6-[18F]-fluoro-O-pivaloyl-L-dopa (6-[18F]FPDOPA) as a prodrug of 6-[18F]FDOPA, and evaluated its potential as a PET tracer in mice. If the 6-[18F]FPDOPA is stable peripherally and is hydrolyzed to 6-[18F]FDOPA in the brain tissues, disadvantage of the 6-[18F]FDOPA will be overcome. Compared with the 6-[18F]FDOPA, the initial brain uptake of the 6-[18F]FPDOPA was lower; however, the uptake in the latter become comparable, and the uptake ratios of striatum to other reference regions were larger. Medication of mice with inhibitors of aromatic amino acid decarboxylase and catechol-O-methyl transferase greatly enhanced the striatal uptake of the two compounds. The reduced brain uptake of the compounds by L-phenylalanine-loading suggested transport through the blood-brain barrier by the neutral amino acid transporter. HPLC analysis showed the presence of 6-[18F]FPDOPA, 6-[18F]FDOPA and 6-[18F]fluorodopamine in the striatum; however, 6-[18F]fluoro-3-O-methyl-L-dopa was a predominate metabolite in the brain and plasma as in the case of [18F]FDOPA. Results suggested that 6-[18F]FPDOPA had characteristics as a prodrug of 6-[18F]FDOPA; however, the compound was also labile to metabolic alteration in vivo.

Animals↗