日本の女子覚醒剤事犯者における薬物依存治療の重要性に関する認識

広島大学(Hiroshima University)博士(医学)Doctor of Philosophy in Medical Sciencedoctora

AMPA受容体拮抗薬の薬理学的研究 -脳虚血病態におけるAMPA受容体の役割の解明ならびに脳血管障害急性期治療薬としての臨床有用性の予測

取得学位：博士(薬学)，学位授与番号：博乙第196号，学位授与年月日：平成11年9月30日,学位授与年：199

Neuroprotective Efficacy of YM872, an ␣-Amino-3-Hydroxy-5- Methylisoxazole-4-Propionic Acid Receptor Antagonist, after Permanent Middle Cerebral Artery Occlusion in Rats

ABSTRACT The neuroprotective efficacy of YM872, a novel, highly watersoluble ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, was investigated in rats subjected to permanent occlusion of the left middle cerebral artery. The rats were assessed either histologically or neurologically 24 hr or 1 wk after ischemia. YM872 was intravenously infused for either 4 or 24 hr at dose rates of 0 to 20 mg/kg/hr starting 5 min after ischemia to examine the effect of prolonged treatment. YM872 was then infused at 20 mg/kg/hr beginning 0 to 4 hr after ischemia to determine the efficacy time window. Additionally, a 20 mg/kg/hr dose rate of YM872 was infused for 4 hr in single day-or 5-day repetitive-administrations to evaluate long-term benefits of the drug. YM872 significantly reduced infarct volume in both 4-and 24-hr treatment groups measured 24 hr after ischemia. No difference was observed in the degree of protection between length of infusion. Significant neuroprotection was maintained even when drug administration was delayed up to 2 hr after ischemia. A single YM872-administration significantly improved neurological deficit and reduced infarct volume (30%, P Ͻ .01) measured 1 wk after ischemia. YM872 treatment did not induce such adverse effects as physiological changes, serious behavioral abnormalities or nephrotoxicity. These data suggest that the ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor plays a crucial role in the progression of neuronal damage in the early phase of ischemia and that YM872 may be useful in treating acute ischemic stroke

Terahertz Magneto Optical Polarization Modulation Spectroscopy

We report the development of new terahertz techniques for rapidly measuring the complex Faraday angle in systems with broken time-reversal symmetry using the cyclotron resonance of a GaAs two-dimensional electron gas in a magnetic field as a system for demonstration of performance. We have made polarization modulation, high sensitivity (< 1 mrad) narrow band rotation measurements with a CW optically pumped molecular gas laser, and by combining the distinct advantages of terahertz (THz) time domain spectroscopy and polarization modulation techniques, we have demonstrated rapid broadband rotation measurements to < 5 mrad precision.Comment: 25 pages including 7 figures, introduces use of rotating polarizer with THz TDS for Complex Faraday Angle determinatio

Analysis of Nociceptive Information Encoded in the Temporal Discharge Patterns of Cutaneous C-Fibers

The generation of pain signals from primary afferent neurons is explained by a labeled-line code. However, this notion cannot apply in a simple way to cutaneous C-fibers, which carry signals from a variety of receptors that respond to various stimuli including agonist chemicals. To represent the discharge patterns of C-fibers according to different agonist chemicals, we have developed a quantitative approach using three consecutive spikes. By using this method, the generation of pain in response to chemical stimuli is shown to be dependent on the temporal aspect of the spike trains. Furthermore, under pathological conditions, gamma-aminobutyric acid resulted in pain behavior without change of spike number but with an altered discharge pattern. Our results suggest that information about the agonist chemicals may be encoded in specific temporal patterns of signals in C-fibers, and nociceptive sensation may be influenced by the extent of temporal summation originating from the temporal patterns.open0

Prolonged Application of High Fluid Shear to Chondrocytes Recapitulates Gene Expression Profiles Associated with Osteoarthritis

BACKGROUND: Excessive mechanical loading of articular cartilage producing hydrostatic stress, tensile strain and fluid flow leads to irreversible cartilage erosion and osteoarthritic (OA) disease. Since application of high fluid shear to chondrocytes recapitulates some of the earmarks of OA, we aimed to screen the gene expression profiles of shear-activated chondrocytes and assess potential similarities with OA chondrocytes. METHODOLOGY/PRINCIPAL FINDINGS: Using a cDNA microarray technology, we screened the differentially-regulated genes in human T/C-28a2 chondrocytes subjected to high fluid shear (20 dyn/cm(2)) for 48 h and 72 h relative to static controls. Confirmation of the expression patterns of select genes was obtained by qRT-PCR. Using significance analysis of microarrays with a 5% false discovery rate, 71 and 60 non-redundant transcripts were identified to be ≥2-fold up-regulated and ≤0.6-fold down-regulated, respectively, in sheared chondrocytes. Published data sets indicate that 42 of these genes, which are related to extracellular matrix/degradation, cell proliferation/differentiation, inflammation and cell survival/death, are differentially-regulated in OA chondrocytes. In view of the pivotal role of cyclooxygenase-2 (COX-2) in the pathogenesis and/or progression of OA in vivo and regulation of shear-induced inflammation and apoptosis in vitro, we identified a collection of genes that are either up- or down-regulated by shear-induced COX-2. COX-2 and L-prostaglandin D synthase (L-PGDS) induce reactive oxygen species production, and negatively regulate genes of the histone and cell cycle families, which may play a critical role in chondrocyte death. CONCLUSIONS/SIGNIFICANCE: Prolonged application of high fluid shear stress to chondrocytes recapitulates gene expression profiles associated with osteoarthritis. Our data suggest a potential link between exposure of chondrocytes/cartilage to abnormal mechanical loading and the pathogenesis/progression of OA

Quaternary Complexes Modified from pDNA and Poly-l-Lysine Complexes to Enhance pH-Buffering Effect and Suppress Cytotoxicity

We developed a modified complex of pDNA and poly-l-lysine (PLL) by the addition of poly-l-histidine (PLH) and γ-polyglutamic acid (γ-PGA) to enhance its pH-buffering effect and suppress cytotoxicity. The binary and ternary complexes of pDNA with PLL or/and PLH showed particle sizes of approximately 52-76 nm with cationic surface charge. The ternary complexes showed much higher gene expression than the binary complexes with PLL. The mixed solution of PLL and PLH showed higher buffering capacity than PLL solution. The high gene expression of ternary complexes was reduced by bafilomycin A1. These results indicated the addition of PLH to PLL complexes promoted endosomal escape by enhancing the pH-buffering effect. The binary and ternary complexes showed cytotoxicity and blood agglutination because of their cationic surface charge. We therefore developed quaternary complexes by the addition of anionic γ-PGA, which was reported to decrease the toxicity of cationic complexes. In fact, quaternary complexes showed no cytotoxicity and blood agglutination. Also, quaternary complexes showed higher gene expression than ternary complexes regardless of their anionic surface charge. Quaternary complexes showed selectively high gene expression in the spleen after their intravenous administration. Thus, we successfully developed the quaternary complexes with high gene expression and no toxicity