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Volume 114, Issue 6
Displaying 1-6 of 6 articles from this issue
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Masaya HASEGAWA, Yukihiro NODA, Yohko MAEDA, Kiyofumi YAMADA, Toshitak ...1999 Volume 114 Issue 6 Pages 327-336
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSRecently, there is a great social problem that geriatric disorders, especially senile dementia, are growing rapidly with the increasing percentage of aged individuals in the total population. However, there is yet no drug that has reliable effects on senile dementia on the market. Therefore, society requires the development of new drugs that can support patients so that they can smoothly live their daily lives by themselves. In this study, we attempted to investigate the 1998 domestic state of development of cognitive enhancers by summarizing many publications and by gathering questionnaires from pharmaceutical, food, synthetic fiber and chemical manufacturing companies. There were 40 currently investigated cognitive enhancers in Japan as of the end of March, 1999 including 37 newly synthesized compounds and 3 new dosage forms or applications of additional effects. On the classification according to the mechanism of drug action, 12 of the investigated drugs are cholinomimetic agents, 12 are ameliorators of neuronal transmission, 1 is an intracellular mediative substance, 3 are neuropeptides, 2 are cerebral metabolic activators, 2 are cerebral circulation enhancers and 7 are neuronal cell protectors, and 1 is another type. For dementia of the Alzheimer's type, there are 1, 3, 10 and 2 drugs in prerecognition, phase late II, early II and I of clinical trials, respectively. For cerebrovascular dementia and cerebrovascular disease, there are 19 drugs being investigated. Seven of these compounds such as E2020 (donepedil HC1), DM-9384 (nefiracetam), TA-0910 (taltirelin), NS-3 (montirelin), TTC-909 (clinprost), DR-3305 (ebselen) and AVS (nicaraven) are at the prerecognition stage for marketing. It is important that effective cognitive enhancers will be supplied for clinical stage use as soon as possible.View full abstractDownload PDF (11268K) -
Taisuke TOMITA, Takeshi IWATSUBO1999 Volume 114 Issue 6 Pages 337-346
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSAlzheimer's disease (AD), the most common cause of dementia in the elderly, is a progressive neurodegenerative disorder characterized pathologically by the presence of senile plaques and neurofibrillary tangles in the brains of affected individuals. Senile plaques are composed of amyloid-β peptides (Aβ), a proteolytic derivative of the β-amyloid precursor protein (βAPP). A subset of AD is inherited as an autosomal dominant trait (familial AD, FAD). Mutations in genes encoding β3APP, presenilin (PS) 1 and PS2 are known to cause FAD. Genetic mutations in all three genes that cosegregate with FAD increase the production of the most amyloidogenic species, Aβ42. Moreover, PSl-deficient neurons exhibit severe defects in the production of Aβ, suggesting that PS1 plays an important role in γ-cleavage that liberates the C terminus of Aβ. The physiological role of PS is still unknown, but data from studies in C. elegans, Drosophila and PS1 knock out mice suggests that PS1 plays a crucial role in Notch signaling, and recently it was shown that PS1 is required for the proteolytic release of the intracellular domain of Notch following activation of Notch by its ligand. Further studies on PS-mediated intra- and jaxtamembranous proteolysis will lead to the understanding of the pathological mechanism of AD as well as of a novel mode of membrane protein processing.View full abstractDownload PDF (11165K) -
Hiroshi UEDA, Makoto INOUE1999 Volume 114 Issue 6 Pages 347-356
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSThe family of the G protein-coupled opioid receptors was recently extended by a novel member that did not bind any of the typical opioid receptor ligands. Identification of the orphan receptor in this way led to the advent of “reverse pharmacology” to identify the corresponding physiological ligands. Nociceptin, a heptadecapeptide, which was discovered as an endogenous ligand, first, attracted us by its reported nociceptive or anti-opioid actions. However, following studies revealed that this peptide has both nociceptive and antinociceptive actions under different conditions; e.g., administration routes or doses affect its actions. In our recent studies using a unique peripheral peripheral nociception test, nociceptin given locally at lower doses was found to produce nociception through substance P release from nociceptor endings, while at higher doses, it produced antinociceptive actions through an inhibition of phospholipase C activity stimulated by nociceptive substances. Such hypothetical mechanisms can be applied to the mechanisms of nociceptin-induced paradoxical actions in the central nervous system. The physiological role of nociceptin has recently been reported using nociceptin receptor knock-out mice. Following the report of a hearing problem in such mice, the nociceptin receptor was found to be involved in the development of morphine analgesic tolerance. In this review, more findings on the physiological roles of nociceptin or its receptor, such as pain control and memory-learning, are discussed on the basis of reports using nociceptin receptor knock-out mice.View full abstractDownload PDF (10820K) -
Masahiko HIRAFUJI, Yohichi SATOH, Masaru MINAMI1999 Volume 114 Issue 6 Pages 357-363
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSAlthough serotonin (5-HT) release from enterochromaffin (EC) cells is considered to be regulated by multiple receptor-mediated mechanisms, little is known about the signal transduction. Here, we introduce the methods to isolate the mouse ileal crypts, which consist of various types of cells including EC cells, and to analyze the intracellular calcium dynamics. Real tissue was inserted with a plastic straw and the smooth muscle layers were peeled off. The mucosa were digested with collagenase and then suspended by moderate pipetting. Ileal crypts were separated by stepwise filtrations through 2 different nylon-meshes. The isolated crypt contained 0-3 EC cells as identified by immunostaining using anti-5-HT antibody followed by confocal microscopy. Isolated crypts were attached to a coverglass by an adhesive material (Cell-Tak) and loaded with fura-2/AM. Intracellular calcium dynamics in EC cells were obtained by digital video-imaging analysis of fura-2 fluorescence followed by the identification of EC cells with immunostaining of 5-HT granules. By these methods, it was suggested that norepinephrine elicited a transient elevation of intracellular calcium concentration in EC cells via α2-adrenoceptors. These methods could be also useful to analyze the signal transduction system in intestinal endocrine cells that contain various intestinal hormones such as gastrin, cholecystokinin or secretin.View full abstractDownload PDF (8524K) -
Tsutomu SUZUKI1999 Volume 114 Issue 6 Pages 365-371
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSThe conditioned place preference (CPP) paradigm is used to evaluate motivational properties such as rewarding or aversive effects of drugs. It was first introduced in the early 1980s to compensate for methodological and interpretive difficulties associated with the self-administration technique, the conventional method for assessing rewarding properties of drugs. The CPP paradigm has become the most frequently used method and its use has been reported more frequently than the self-administration paradigm. Although the CPP paradigm has mainly been performed in the rat, we have successfully established the CPP paradigm for the mouse. Thus, the CPP paradigm is now widely accepted as the behavioral approach to pave the way for the neural mechanisms of rewarding effect and for screening drugs for abuse liability. In this review, I focused on the significance, one's way of thinking, methodology, application and controversial points of the CPP paradigm.View full abstractDownload PDF (7401K) -
Nobuyuki MIKODA, Haruto NAKAGAWA, Kiminori KAWAHARA1999 Volume 114 Issue 6 Pages 373-382
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSThe present study investigated the development of hypertension and the functional and morphological changes in the kidney in Dahl salt-sensitive (Dahl S) rats fed with a normal salt diet during aging. Furthermore, the effects of calcium channel antagonists nitrendipine and nicardipine on these changes were examined. The rats showed proteinuria from 6 weeks of age and gradually developed hypertension accompanied by the decrease in the glomerular filtration rate during aging. Glomerular screlosis and degeneration of the renal tubule were found by histological examinations at 17 weeks of age. Nitrendipine (20 mg/kg chow), given from 7 weeks of age for 10 weeks, inhibited the elevation in systolic blood pressure from 3 weeks after the dosing, whereas nicardipine (20 mg/kg chow) inhibited it only at 5 weeks after dosing. Both drugs decreased glomerular sclerosis, but did not affect the glomerular filtration rate, urine volume, urinary excretion of protein and N-acetyl-β-D-glucosaminidase and serum concentrations of creatinine and urea nitrogen. These results demonstrated that Dahl S rats fed with a normal salt diet spontaneously developed the renal disorder in the early stage of hypertension and reinforce the validity of nitrendipine for the treatment of hypertensive patients with renal failure.View full abstractDownload PDF (9971K)
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