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Volume 124 (2004)
- Issue 6 Pages 375-
- Issue 5 Pages 301-
- Issue 4 Pages 201-
- Issue 3 Pages 135-
- Issue 2 Pages 69-
- Issue 1 Pages 3-
Volume 124, Issue 3
Displaying 1-5 of 5 articles from this issue
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Reviews: Update on the Therapeutic Drugs for Alzheimer's Disease
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Yasuo NAGAI, Aichi OGASAWARA, Klaus HEESE2004 Volume 124 Issue 3 Pages 135-143
Published: 2004
Released on J-STAGE: August 27, 2004
JOURNAL FREE ACCESSAmyloidβpeptide (Aβ) is implicated in neuronal cell death in Alzheimer's disease, but the molecular mechanisms are still unclear. We analyzed its mechanism and found several potential rescue factors against Aβ-mediated apoptosis. Aβ(1-40) stimulated phosphorylation of tau and JNK and induced cell death in SH-SY5Y cells. The cell death was inhibited by insulin-like growth factor-1, suggesting that the JNK pathway may be involved in Aβ(1-40)-induced cytotoxicity. Using the human fetus brain cDNA library-targeted differential display technique, a new gene BF5-1 (32aa) was found as a rescue factor against Aβ(1-40). BF5-1 has partially the same amino acid sequences as those of the C-terminus of cytochrome c oxidase subunit VIIb (COX-VIIb). COX-VIIb mRNA is increased in AD brains and its overexpression in cells enhanced Aβ(1-40)-toxicity. These data suggest that BF5-1 may act as a dominant negative mutant of COX-VIIb. Aβ(1-42) also induced cell death in rat neuroblastoma B104 cells, which was abolished by addition of IL-11. By cDNA subtraction analysis in the cell death, the enhanced expression of L-phosphoserine phosphatase was found, but this was also abolished by IL-11. The glutamate neurotoxicity was stimulated in the presence of D-serine, suggesting that NMDA receptors may be involved in Aβ(1-42)-induced cytotoxicity. Aβ(1-42) also induced increase of a new gene p18AβrP (p18-amyloid-β-responsive protein; 166 aa) mRNA expression; overexpression of this gene in PC12 cells induced cell death. By the application of a death trap method, a new gene, p60TRP (p60-Transcription-Regulating-Protein;rat:539 aa, human:547aa), was found as a potential rescue factor against the cell death by p18AβrP. Thus, our cell death systems and/or new rescue proteins may provide suitable tools for the establishment of drug screening systems leading to the identification of new low-molecular candidates applicable for the treatment of AD.
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Takeshi KATO2004 Volume 124 Issue 3 Pages 145-151
Published: 2004
Released on J-STAGE: August 27, 2004
JOURNAL FREE ACCESSMemantine is agreed officially as a therapeutic drug for moderate-to-severe Alzheimer's disease (AD) in EU and USA. Memantine is a similar uncompetitive NMDA-receptor antagonist to MK-801 and phencyclidine (PCP), and it prevents nerve cell death induced by the ischemia which induces as excessive release of glutamate. These medicines act on an ion channel binding site similar to the magnesium ion binding site. However, MK-801 and PCP cause schizophrenic symptoms, so they are not being used as a therapeutic drug for AD. Memantine does not have those toxicities and does not stimulate acetylcholine release in the cerebral cortex. Although the mechanism of the difference from memantine and MK-801 has not been made clear yet, it seems that memantine is combined and released with the ion channel depending on electric potential in the same way as the magnesium ion. Basic and clinical research will clarify the control mechanism of memantine.
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Hideo TSUKADA2004 Volume 124 Issue 3 Pages 153-161
Published: 2004
Released on J-STAGE: August 27, 2004
JOURNAL FREE ACCESSThe present review described the effects of acetylcholinesterase (AChE) inhibition on the cerebral cholinergic neuronal system in the conscious monkey brains with PET. Somatosensory stimulation induced a regional cerebral blood flow (rCBF) response, revealed with [15O]H2O, in the contralateral somatosensory cortex. Scopolamine resulted in an abolished rCBF response to stimulation, and this abolished rCBF response was recovered by physostigmine, donepezil, and tacrine. Donepezil suppressed AChE activity, analyzed by [11C]MP4A, in all cortical regions in a dose-dependent manner. AChE inhibition by donepezil resulted in a dose-dependent increase in acetylcholine levels in the prefrontal cortex as measured by microdialysis. Binding of [11C](+)3-PPB to cortical muscarinic receptors was reduced by donepezil, probably in a competitive inhibition manner. Aged monkeys showed less reduction of [11C](+)3-PPB binding than young animals. As evaluated by an oculomotor delayed response task, aged monkeys showed impaired working memory performance compared to young monkeys, and the impaired performance was partly improved by the administration of donepezil, due to the facilitation of the cholinergic neuronal system by AChE inhibition by donepezil. These results demonstrated that PET imaging with specifically labeled compounds in combination with microdialysis and a behavioral cognition task could be a useful tool for pre-clinical evaluation of novel drugs.
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Hachiro SUGIMOTO2004 Volume 124 Issue 3 Pages 163-170
Published: 2004
Released on J-STAGE: August 27, 2004
JOURNAL FREE ACCESSEnhancement of the activity of cholinergic neurons has been regarded as one of the most promising methods for treating Alzheimer's disease (AD). Donepezil is a representative acetylcholinesterase inhibitor (AChEI) and is a great success among the AChEI drugs. AChEIs are being studied for other mechanisms of action, neuroprotective action, and nicotinic receptor enhancement. AD is a type of neurodegenerative disease and AChEIs have been found to be an effective anti-AD medication. AChEI can alleviate the symptoms and delay the progression of AD, but it cannot cure the disease. However, AChEIs are now the subject of a wide range of clinical studies for other diseases, for example, other types of dementia (such as Lewy body disease, cerebral vascular dementia, and Parkinson's disease dementia), and migraine. These drugs are also being studied as a combination therapy, for example, with an antioxidant, SERM, and NMDA antagonist.
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Review on New Drug
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Kazuko TAIJI2004 Volume 124 Issue 3 Pages 171-179
Published: 2004
Released on J-STAGE: August 27, 2004
JOURNAL FREE ACCESSDexmedetomidine hydrochloride (Precedex) is a potent and highly selective central α2-adrenoreceptor agonist. In a test of affinity to receptors in rat brain cortex, this drug showed a high affinity and selectivity to the α2-adrenoreceptor. This drug induced a dose-dependent decrease in activity, loss of righting reflex, an increase in sedation score, and a dose-dependent prolongation of the latent time of escape from pain in various animal models. The site of action for the sedative action of this drug is considered to be the locus coeruleus. With administration of this drug into the locus coeruleus, loss of righting reflex was observed in almost all animals. Test results using mice with variant α2A-receptor suggested that the sedative action of this drug is expressed through the α2A-receptor subtype. This drug is promptly eliminated from blood. In the phase II/III multi-center placebo-controlled double blind bridging study conducted in Japan, efficacy and safety were examined in patients brought to the ICU. As regards sedative action, the ratio of patients who did not require additional propofol medication (>50 mg) while intubated was taken as the effective rate. The drug group showed a significantly high effective rate (90.9%; placebo group, 44.6%). Similarly, with analgesic action, the ratio of patients who did not require additional morphine medication during intubation was taken as the effective rate. The effective rate for the drug group was significantly high (87.3%; placebo group, 75.0%). The main adverse events observed in the drug group were hypertension and hypotension.
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