Naunyn-Schmiedeberg's archives of pharmacology
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Naunyn Schmiedebergs Arch. Pharmacol. · Jun 2008
ReviewProthymosin alpha plays a key role in cell death mode-switch, a new concept for neuroprotective mechanisms in stroke.
After stroke or traumatic damages, both necrotic and apoptotic neuronal death cause a loss of functions including memory, sensory perception, and motor skills. From the fact that necrosis has a nature to expand, while apoptosis to cease the cell death cascade in the brain, it is considered that the promising target for the rapid treatment for stroke is the necrosis. In this study, I introduce the discovery of prothymosin alpha (ProTalpha), which inhibits neuronal necrosis, and propose its potentiality of clinical use for stroke. ⋯ However, we found that ProTalpha-induced apoptosis is completely inhibited by the concomitant treatment with neurotrophins, which are up-regulated by ischemic stress in the brain. Of most importance is the finding that the systemic injection of ProTalpha completely inhibits the brain damages, motor dysfunction and learning memory defect induced by cerebral ischemia-reperfusion stress. As ProTalpha almost entirely prevents the focal ischemia-induced motor dysfunction 4 h after the start of ischemia, this protein seems to have a promising potentiality for clinical use.
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Naunyn Schmiedebergs Arch. Pharmacol. · Jun 2008
ReviewAt the frontline of Alzheimer's disease treatment: gamma-secretase inhibitor/modulator mechanism.
Genetic and biological studies provide evidence that the production and deposition of amyloid-beta peptides (Abeta) contribute to the etiology of Alzheimer's disease. beta- and gamma-secretases, which are responsible for the generation of Abeta, are plausible molecular targets for Alzheimer's disease treatment. gamma-Secretase is an unusual aspartic protease that cleaves the scissile bond within the transmembrane domain. This unusual enzyme is composed of a high molecular weight membrane protein complex containing presenilin, nicastrin, Aph-1 and Pen-2. ⋯ Thus, understanding the molecular mechanism whereby gamma-secretase recognizes and cleaves its substrate is a critical issue for the development of compounds that specifically regulate Abeta-generating gamma-secretase activity. This review focuses on the structure and function relationship of gamma-secretase complex and the mode of action of the gamma-secretase inhibitors.
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Naunyn Schmiedebergs Arch. Pharmacol. · Jun 2008
ReviewCandidate gene polymorphisms predicting individual sensitivity to opioids.
Significant interindividual differences in opioid sensitivity can hamper effective pain treatment and increase the risk for substance abuse. Elucidation of the genetic mechanisms involved in the interindividual differences in opioid sensitivity would help establish personalized pain management. ⋯ Such information should aid in developing and improving the methods of predicting interindividual differences in opioid sensitivity. In the near future, it will be possible to predict the appropriate kinds and doses of opioids for individuals by analyzing genetic variations contributing to opioid sensitivity.
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Naunyn Schmiedebergs Arch. Pharmacol. · Jun 2008
The activation of transient receptor potential vanilloid receptor subtype 1 by capsaicin without extracellular Ca2+ is involved in the mechanism of distinct substance P release in cultured rat dorsal root ganglion neurons.
Using a highly sensitive substance P (SP) radioimmunoassay, we attempted to elucidate the molecular mechanism of SP release from cultured adult rat dorsal root ganglion (DRG) neurons triggered by capsaicin. As a result, we found that capsaicin can induce SP release in the absence of extracellular Ca2+ by activating transient receptor potential vanilloid receptor subtype 1 (TRPV1). Therefore, we compared the pharmacological profile of SP release involved in several intracellular effectors (phosphoinositide 3-kinase (PI3K), Ca2+ release from intracellular stores, and mitogen-activated protein (MAP) kinases) in the presence/absence of extracellular Ca2+ by stimulating DRG neurons with various concentrations (10 to 1,000 nM) of capsaicin. ⋯ In contrast, in the absence of extracellular Ca2+, only a high concentration (1 microM) of capsaicin induced a significant increase in the SP release, which was then completely abolished by either a mitogen-activated protein kinase kinase (MEK) inhibitor U0126 or capsazepine, and significantly inhibited by either thapsigargin (a Ca2+-ATPase inhibitor) or BAPTA-AM (a rapid Ca2+ chelator). In summary, the activation of TRPV1 by capsaicin modulates the SP release from DRG neurons via two different mechanisms, one requiring extracellular Ca2+, the activation of PI3K and the IP3-dependent intracellular Ca2+ release, and the other which is independent of extracellular Ca2+ but involves the activation of MEK. These data suggest that a distinct SP release mechanism exists on DRG through the activation of TRPV1 without extracellular Ca2+ by capsaicin to facilitate neuropeptide release.