Blockade of the K channel Kir6.2 by memantine represents a novel mechanism relevant to Alzheimer's disease therapy.

Here, we report a novel target of the drug memantine, ATP-sensitive K (K) channels, potentially relevant to memory improvement. We confirmed that memantine antagonizes memory impairment in Alzheimer's model APP23 mice. Memantine increased CaMKII activity in the APP23 mouse hippocampus, and memantine-induced enhancement of hippocampal long-term potentiation (LTP) and CaMKII activity was totally abolished by treatment with pinacidil, a specific opener of K channels.

CaMKII activity is essential for improvement of memory-related behaviors by chronic rivastigmine treatment.

Because the cholinergic system is down-regulated in the brain of Alzheimer's disease patients, cognitive deficits in Alzheimer's disease patients are significantly improved by rivastigmine treatment. To address the mechanism underlying rivastigmine-induced memory improvements, we chronically treated olfactory bulbectomized (OBX) mice with rivastigmine. The chronic rivastigmine treatments for 12-13 days starting at 10 days after OBX operation significantly improved memory-related behaviors assessed by Y-maze task, novel object recognition task, passive avoidance task, and Barnes maze task, whereas the single rivastigmine treatment failed to improve the memory.

Novel nootropic drug sunifiram enhances hippocampal synaptic efficacy via glycine-binding site of N-methyl-D-aspartate receptor.

Sunifiram is a novel pyrrolidone nootropic drug structurally related to piracetam, which was developed for neurodegenerative disorder like Alzheimer's disease. Sunifiram is known to enhance cognitive function in some behavioral experiments such as Morris water maze task. To address question whether sunifiram affects N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic function in the hippocampal CA1 region, we assessed the effects of sunifiram on NMDAR-dependent long-term potentiation (LTP) by electrophysiology and on phosphorylation of synaptic proteins by immunoblotting analysis.

Novel nootropic drug sunifiram improves cognitive deficits via CaM kinase II and protein kinase C activation in olfactory bulbectomized mice.

Alzheimer's disease (AD) shows degeneration of the cholinergic system in the medial septum, thereby eliciting down-regulation of the olfactory function in patients. We have previously reported that olfactory bulbectomized (OBX) mice show hippocampus-dependent memory impairment as assessed by memory-related behavioral tasks and hippocampal long-term potentiation (LTP). In the present study, we focused whether novel pyrrolidone nootropic drug sunifiram improves both memory impairment and depression observed in OBX mice.

Effects of general anesthetics on P2X4 receptors in a mouse microglial cell line.

The purinergic P2X4 receptors (P2X4Rs) of spinal microglia are upregulated after a peripheral nerve injury and play important roles in the pathogenesis of chronic pain. The effects of general anesthetics on chronic pain and the mechanisms are still unclear. The aim of this study is to examine the effects of general anesthetics on microglial P2X4Rs.

Inhibition of voltage-gated proton channels by local anaesthetics in GMI-R1 rat microglia.

Voltage-gated proton channels play crucial roles during the respiratory burst in phagocytes, such as microglia. As local anaesthetics have a variety of anti-inflammatory properties, including inhibition of phagocytosis, they may act on the proton channels. Most local anaesthetics are tertiary amines and may affect proton channels through modification of pH(i) as weak bases.

Antidepressants inhibit proton currents and tumor necrosis factor-α production in BV2 microglial cells.

Proton channels are gated by voltage and pH gradients, and play an important role in the microglial production of pro-inflammatory cytokines, which are known to be suppressed by antidepressants. In the present study we tested the hypothesis that cytokine inhibition by antidepressants is due to an inhibitory action on proton currents by comparing their effects on tumor necrosis factor-α production with the effects on the proton currents in BV2 murine microglial cells. Imipramine, amitriptyline, desipramine and fluoxetine potently and reversibly inhibited proton currents at micromolar concentrations at an intracellular/extracellular pH gradient of 5.

Glutamate-activated chloride channels: Unique fipronil targets present in insects but not in mammals.

Selectivity to insects over mammals is one of the important characteristics for a chemical to become a useful insecticide. Fipronil was found to block cockroach GABA receptors more potently than rat GABA(A) receptors. Furthermore, glutamate-activated chloride channels (GluCls), which are present in cockroaches but not in mammals, were very sensitive to the blocking action of fipronil.

Nefiracetam activation of CaM kinase II and protein kinase C mediated by NMDA and metabotropic glutamate receptors in olfactory bulbectomized mice.

Aberrant behaviors related to learning and memory in olfactory bulbectomized (OBX) mice have been documented in the previous studies. We reported that the impairment of long-term potentiation (LTP) of hippocampal CA1 regions from OBX mice was associated with down-regulation of CaM kinase II (CaMKII) and protein kinase C (PKC) activities. We now demonstrated that the nootropic drug, nefiracetam, significantly improved spatial reference memory-related behaviors as assessed by Y-maze and novel object recognition task in OBX mice.

Synaptic and behavioral interactions of oseltamivir (Tamiflu) with neurostimulants.

Oseltamivir (Tamiflu), a neuraminidase inhibitor, is widely used for treatment of influenza. Because abnormal behaviors have been observed in some Japanese teenagers following oseltamivir use, its safety has been questioned. Oseltamivir is known to alter neuronal function and behavior in animals, particularly when administered in combination with ethanol.

Nefiracetam and galantamine modulation of excitatory and inhibitory synaptic transmission via stimulation of neuronal nicotinic acetylcholine receptors in rat cortical neurons.

The cholinergic and glutamatergic systems are known to be downregulated in the brain of Alzheimer's disease patients. Galantamine and nefiracetam have been shown to potentiate the phasic activity of nicotinic acetylcholine receptors (nAChRs) in the brain. Stimulation of nAChRs is also known to cause release of various neurotransmitters including glutamate and gamma-aminobutyric acid (GABA).

Galantamine enhancement of long-term potentiation is mediated by calcium/calmodulin-dependent protein kinase II and protein kinase C activation.

Galantamine, a novel Alzheimer's drug, is known to inhibit acetylcholinesterase activity and potentiate nicotinic acetylcholine receptor (nAChR) in the brain. We previously reported that galantamine potentiates the NMDA-induced currents in primary cultured rat cortical neurons. We now studied the effects of galantamine on long-term potentiation (LTP) in the rat hippocampal CA1 regions.

Tetrodotoxin: a brief history.

Tetrodotoxin (TTX), contained in puffer, has become an extremely popular chemical tool in the physiological and pharmacological laboratories since our discovery of its channel blocking action in the early 1960s. This brief review describes the history of discovery of TTX action on sodium channels, and represents a story primarily of my own work. TTX inhibits voltage-gated sodium channels in a highly potent and selective manner without effects on any other receptor and ion channel systems.

[Prevention of phlebitis caused by vinorelbine chemotherapy in outpatients with breast cancer].

We studied the prevention of phlebitis in 10 patients who had developed the symptoms after receiving vinorelbine to treat breast cancer at our outpatient chemotherapy clinic from July 2005 to August 2006. Veins proximal to the injection site were warmed using hot compresses during the vinorelbine injection and physiological saline was increased to wash out the drug after the injection from 250 mL to 500 mL in combination to investigate whether the treatment was effective in preventing phlebitis. The severity of phlebitis was significantly decreased after the combined treatment compared with the pre-treatment level (p=0.

Use of non-mammalian alternative models for neurotoxicological study.

The field of neurotoxicology needs to satisfy two opposing demands: the testing of a growing list of chemicals, and resource limitations and ethical concerns associated with testing using traditional mammalian species. National and international government agencies have defined a need to reduce, refine or replace mammalian species in toxicological testing with alternative testing methods and non-mammalian models. Toxicological assays using alternative animal models may relieve some of this pressure by allowing testing of more compounds while reducing expense and using fewer mammals.

CaM kinase II and protein kinase C activations mediate enhancement of long-term potentiation by nefiracetam in the rat hippocampal CA1 region.

Nefiracetam is a pyrrolidine-related nootropic drug exhibiting various pharmacological actions such as cognitive-enhancing effect. We previously showed that nefiracetam potentiates NMDA-induced currents in cultured rat cortical neurons. To address questions whether nefiracetam affects NMDA receptor-dependent synaptic plasticity in the hippocampus, we assessed effects of nefiracetam on NMDA receptor-dependent long-term potentiation (LTP) by electrophysiology and LTP-induced phosphorylation of synaptic proteins by immunoblotting analysis.

Efficacy of intravaginal progesterone administration as an additional treatment on two types of timed AI protocols in a commercial herd of Holstein heifers.

Reproductive performance of two types of timed artificial insemination (TAI) protocols with or without intravaginal progesterone insert (CIDR) was investigated in a commercial herd of Holstein heifers. A total of seventy-four heifers with 14.4 months of age were allocated to two groups; Ovsynch (n=44) and estradiol benzoate (EB) used Heatsynch (EB-Heatsynch, n=30), and each group was additionally divided into two subgroups with CIDR insertion from day 0 to 7 (n=36) and without CIDR group (n=38).

Neuroexcitatory actions of Tamiflu and its carboxylate metabolite.

Oseltamivir (Tamiflu) is now being stockpiled by several governments as a first line treatment for an anticipated outbreak of avian influenza caused by H5N1. However, abnormal behaviors and death associated with the use of Tamiflu have developed into a major issue in Japan where Tamiflu is often prescribed for seasonal influenza. Thus, it is critical to determine neuropsychiatric effects of oseltamivir and to establish methods for safe administration.

Differential actions of insecticides on target sites: basis for selective toxicity.

Whereas the selective toxicity of insecticides between insects and mammals has a long history of studies, it is now becoming abundantly clear that, in many cases, the differential action of insecticides on insects and mammalian target receptor sites is an important factor. In this paper, we first introduce the mechanism of action and the selective toxicity of pyrethroids as a prototype of study. Then, a more detailed account is given for fipronil, based primarily on our recent studies.

Inhibition of inward rectifier K+ currents by angiotensin II in rat atrial myocytes: lack of effects in cells from spontaneously hypertensive rats.

We examined the effects of angiotensin II (Ang II) on inward rectifier K+ currents (IK1) in rat atrial myocytes. [125I]Ang II-binding assays revealed the presence of both Ang II type 1 (AT1) and type 2 (AT2) receptors in atrial membrane preparations. Ang II inhibited IK1 in isolated atrial myocytes with an IC50 of 46 nmol/l.

Effects of ethanol on excitatory and inhibitory synaptic transmission in rat cortical neurons.

Background: The gamma-aminobutyric acid-A (GABA(A)) receptor and glutamate receptors are among the most important target sites for the behavioral effects of ethanol. However, data in the literature concerning the ethanol modulation of the GABA(A) and glutamate receptors have been controversial. The activity of the neuronal nicotinic acetylcholine (ACh) receptors (nAChRs) has recently been reported to be potently augmented by ethanol.

Nefiracetam potentiates N-methyl-D-aspartate (NMDA) receptor function via protein kinase C activation and reduces magnesium block of NMDA receptor.

Nicotinic acetylcholine receptors and N-methyl-D-aspartate (NMDA) receptors are known to be down-regulated in the brain of Alzheimer's disease patients. We have previously demonstrated that the nootropic drug nefiracetam potentiates the activity of both nicotinic acetylcholine and NMDA receptors and that nefiracetam modulates the glycine binding site of the NMDA receptor. Because the NMDA receptor is also modulated by Mg2+ and protein kinases, we studied their roles in nefiracetam action on the NMDA receptor by the whole-cell patch-clamp technique and immunoblotting analysis using rat cortical or hippocampal neurons in primary culture.

In vitro galantamine-memantine co-application: mechanism of beneficial action.

Several drugs are in clinical use for symptomatic treatment of Alzheimer's disease patients. Since Alzheimer's disease is known to be associated with down-regulation of the cholinergic and N-methyl-D-aspartate (NMDA) systems, most of these drugs inhibit acetylcholinesterase, potentiate the activity of nicotinic acetylcholine receptors (nAChRs), or modulate NMDA receptors. Galantamine is an anticholinesterase and allosterically potentiates the activity of the nicotinic receptors.

Cytoplasmic localization of p63 is associated with poor patient survival in lung adenocarcinoma.

Aims: To determine the significance of p63 protein expression in the development and progression of lung adenocarcinoma.

Methods And Results: The expression of p63 was immunohistochemically investigated in 92 cases of lung adenocarcinoma with a maximum diameter of 30 mm or less. p63 expression was observed not only in the nuclei (46/92 cases, 50%), but also in the cytoplasm of neoplastic cells (47/92, 51%).

Effects of ethanol on tonic GABA currents in cerebellar granule cells and mammalian cells recombinantly expressing GABA(A) receptors.

The effects of ethanol on the GABA(A) receptors, which are regarded as one of the most important target sites of ethanol, are very controversial, ranging from potentiation to no effect. The delta subunit-containing GABA(A) receptors expressed in Xenopus oocytes were recently reported to be potently augmented by ethanol. We performed patch-clamp experiments using the cerebellar granule cells and mammalian cells expressing recombinant GABA(A) receptors.