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Shin Ishikane,
Kenichi Yamahara,
Masaharu Sada,
Kazuhiko Harada,
Makoto Kodama,
Hatsue Ishibashi-Ueda,
Kazuhide Hayakawa,
Kenichi Mishima, Katsunori Iwasaki,
Michihiro Fujiwara,
Kenji Kangawa,
Tomoaki Ikeda
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ABSTRACT: We reported previously that the autologous administration of bone marrow-derived mesenchymal stem cells (BM-MSC) significantly attenuated myocardial dysfunction and injury in a rat model of acute myocarditis by stimulating angiogenesis and reducing inflammation. Because BM aspiration procedures are invasive and can yield low numbers of MSC after processing, we focused on fetal membranes (FMs) as an alternative source of MSC to provide a large number of cells. We investigated whether the allogeneic administration of FM-derived MSC (FM-MSC) attenuates myocardial injury and dysfunction in a rat myocarditis model. Experimental autoimmune myocarditis (EAM) was induced in male Lewis rats by injecting porcine cardiac myosin. Allogeneic FM-MSC obtained from major histocompatibility complex-mismatched ACI rats (5 × 10(5) cells/animal) were injected intravenously into Lewis rats one week after myosin administration. At day 21, severe cardiac inflammation and deterioration of cardiac function were observed. The allogeneic administration of FM-MSC significantly attenuated inflammatory cell infiltration and monocyte chemoattractant protein 1 expression in the myocardium and improved cardiac function. In a T-lymphocyte proliferation assay, the proliferative response of splenic T lymphocytes was significantly lower in cells obtained from FM-MSC-treated EAM rats that reacted to myosin than in cells obtained from vehicle-treated rats with EAM. T-lymphocyte activation was significantly reduced by coculture with FM-MSC. The allogeneic administration of FM-MSC attenuated myocardial dysfunction and inflammation, and the host cell-mediated immune response was attenuated in a rat model of acute myocarditis. These results suggest that allogeneic administration of FM-MSC might provide a new therapeutic strategy for the treatment of acute myocarditis.
Journal of Molecular and Cellular Cardiology 11/2010; 49(5):753-61. · 5.17 Impact Factor
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Tamami Haraguchi, Katsunori Iwasaki,
Kotaro Takasaki,
Kanako Uchida,
Tetsuya Naito,
Ai Nogami,
Kaori Kubota,
Taro Shindo,
Naoki Uchida,
Shutaro Katsurabayashi,
Kenichi Mishima,
Ryoji Nishimura,
Michihiro Fujiwara
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ABSTRACT: Telmisartan, an angiotensin type 1 receptor blocker (ARB), is used for hypertension to control blood pressure and has been shown to have a partial agonistic effect on peroxisome proliferator-activated receptor gamma (PPARgamma). Recently, the ligand of PPARgamma has been implicated in cerebroprotection due to its anti-inflammatory effect. In this study, we investigated whether telmisartan has a cerebroprotective effect on memory impairment and neuronal cell death induced by repeated cerebral ischemia. Repeated cerebral ischemia (RI: 10 min x 2) significantly induced impairment of spatial memory and hippocampal apoptosis in rats. Fourteen-day pre- and post-ischemic administration of telmisartan (0.3, 1, 3mg/kg/day, p.o.) increased the number of correct choices and reduced the number of errors made in the eight-arm radial maze task in a dose-dependent manner in RI treated rats. TUNEL-positive cells in the hippocampus CA1 areas were also reduced following 14-day administration of telmisartan (3mg/kg/day, p.o.). Seven-day post-ischemic administration of telmisartan improved spatial memory and reduced TUNEL-positive cells while 7-day pre-ischemic administration of telmisartan did not. These effects of telmisartan were inhibited by the PPARgamma antagonist, GW9662. On further experiment, 7-day post-ischemic administration of telmisartan reduced the expression of caspase-3 in the hippocampus, and this effect was also inhibited by GW9662. These results suggest that telmisartan improves memory impairment and reduces neuronal apoptosis via a PPARgamma-dependent caspase-3 inhibiting mechanism. Telmisartan, which has the unique character of having both ARB and PPARgamma agonistic effect, will be useful for preventing memory impairment after cerebrovascular disease.
Brain research 09/2010; 1353:125-32. · 2.46 Impact Factor
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ABSTRACT: Alzheimer's disease (AD) is progressive dementia with senile plaques composed of beta-amyloid (Abeta). Recent studies suggest that synaptic dysfunction is one of the earliest events in the pathogenesis of AD. Here we provide the first experimental evidence that a change in the level of dynamin 1 induced by Abeta correlates with memory impairment in vivo. We treated rats with transient cerebral ischemia with oligomeric forms of Abeta (Abeta oligomers), including dimers, trimers, and tetramers, intracerebroventricularly. The combination of Abeta oligomers and cerebral ischemia, but not cerebral ischemia alone, significantly impaired memory and decreased the level of dynamin 1, which plays a critical role in synaptic vesicle recycling, but did not affect the levels of other synaptic proteins, such as synaptophysin and synaptobrevin, in the hippocampus. Furthermore, the N-methyl-D-aspartate (NMDA) receptor antagonist memantine prevented memory impairment and dynamin 1 degradation, suggesting that these changes might be mediated by NMDA receptors. These results suggest that Abeta oligomers induce memory impairment via dynamin 1 degradation, which may imply that dynamin 1 degradation is one of the causes of synaptic dysfunction in AD.
Journal of Neuroscience Research 07/2010; 88(9):1908-17. · 2.74 Impact Factor
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ABSTRACT: During aging, levels of testosterone gradually decline in men and low levels of testosterone in aged men are accompanied by increased incidence of depressive disorders. The senescence-accelerated-prone mouse 10 (SAMP10) is well known as an animal model of aging. The purpose of this study was to investigate the motor function, anxiety levels, depression-related emotional responses, attentional function and plasma levels of testosterone and dehydroepiandrosterone (DHEA) in SAMP10. SAMP10 exhibited a significant prolongation of immobility time compared to that of the aged-matched control senescence-accelerated-resistant mouse 1 (SAMR1) in the tail suspension test for measuring depression. Moreover, significant low levels of plasma testosterone but not DHEA were found in SAMP10, and the testosterone levels were inversely correlated with the depression-like behavior. By contrast, we did not observe any significant differences between SAMP10 and SAMR1 in the open-field, rota-rod, elevated plus-maze, marble-burying behavior, or prepulse inhibition test. The results of the present study indicate that testosterone may play an important role in the depression-like behavior in SAMP10.
Behavioural brain research 05/2010; 209(1):142-7. · 3.22 Impact Factor
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Koichi Matsuo,
Minako Higuchi,
Yoshimi Sasaki,
Sanae Iwatsubo,
Yoriko Wada,
Kyoko Hasegawa,
Atsunori Shirakawa,
Kenichi Mishima, Katsunori Iwasaki,
Michihiro Fujiwara,
Hiroaki Nishino
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ABSTRACT: Thirty-seven patients with advanced or recurrent colorectal cancer were treated with mFOLFOX6 or mFOLFOX6 with a Bevacizumab regimen between September 2008 and March 2009. Then, we evaluated persistent neuropathy using the National Cancer Institute Common Terminology Criteria for Adverse Events (ver. 3). As a result of the research, grade 1-3 sensory neuropathy was observed in 5.6% after 3 cycles, 44. 4% after 5 cycles, 83. 3% after 8 cycles, and 83. 4% after 10 cycles. The average dose of L-OHP (mg/m2) until persistent sensory neuropathy appeared was grade 1: 399.7+/-157. 0 (17/ 37 patients); grade 2: 418.0+/-214. 1 (5/37 patients); and grade 3: 498.0+/-152. 8 (3/37 patients). As has been shown in international clinical trials, the severity and frequency of L-OHP-induced neurotoxicity are associated with the cumulative dose and duration of L-OHP administration. Further research is necessary to develop strategies for preventing or treating this side effect.
Gan to kagaku ryoho. Cancer & chemotherapy 03/2010; 37(3):551-4.
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Fengling Pu,
Tomohiro Kaneko,
Makiko Enoki,
Keiichi Irie,
Takuya Okamoto,
Yasuo Sei,
Nobuaki Egashira,
Ryozo Oishi,
Kenichi Mishima,
Hidetoshi Kamimura, Katsunori Iwasaki,
Michihiro Fujiwara
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ABSTRACT: We previously reported that 21-day (14-day pre-ischemic and 7-day post-ischemic) treatment with Kangen-karyu (KGKR) improved spatial memory impairment and hippocampal neuronal death induced by repeated cerebral ischemia (2 x 10-min, 1-h interval) in rats. In the present study, we examined the effect of single and 14-day pre-ischemic KGKR treatment on neuronal damage in the same repeated cerebral ischemia model. Additionally, to determine the mechanisms of neuroprotection by KGKR at glutamatergic neurons, we examined the effects of KGKR on glutamate release induced by repeated cerebral ischemia in vivo, and on cell damage induced by both glutamate and kainate in primary cultured hippocampal neurons in vitro. The 14-day pre-ischemic KGKR (300 mg/kg, oral administration (p.o.)) treatment reduced neuronal damage and astrocyte expression induced by repeated cerebral ischemia. No effect was observed after single pre-ischemic KGKR treatment. Both single and 14-day KGKR treatment decreased glutamate release in the hippocampal CA1 region in intact rats; however, neither pre-ischemic KGKR treatment altered glutamate release during cerebral ischemia. In vitro, KGKR (100-1000 microg/mL) dose-dependently suppressed hippocampal neuronal damage induced by both glutamate (100 microM) and kainate (1 mM). These data suggest neuroprotection with KGKR requires continuous pre-ischemic treatment, and that the mechanisms of protection may be involved in inhibiting the glutamatergic receptors of the post-synaptic neurons.
Journal of Natural Medicines 02/2010; 64(2):167-74. · 1.39 Impact Factor
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Sei Higuchi,
Keiichi Irie,
Shohei Mishima,
Maiko Araki,
Makiko Ohji,
Atsunori Shirakawa,
Yoshiharu Akitake,
Kiyoshi Matsuyama,
Kenji Mishima,
Kenichi Mishima, Katsunori Iwasaki,
Michihiro Fujiwara
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ABSTRACT: Endocannabinoids have been shown to activate reward-related feeding and to promote astrocytic differentiation. We investigated whether high-fat diet (HFD) intake produced a preference for HFD via an endocannabinoid-dependent mechanism. In the conditioned place preference test, the 2-week HFD-intake group showed preference for HFD and had increased expression of a marker for reactive astrocytes, glial fibrillary acid protein (GFAP), in the hypothalamus. The cannabinoid CB(1)-receptor antagonist O-2050 reduced the preference for HFD and expression of GFAP in the hypothalamus. These results suggested that HFD intake led to the development of a preference for HFD via astrocytic CB(1) receptors in the hypothalamus.
Journal of Pharmacological Sciences 02/2010; 112(3):369-72. · 2.08 Impact Factor
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Sei Higuchi,
Keiichi Irie,
Takafumi Nakano,
Yuya Sakamoto,
Yoshiharu Akitake,
Maiko Araki,
Makiko Ohji,
Riyo Furuta,
Mai Katsuki,
Ryuji Yamaguchi,
Kiyoshi Matsuyama,
Kenji Mishima,
Kenichi Mishima, Katsunori Iwasaki,
Michihiro Fujiwara
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ABSTRACT: Endocannabinoid 2-arachidonoylglycerol (2-AG) regulates several important physiological processes in the brain. 2-AG is commonly quantified by gas chromatography mass spectrometry after an initial purification step. The most precise and rapid purification utilizes C(18) solid-phase extraction, but quantification problems can arise with acyl migration from 2-AG to 1-arachidonoylglycerol. We found that extraction with methanol promoted this migration, but acetone and diethyl ether (Et(2)O) did not. Acetone and Et(2)O were used to develop a purification method for the direct determination of 2-AG.
Analytical Sciences 01/2010; 26(11):1199-202. · 1.25 Impact Factor
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Kazunori Sano,
Emi Koushi,
Keiichi Irie,
Sei Higuchi,
Ryota Tsuchihashi,
Junei Kinjo,
Nobuaki Egashira,
Ryozo Oishi,
Naoki Uchida,
Hiroshi Nagai,
Ryoji Nishimura,
Hiroyuki Tanaka,
Satoshi Morimoto,
Kenichi Mishima, Katsunori Iwasaki,
Michihiro Fujiwara
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ABSTRACT: The present study was designed to determine the effect of delta(9)-tetrahydrocannabinol (THC) on susceptibility to stress. We reported that THC significantly prolonged the immobility time during the forced swim-stress. The selective cannabinoid CB(1) receptor antagonist O-2050 significantly reduced the enhancement of immobility by THC. We investigated the effect of THC on levels of stress hormone corticosterone under non-stress and forced swim-stress conditions. THC did not affect plasma corticosterone levels under non-stress conditions. However, THC, together with forced swim-stress, significantly increased plasma corticosterone levels. This effect was inhibited by O-2050. This evidence suggests that THC, under stressful conditions, enhances the susceptibility of the hypothalamus-pituitary-adrenal-axis to stress via the CB(1) receptor, thereby increasing the risk of depression.
Biological & Pharmaceutical Bulletin 12/2009; 32(12):2065-7. · 1.66 Impact Factor
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Kazuhide Hayakawa,
Takafumi Nakano,
Keiichi Irie,
Sei Higuchi,
Masayuki Fujioka,
Kensuke Orito, Katsunori Iwasaki,
Guang Jin,
Eng H Lo,
Kenichi Mishima,
Michihiro Fujiwara
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ABSTRACT: Glial scarring is traditionally thought to be detrimental after stroke. But emerging studies now suggest that reactive astrocytes may also contribute to neurovascular remodeling. Here, we assessed the effects and mechanisms of metabolic inhibition of reactive astrocytes in a mouse model of stroke recovery. Five days after stroke onset, astrocytes were metabolically inhibited with fluorocitrate (FC, 1 nmol). Markers of reactive astrocytes (glial fibrillary acidic protein (GFAP), HMGB1), markers of neurovascular remodeling (CD31, synaptophysin, PSD95), and behavioral outcomes (neuroscore, rotarod latency) were quantified from 1 to 14 days. As expected, focal cerebral ischemia induced significant neurological deficits in mice. But over the course of 14 days after stroke onset, a steady improvement in neuroscore and rotarod latencies were observed as the mice spontaneously recovered. Reactive astrocytes coexpressing GFAP and HMGB1 increased in peri-infarct cortex from 1 to 14 days after cerebral ischemia in parallel with an increase in the neurovascular remodeling markers CD31, synaptophysin, and PSD95. Compared with stroke-only controls, FC-treated mice demonstrated a significant decrease in HMGB1-positive reactive astrocytes and neurovascular remodeling, as well as a corresponding worsening of behavioral recovery. Our results suggest that reactive astrocytes in peri-infarct cortex may promote neurovascular remodeling, and these glial responses may aid functional recovery after stroke.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 12/2009; 30(4):871-82. · 5.46 Impact Factor
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Kazuhide Hayakawa,
Keiichi Irie,
Kazunori Sano,
Takuya Watanabe,
Sei Higuchi,
Makiko Enoki,
Takafumi Nakano,
Kazuhiko Harada,
Shin Ishikane,
Tomoaki Ikeda,
Masayuki Fujioka,
Kensuke Orito, Katsunori Iwasaki,
Kenichi Mishima,
Michihiro Fujiwara
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ABSTRACT: Cannabidiol decreases cerebral infarction and high-mobility group box1 (HMGB1) in plasma in ischemic early phase. However, plasma HMGB1 levels in ischemic delayed phase reach higher concentration with the progressing brain injury. In this study, we investigated the therapeutic time window of cannabidiol on functional deficits, glial HMGB1 and plasma HMGB1 levels in a 4 h mouse middle cerebral artery (MCA) occlusion model. Cannabidiol-treated mice were divided into 3 groups as follows: group (a) treated from day 1, group (b) treated from day 3, group (c) treated from day 5 after MCA occlusion. Moreover, minocycline, microglia inhibitor, and fluorocitrate, an inhibitor of astroglial metabolism, were used to compare with cannabidiol-treated group. Repeated treatment with cannabidiol from 1 and 3 d at the latest after cerebral ischemia improved functional deficits and survival rates. However, cannabidiol from 5 d could not improve the ischemic damage as well as fluorocitrate-treated group. Moreover, both group (a), group (b) and minocycline but not group (c) and fluorocitrate-treated group had a decrease in the number of Iba1 expressing HMGB1 positive cells and HMGB1 levels in plasma. Cannabidiol may provide therapeutic possibilities for the progressing brain injury via HMGB1-inhibiting mechanism.
Biological & Pharmaceutical Bulletin 10/2009; 32(9):1538-44. · 1.66 Impact Factor
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ABSTRACT: To examine the effects of deletion of gangliosides on the nervous system by avoiding masking effects with the remaining structures, we established double knockout (DKO) mice of GM2/GD2 synthase and GD3 synthase genes, i.e., GM3-only mice. They showed progressive sensory and motor neuron deficits with aging. We further examined higher order neurological functions, and found progressive dysfunction of motor coordination with rota-rod test and marked deterioration in memory and learning with eight-arm radial maze test in the DKO mice. The results of oxotremorine treatment suggested that they undergo strong suppression of muscarinic type acetylcholine receptors (mAChRs) functions, and that the damage in the GM3-only mice is due to a mAChR receptor deficit. On the other hand, expression levels of mRNAs of mAChRs were generally up-regulated, suggesting compensatory increase of expression due to reduced functions. Since central mAChRs are involved in the regulation of cognitive, behavioral, sensory, motor, and autonomic functions, we investigated changes in the expressions levels of subtypes of the mAChR genes in various regions of brain tissues. M1 and M4 receptors were conspicuously up-regulated in cortex and striatum in the DKO, suggesting that suppressed functions of mAChRs are responsible for the altered neurological features, in particular for deteriorated memory and learning, observed in the behavioral analyses. Thus, dysfunction of mAChRs might be a substantial basis for the progressive neurological deterioration in DKO mice.
Behavioural brain research 10/2009; 206(1):101-8. · 3.22 Impact Factor
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ABSTRACT: Telmisartan is known to block angiotensin (Ang) II type-1 receptors (AT(1)R), and also activate peroxisome proliferator-activated receptor gamma (PPARgamma) signaling. Recently, PPARgamma has been implicated as a regulator of cellular proliferation and inflammatory responses. In the present study, we investigated the anti-inflammatory effects of telmisartan on middle cerebral artery (MCA) occlusion in mice. Telmisartan was administered orally to mice at 2h before and 2h after MCA occlusion. Infarct size was determined at 24h after MCA occlusion. In addition, cerebral blood flow (CBF) was measured during MCA occlusion. The effect of telmisartan on inflammatory markers, including Iba1 (macrophage/microglia marker) immunoreactivity and plasma high-mobility group box1 (HMGB1), was also investigated at 24h after MCA. Telmisartan significantly decreased the infarct area in dose-dependent manner without affecting CBF. Furthermore, the cerebroprotective effect of telmisartan was inhibited by GW9662, PPARgamma antagonist. Telmisartan significantly decreased the number of Iba1-positive cells expressing HMGB1 and decreased plasma HMGB1 levels. These effects were partially inhibited by GW9662. These data suggest that telmisartan may be a potential treatment for post-ischemic injury by partially inhibiting the inflammatory reaction after cerebral ischemia via a PPARgamma-dependent HMGB1 inhibiting mechanism.
Neuroscience Letters 09/2009; 464(3):151-5. · 2.11 Impact Factor
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Folia Pharmacologica Japonica 08/2009; 134(1):3-7.
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Misato Yoshikawa,
Shinji Go,
Kotaro Takasaki,
Yasuhiro Kakazu,
Mitsuru Ohashi,
Masakazu Nagafuku,
Kazuya Kabayama,
Junji Sekimoto,
Shun-ichi Suzuki,
Kazutaka Takaiwa,
Takashi Kimitsuki,
Nozomu Matsumoto,
Shizuo Komune,
Daisuke Kamei,
Masaki Saito,
Michihiro Fujiwara, Katsunori Iwasaki,
Jin-ichi Inokuchi
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ABSTRACT: The ganglioside GM3 synthase (SAT-I), encoded by a single-copy gene, is a primary glycosyltransferase for the synthesis of complex gangliosides. In SAT-I null mice, hearing ability, assessed by brainstem auditory-evoked potentials (BAEP), was impaired at the onset of hearing and had been completely lost by 17 days after birth (P17), showing a deformity in hair cells in the organ of Corti. By 2 months of age, the organ of Corti had selectively and completely disappeared without effect on balance or motor function or in the histology of vestibule. Interestingly, spatiotemporal changes in localization of individual gangliosides, including GM3 and GT1b, were observed during the postnatal development and maturation of the normal inner ear. GM3 expressed in almost all regions of cochlea at P3, but at the onset of hearing it distinctly localized in stria vascularis, spiral ganglion, and the organ of Corti. In addition, SAT-I null mice maintain the function of stria vascularis, because normal potassium concentration and endocochlear potential of endolymph were observed even when they lost the BAEP completely. Thus, the defect of hearing ability of SAT-I null mice could be attributed to the functional disorganization of the organ of Corti, and the expression of gangliosides, especially GM3, during the early part of the functional maturation of the cochlea could be essential for the acquisition and maintenance of hearing function.
Proceedings of the National Academy of Sciences 07/2009; 106(23):9483-8. · 9.68 Impact Factor
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Naoki Uchida,
Nobuaki Egashira, Katsunori Iwasaki,
Ayumi Ishibashi,
Ryosuke Tashiro,
Ai Nogami,
Naomi Manome,
Moe Abe,
Kotaro Takasaki,
Kenichi Mishima,
Jiro Takata,
Ryozo Oishi,
Ryoji Nishimura,
Michihiro Fujiwara
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ABSTRACT: Behavioral and psychological symptoms of dementia (BPSD) are commonly seen in patients with Alzheimer's disease (AD) and other forms of senile dementia. BPSD have a serious impact on the quality of life of dementia patients, as well as on that of their caregivers. However, effective drug therapy for BPSD has not been established. Recently, the traditional Japanese medicine Yokukansan (YKS, Yi-gan san in Chinese) has been reported to improve BPSD, such as aggression, agitation, irritability, and hallucinations, in a randomized, single-blind, placebo-controlled study. However, the psychopharmacologic effects of YKS remain unexplored. In the present study, we investigated the effects of YKS on social isolation-induced aggressive behavior and methamphetamine- or MK-801-induced hyperlocomotion in rodents. Social isolation markedly induced aggressive behavior in male Wistar rats. Quetiapine at a dose of 10 mg/kg (per os (p.o.)) significantly inhibited this social isolation-induced aggressive behavior. YKS (100, 300 mg/kg, p.o.) also significantly inhibited the aggressive behavior. Moreover, risperidone (0.1 mg/kg, p.o.) significantly inhibited methamphetamine- or MK-801-induced hyperlocomotion in mice. YKS (300 mg/kg, p.o.) inhibited methamphetamine-induced hyperlocomotion, while YKS at the same dose had no effect on MK-801-induced hyperlocomotion. These findings suggest that YKS may be useful for the treatment of aggression and agitation, and that the psychopharmacologic effects of YKS might be mediated, in part, by inhibiting the activity of the dopaminergic system.
Biological & Pharmaceutical Bulletin 04/2009; 32(3):372-5. · 1.66 Impact Factor
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Fengling Pu,
Kyoko Motohashi,
Tomohiro Kaneko,
Yurika Tanaka,
Naomi Manome,
Keiichi Irie,
Jirou Takata,
Nobuaki Egashira,
Ryozo Oishi,
Takuya Okamoto,
Yasuo Sei,
Takako Yokozawa,
Kenichi Mishima, Katsunori Iwasaki,
Michihiro Fujiwara
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ABSTRACT: In the present study, we investigated the neuroprotective effects of Kangen-karyu (KGK) in a repeated cerebral ischemia model (2 x 10 min, 1-h interval). A 21-day pre- and post-ischemic treatment with KGK (10 - 300 mg/kg) and aspirin (5 mg/kg) improved the spatial memory impairment and neuronal death in the hippocampal CA1 region induced by repeated cerebral ischemia. However, a 7-day post-ischemic treatment with KGK did not attenuate the spatial memory impairment and neuronal death in this model. To determine the mechanism of action of KGK, we investigated the effects of a 14-day pre-ischemic treatment with KGK on cerebral blood flow in the hippocampal area of the repeated cerebral ischemia model using laser Doppler flowmetry. The 14-day pre-ischemic treatment with KGK increased the cerebral blood flow during reperfusion. These results suggest that a 21-day pre- and post-ischemic treatment with KGK can protect against brain damage caused by cerebral ischemia by increasing the cerebral blood flow in the hippocampal area.
Journal of Pharmacological Sciences 04/2009; 109(3):424-30. · 2.08 Impact Factor
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ABSTRACT: Arginine vasopressin (AVP) is a neurohypophyseal peptide best known as an antidiuretic hormone. AVP receptors have been classified into three subtypes: V1a, V1b, and V2 receptors. V1a receptor (V1aR) and V1b receptor (V1bR) are widely distributed in the central nervous system, including the septum, cortex, hippocampus, and hypothalamus. Clinical studies have demonstrated an involvement of AVP in psychiatric disorders. In the present study, we examined the performance of V1aR or V1bR knockout (KO) mice compared to wild-type (WT) mice in behavioral tests. V1aR and V1bR KO mice exhibited deficits of social behavior and prepulse inhibition in comparison to WT mice. Moreover, V1aR KO mice exhibited reduced anxiety-like behavior and impairment of spatial learning. These results suggest that V1aR and V1bR play an important role in psychological and cognitive functions.
Journal of Pharmacological Sciences 02/2009; 109(1):44-9. · 2.08 Impact Factor
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Kazuhide Hayakawa,
Kenichi Mishima,
Keiichi Irie,
Mai Hazekawa,
Shohei Mishima,
Masayuki Fujioka,
Kensuke Orito,
Nobuaki Egashira,
Shutaro Katsurabayashi,
Kotaro Takasaki, Katsunori Iwasaki,
Michihiro Fujiwara
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ABSTRACT: We examined the cerebroprotective mechanism of cannabidiol, the non-psychoactive component of marijuana, against infarction in a 4-h mouse middle cerebral artery (MCA) occlusion model. Cannabidiol was intraperitoneally administrated immediately before and 3h after cerebral ischemia. Infarct size and myeloperoxidase (MPO) activity, a marker of neutrophil, monocyte/macropharge, were measured at 24h after cerebral ischemia. Activated microglia and astrocytes were evaluated by immunostaining. Moreover, high-mobility group box1 (HMGB1) was also evaluated at 1 and 3 days after MCA occlusion. In addition, neurological score and motor coordination on the rota-rod test were assessed at 1 and 3 days after cerebral ischemia. Cannabidiol significantly prevented infarction and MPO activity at 20h after reperfusion. These effects of cannabidiol were not inhibited by either SR141716 or AM630. Cannabidiol inhibited the MPO-positive cells expressing HMGB1 and also decreased the expression level of HMGB1 in plasma. In addition, cannabidiol decreased the number of Iba1- and GFAP-positive cells at 3 days after cerebral ischemia. Moreover, cannabidiol improved neurological score and motor coordination on the rota-rod test. Our results suggest that cannabidiol inhibits monocyte/macropharge expressing HMGB1 followed by preventing glial activation and neurological impairment induced by cerebral ischemia. Cannabidiol will open new therapeutic possibilities for post-ischemic injury via HMGB1-inhibiting mechanism.
Neuropharmacology 12/2008; 55(8):1280-6. · 4.81 Impact Factor
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ABSTRACT: Acetylcholine (ACh) release is one of the key factors in memory mechanisms. To clarify whether beta-amyloid (Abeta) induces a disturbance of the cholinergic system leading to memory impairment, we examined memory impairment and measured hippocampal ACh release in Tg2576 (Tg) mice that over-express the Swedish mutant amyloid precursor protein (APPsw). Furthermore, we examined Abeta burden with aging. Tg mice aged 9-11 months, but not aged 4-6 months, showed memory impairment in the 8-arm radial maze behavior test. Spontaneous ACh release was not altered in Tg mice compared with age-matched control mice at 4-6 or 9-11 months of age. On the other hand, high-K(+)-evoked ACh release was decreased in Tg mice aged 9-11 months, but not in Tg mice aged 4-6 months. Hippocampal Abeta increased in an age-dependent manner, but evident amyloid plaques were not found in the hippocampus of Tg mice aged 11 months. These results suggest that memory impairment in Tg mice could be attributed to cholinergic synapse dysfunction that could not be caused predominantly by amyloid plaques. Measuring ACh release in this model might be a useful index for the screening of new drugs to treat the early-phase of Alzheimer's disease.
Brain research 11/2008; 1249:222-8. · 2.46 Impact Factor
