Papers by Masanori Yoneyama
Global Drugs and Therapeutics, 2017
Here, we evaluated the effect of in vivo treatment with melatonin on neuronal regeneration after ... more Here, we evaluated the effect of in vivo treatment with melatonin on neuronal regeneration after neuronal loss in the dentate gyrus of TMT-treated mouse, which is an in vivo model for neuronal repair following neuronal loss in the hippocampal dentate gyrus.Fourteen-days treatment with melatonin (50 mg/kg, i.p.) dramatically suppressed the increase in the number of 5-bromo-2'-deoxyuridine (BrdU)-incorporating cells and NeuN-positive BrdU-incorporated cells generated after neuronal loss in the dentate gyrus of TMT treated animals on day 30 post-TMT treatment. Melatonin was effective in decreasing the level of ionized calcium-binding adapter molecule 1 expressed in the dentate gyrus of TMT-treated animals.Our data suggest that that melatonin suppresses neuronal repair following neuronal loss in the dentate gyrus. Yoneyama M (2017) Melatonin suppresses neuronal regeneration following neuronal degeneration in the hippocampal dentate gyrus
Global Drugs and Therapeutics, 2018
The organotin trimethyltin (TMT) induces neurodegeneration in the hippocampal dentate gyrus and p... more The organotin trimethyltin (TMT) induces neurodegeneration in the hippocampal dentate gyrus and psychiatric changes in mice such as cognitive dysfunction. We previously established a TMT-treated mouse model of cognitive dysfunction with hippocampal neurodegeneration. Olanzapine is an antipsychotic drug that has neuroprotective effects and improves cognitive dysfunction observed in schizophrenia. The present study aimed to elucidate the effects of olanzapine on cognitive dysfunction and hippocampal neurodegeneration in TMT-treated mice. Our results indicated that olanzapine effectively prevented TMT-induced neurotoxicity and the subsequent activation of microglia in the hippocampus, thus protecting hippocampal neurons from damage and preserving cognitive function. Minocycline (an inhibitor of microglial activation) also prevented TMT-induced neurotoxicity and demonstrated a synergistic effect with olanzapine. Collectively, our findings indicate that olanzapine may prevent TMT-related neurotoxicity, including hippocampal neurodegeneration and cognitive dysfunction.
Proceedings for Annual Meeting of The Japanese Pharmacological Society, 2018
Hippocampal neurodegeneration is related with cognitive dysfunction in neurodegenerative diseases... more Hippocampal neurodegeneration is related with cognitive dysfunction in neurodegenerative diseases including Alzheimer's diseases. Trimethyltin (TMT) is an organotin, which causes cognitive dysfunction with selective neurodegeneration of hippocampus in mice. Thus, TMT-treated mouse is a useful model for analyzing the effect of drugs on cognitive dysfunction with hippocampal neurodegeneration. Olanzapine is known to improve cognitive dysfunction accompanied by neuroprotective effect in schizophrenia and Alzheimer's diseases. However, little has been studied on the effect of olanzapine on both cognitive dysfunction and neurodegeneration in animal models. In the present study, we aimed to elucidate whether olanzapine improves cognitive dysfunction and neurodegeneration in TMT-treated mice. Male ddY mice (8-week old) were intraperitoneally given TMT (2.6 mg/kg). Olanzapine (0.6 mg/kg) was intraperitoneally injected once a day for 3 days at 30 min after treatment with TMT. To assess cognitive function, novel object recognition test (NORT) was performed at 30 min after the third treatment with olanzapine. For tissue staining, olanzapine (0.6 mg/kg) and minocycline (50 mg/kg) were treated once a day for 2 days at 30 min after TMT treatment. Brain tissues were dissected 24 h after the final treatment with olanzapine or minocycline. Fluoro-Jade B (FJB) staining or Iba-1 immunostaining was performed to assess neurodegeneration or microglial activation, respectively. Cognitive dysfunction in TMT-treated animals was suppressed by treatment with olanzapine. Olanzapine also suppressed increased number of FJB-positive cells and Iba-1-positive activated microglial cells in TMT-treated animals. To evaluate whether microglial activation is necessary for TMT-induced neurodegeneration, we examined the effect of minocycline, an inhibitor of microglial activation on FJB-positive cells in TMT-treated animals. In results, minocycline was effective in preventing increased number of FJB positive cells by TMT. These data suggest the possibility that olanzapine improve cognitive dysfunction via suppression of activation of microglia followed by neurodegeneration induced by TMT.
Biological and Pharmaceutical Bulletin, 2019
It is well-known that outer hair cell (OHC) loss occurs in the cochlea of animal models of perman... more It is well-known that outer hair cell (OHC) loss occurs in the cochlea of animal models of permanent hearing loss induced by intense noise exposure. Our earlier studies demonstrated the production of hydroxynonenal and peroxynitrite, as well as the disruption of gap junction-mediated intercellular communication (GJIC), in the cochlear spiral ligament prior to noise-induced sudden hearing loss. The goal of the present study was to evaluate the mechanism underlying cochlear OHC loss after sudden hearing loss induced by intense noise exposure. In organ of Corti explant cultures from mice, no significant OHC loss was observed after in vitro exposure to 4-hydroxynonenal (a product of lipid peroxidation), H 2 O 2 , SIN-1 (peroxynitrite generator), and carbenoxolone (a gap junction inhibitor). Interestingly, in vivo intracochlear carbenoxolone injection through the posterior semicircular canal caused marked OHC and hearing loss, as well as the disruption of gap junction-mediated intercellular communication in the cochlear spiral ligament. However, no significant OHC loss was observed in vivo in animals treated with 4-hydroxynonenal and SIN-1. Taken together, our data suggest that disruption of GJIC in the cochlear lateral wall structures is an important cause of cochlear OHC loss in models of hearing loss, including those induced by noise.
Journal of Pharmacological Sciences, 2005
Differential regulation of gene expression by transcription factors is widely viewed as one of th... more Differential regulation of gene expression by transcription factors is widely viewed as one of the principal mechanisms guiding development. Although numerous DNA binding proteins have been identified in various tissues, the role of individual transcription factors in the differentiation of specific cell groups, such as those populating the inner ear, is just beginning to be elucidated. It is known that transcription factors are induced in response to many signals that lead to cell growth, differentiation, inflammatory responses, the regulation of apoptosis, and neoplastic transformation. There are various transcription factors in the cochlea of the inner ear. These include activator protein-1 and nuclear factor-kappa B, glucocorticoid receptor, and so on. Based on recent reports and our investigation, in this article we review possible functions and expression of these transcription factors.
PloS one, 2014
Noise-induced hearing loss is at least in part due to disruption of endocochlear potential, which... more Noise-induced hearing loss is at least in part due to disruption of endocochlear potential, which is maintained by various K(+) transport apparatuses including Na(+), K(+)-ATPase and gap junction-mediated intercellular communication in the lateral wall structures. In this study, we examined the changes in the ion-trafficking-related proteins in the spiral ligament fibrocytes (SLFs) following in vivo acoustic overstimulation or in vitro exposure of cultured SLFs to 4-hydroxy-2-nonenal, which is a mediator of oxidative stress. Connexin (Cx)26 and Cx30 were ubiquitously expressed throughout the spiral ligament, whereas Na(+), K(+)-ATPase α1 was predominantly detected in the stria vascularis and spiral prominence (type 2 SLFs). One-hour exposure of mice to 8 kHz octave band noise at a 110 dB sound pressure level produced an immediate and prolonged decrease in the Cx26 expression level and in Na+, K(+)-ATPase activity, as well as a delayed decrease in Cx30 expression in the SLFs. The noi...
Journal of Pharmacological Sciences, 2009
The organotin trimethyltin (TMT) is known to cause neuronal degeneration in the murine brain. Ear... more The organotin trimethyltin (TMT) is known to cause neuronal degeneration in the murine brain. Earlier studies indicate that TMT-induced neuronal degeneration is enhanced by adrenalectomy. However, no evaluation has been attempted to determine the mechanism underlying the enhancement of TMT neurotoxicity by adrenalectomy and its implications in neuronal degeneration. To assess the implications and determine the mechanism of adrenalectomyelicited enhancement of TMT neurotoxicity, we examined neuronal degeneration and associated signaling pathways in adrenalectomized mice. Adrenalectomy dramatically enhanced the TMTinduced neuronal damage in certain brain regions including the dentate gyrus, olfactory bulb, and anterior olfactory nucleus, in addition to exacerbating the behavioral abnormalities. TMTinduced activation of caspase-3 and calpain was also enhanced by adrenalectomy. The above events elicited by TMT were almost entirely prevented by treatment with dexamethasone. In addition to the above events, adrenalectomy clearly enhanced the activation of c-Jun-N-terminal kinases and the formation of 4-hydroxynonenal in the dentate gyrus following TMT treatment. The dentate granule cell damage induced by TMT was exacerbated by mifepristone, a glucocorticoid-receptor antagonist. Taken together, our data suggest that endogenous and exogenous glucocorticoids prevent neurodegeneration induced by TMT in the central nervous system by attenuating intensive oxidative stress and associated signaling pathways.
Biological and Pharmaceutical Bulletin, 2014
Caspases are well-known enzymes that work as initiators and effectors of apoptosis. To elucidate ... more Caspases are well-known enzymes that work as initiators and effectors of apoptosis. To elucidate the role of caspases in neurodevelopment, we sought to determine if caspases are involved in the proliferation of neural stem/progenitor cells (NPCs) in the developing mouse brain. Labeling with 5-bromo-2′-deoxyuridine (BrdU) from days 14 to 18 of pregnant mice revealed that the 18-d old fetus had many BudU-positive cells in its brain. Double-labeling revealed that active caspase-3 was co-localized with these BrdU-positive cells in the neocortex, hippocampus, and subventricular zone of the fetal brain. Active caspase-3 was detected in cultures of NPCs derived from the neocortex of 15-d old fetuses during culture periods. Importantly, the pancaspase inhibitor z-VAD-FMK was effective at completely inhibiting neurosphere formation by the NPCs. These results suggest the possibility that the caspase cascade is essential for the proliferation of neocortical NPCs in the developing mouse brain.
Biological & Pharmaceutical Bulletin, 2011
The organotin trimethyltin (TMT) is well known to cause neuronal degeneration in the hippocampal ... more The organotin trimethyltin (TMT) is well known to cause neuronal degeneration in the hippocampal dentate gyrus of mice. The first purpose of the present study was to examine whether the cyclooxygenase (COX) inhibitor indomethacin could ameliorate neuronal degeneration in the dentate gyrus of mice following TMT treatment in vivo. The systemic injection into mice of TMT at 2.8 mg/kg produced activation of endogenous caspase-3 and calpain, enhanced the gene expression of COX-1 and COX-2, activated microglial cells, and caused the formation of the lipid peroxidation product 4-hydroxynonenal in the hippocampus. Given at 12-h post-TMT treatment, the systemic injection of indomethacin (5 or 10 mg/kg, subcutaneously) significantly decreased the TMT-induced damage to neurons having active caspase-3 and single-stranded DNA in the dentate granule cell layer of the hippocampus. The results of the a a-Fodrin degradation test revealed that the post-treatment with indomethacin was effective in attenuating TMT-induced activation of endogenous caspases and calpain in the hippocampus. In TMT-treated animals, interestingly, the post-treatment with indomethacin produced not only activation of microglial cells in the dentate gyrus but also the formation of 4-hydroxynonenal in the dentate granule cell layer. Taken together, our data suggest that COX inhibition by indomethacin ameliorated TMT-induced neuronal degeneration in the dentate gyrus by attenuating intensive oxidative stress.
Proceedings for Annual Meeting of The Japanese Pharmacological Society, 2018
It is now clear that there is a continual turnover of the mammalian hippocampal dentate gyrus (DG... more It is now clear that there is a continual turnover of the mammalian hippocampal dentate gyrus (DG) neurons throughout life even in adult. Various neurological injuries are widely recognized as promoting endogenous neurogenesis in DG. Thrombin-activated/protease-activated receptor-1 (PAR-1) is known to regulate proliferation of neural cells following brain injury including intracellular hemorrhage. Our previous studies demonstrated that the systemic treatment with trimethyltin chloride (TMT) causes the granule cell loss in the mouse DG, with being regenerated in the dentate granule cell after neuronal loss. To elucidate the roles of PAR-1 in neuroregeneration after neuronal degeneration, we evaluated the expression of PAR-1 in the newly generated cells following neurodegeneration in the DG of adult mouse. In vivo experiments, mice were given TMT to prepare hippocampal slices for immunohistochemical analysis using antibody against PAR-1 and nestin [neural stem/progenitor cells (NPCs) marker]. Cells positive for PAR-1 and nestin markedly increased in the DG on day 3 to 5 after TMT treatment. As vitro experiments, we evaluated the effects of thrombin on proliferative activity of the NPCs isolated from the DG on day 3 post-TMT treatment. NPCs prepared from the dentate gyrus were cultured in the neurobasal medium with B27 supplement, EGF, and bFGF for 14 days in vitro (DIV). After secondary replating nestin-positive cells were cultured for 5 DIV under the same conditions in the absence or presence of thrombin, Y27632, and/or fasudil for assessment of cell proliferation. Immunostaining revealed that PAR-1 was colocalized with most of nestin-positive cells. Exposure of the cells to thrombin significantly attenuated the cell proliferation by bromodeoxyuridine incorporation assay without cell damage. Increased RhoA-GTP (activated RhoA) level was determined after the exposure to thrombin. Thrombin-induced attenuation of proliferative activity was completely abolished by Rho kinase inhibitors such as Y27632 and fasudil. These results suggest that activation of PAR-1 causes Rho kinase pathway-dependent suppression of cell proliferation of the NPCs.
Journal of Pharmacological Sciences, 2011
Nitric oxide (NO) activates the cyclic GMP (cGMP) / protein kinase G (PKG) pathway during physiol... more Nitric oxide (NO) activates the cyclic GMP (cGMP) / protein kinase G (PKG) pathway during physiological processes in numerous types of cells. Here, we evaluated whether this NO/cGMP/PKG pathway is involved in the proliferation of neural stem/progenitor cells (NPCs) derived from the hippocampus of embryonic mice. In culture, the exposure to the NO synthase inhibitor N ω-nitro-L-arginine methyl ester (L-NAME) significantly decreased the number of viable cells and 5-bromo-2′-deoxyuridine (BrdU) incorporation into the cells, as well as the levels of intracellular reactive oxygen species, extracellular NO 2 , and intracellular cGMP. Like L-NAME, the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and PKG inhibitor KT5823 also decreased cell viability and BrdU incorporation. The membrane-permeable cGMP analogue 8-bromo-cGMP partially abolished the L-NAME-induced decrease in the BrdU incorporation. BrdU incorporation was decreased by Ca 2+-channel blockers, including dantrolene, MK-801, ifenprodil, and nifedipine. Interestingly, the NO 2 level was decreased by dantrolene, but not by the other 3 blockers. L-NAME and ODQ attenuated phosphorylation of Akt, but not that of extracellular signal-regulated kinases or epidermal growth factor receptors. Our data suggest that endogenous NO generation linked to dantrolene-sensitive ryanodine receptors activates the cGMP/ PKG signaling pathway for positive regulation of proliferation of hippocampal NPCs derived from embryonic mice.
International Journal of Molecular Sciences, 2020
Bacopa monnieri L. Wettst. (BM) is a botanical component of Ayurvedic medicines and of dietary su... more Bacopa monnieri L. Wettst. (BM) is a botanical component of Ayurvedic medicines and of dietary supplements used worldwide for cognitive health and function. We previously reported that administration of BM alcoholic extract (BME) prevents trimethyltin (TMT)-induced cognitive deficits and hippocampal cell damage and promotes TMT-induced hippocampal neurogenesis. In this study, we demonstrate that administration of BME improves spatial working memory in adolescent (5-week- old) healthy mice but not adult (8-week-old) mice. Moreover, improved spatial working memory was retained even at 4 weeks after terminating 1-week treatment of adolescent mice. One-week BME treatment of adolescent mice significantly enhanced hippocampal BrdU incorporation and expression of genes involved in neurogenesis determined by RNAseq analysis. Cell death, as detected by histochemistry, appeared not to be significant. A significant increase in neurogenesis was observed in the dentate gyrus region 4 weeks after...
Journal of Pharmacological Sciences, 2016
Thrombin-activated protease-activated receptor (PAR)-1 regulates the proliferation of neural cell... more Thrombin-activated protease-activated receptor (PAR)-1 regulates the proliferation of neural cells following brain injury. To elucidate the involvement of PAR-1 in the neurogenesis that occurs in the adult hippocampus, we examined whether PAR-1 regulated the proliferation of neural stem/progenitor cells (NPCs) derived from the murine hippocampal dentate gyrus. NPC cultures expressed PAR-1 protein and mRNA encoding all subtypes of PAR. Direct exposure of the cells to thrombin dramatically attenuated the cell proliferation without causing cell damage. This thrombin-induced attenuation was almost completely abolished by the PAR antagonist RWJ 56110, as well as by dabigatran and 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF), which are selective and non-selective thrombin inhibitors, respectively. Expectedly, the PAR-1 agonist peptide (AP) SFLLR-NH 2 also attenuated the cell proliferation. The cell proliferation was not affected by the PAR-1 negative control peptide RLLFT-NH 2 , which is an inactive peptide for PAR-1. Independently, we determined the effect of in vivo treatment with AEBSF or AP on hippocampal neurogenesis in the adult mouse. The administration of AEBSF, but not that of AP, significantly increased the number of newly-generated cells in the hippocampal subgranular zone. These data suggest that PAR-1 negatively regulated adult neurogenesis in the hippocampus by inhibiting the proliferative activity of the NPCs.
Neurochemistry …, 2008
Recently we showed that the level of mitochondrial mRNA was decreased prior to neuronal death ind... more Recently we showed that the level of mitochondrial mRNA was decreased prior to neuronal death induced by glutamate. As the level of mRNA is regulated by ribonuclease (RNase), we examined RNase activity and its expression in the primary cultures of cortical neurons after glutamate treatment in order to evaluate the involvement of RNase in glutamate-induced neuronal death. A 15-min exposure of the cultures to glutamate at the concentration of 100 mM produced marked neuronal damage (more than 70% of total cells) at 24-h post-exposure. Under the experimental conditions used, RNA degradation was definitely observed at a period of 4-12-h post-exposure, a time when no damage was seen in the neurons. Glutamate-induced RNA degradation was completely prevented by the N-methyl-D-aspartic acid (NMDA) receptor channel blocker MK-801 or the NR2B-containing NMDA receptor antagonist ifenprodil. Glutamate exposure produced enhanced expression of RNase L at least 2-12 h later, which was absolutely abolished by MK-801. However, no significant change was seen in the level of RNase H1 mRNA at any time point post-glutamate treatment. Immunocytochemical studies revealed that RNase L expressed in response to glutamate was localized within the nucleus, mitochondria, and cytoplasm in the neurons. Taken together, our data suggest that expression of RNase L is a signal generated by NMDA receptor in cortical neurons. RNase L expression and RNA degradation may be events that cause neuronal damage induced by NMDA receptor activation.
Journal of Pharmacological Sciences, 2009
The organotin trimethyltin (TMT) is known to cause neuronal degeneration in the central nervous s... more The organotin trimethyltin (TMT) is known to cause neuronal degeneration in the central nervous system. A systemic injection of TMT produced neuronal damage in the cerebral frontal cortex of mice. To elucidate the mechanism(s) underlying the toxicity of TMT toward neurons, we prepared primary cultures of neurons from the cerebral cortex of mouse embryos for use in this study. Microscopic observations revealed that a continuous exposure to TMT produced neuronal damage with nuclear condensation in an incubation time-dependent manner up to 48 h. The neuronal damage induced by TMT was not blocked by N-methyl-D-aspartate receptor channel-blocker MK-801. The exposure to TMT produced an elevation of the phosphorylation level of c-Jun N-terminal kinase (JNK) p46 , but not JNK p54 , prior to neuronal death. Under the same conditions, a significant elevation was seen in the phosphorylation level of stress-activated protein kinase 1, which activates JNKs. Furthermore, TMT enhanced the expression and phosphorylation of c-Jun during a continuous exposure. The JNK inhibitor SP600125 was effective in significantly but only partially attenuating the TMT-induced nuclear condensation and accumulation of lactate dehydrogenase in the culture medium. Taken together, our data suggest that the neuronal damage induced by TMT was independent of excitotoxicity but that at least some of it was dependent on the JNK cascades in primary cultures of cortical neurons.
Journal of Pharmacological Sciences, 2011
Adult neurogenesis is the process of generating new neurons that become integrated into existing ... more Adult neurogenesis is the process of generating new neurons that become integrated into existing circuits after fetal and early postnatal development has ceased. In most mammalian species, adult neurogenesis only appears to occur in the olfactory bulb and the hippocampus, where neural stem/progenitor cells (NPCs) exist to create new neurons. In adult neurogenesis, microenviromental change is thought to provide a specific modulation for maintaining the multi-potent state of these NPCs. Neurodegeneration is driven by the activation of resident microglia, astrocytes, and infiltrating peripheral macrophages, which release a plethora of cytokines, chemokines, neurotransmitters, and reactive oxygen species. These endogenous factors cause further bystander damage to neurons and produces both detrimental and favorable conditions for neurogenesis. Interestingly, these endogenous factors also affect the proliferation, migration, differentiation, and survival of the NPCs, as well as regulate the incorporation of newly formed neurons into the brain circuitry. The unique profile of the endogenous factors released can vary the degree of neuroregeneration after neurodegeneration. This current review summarizes recent knowledge in the emerging field that is showing that adult neurogenesis is regulated by endogenous factors produced during neurodegeneration.
Journal of Pharmacological Sciences, 2013
Edaravone is clinically used in Japan for treatment of patients with acute cerebral infarction. T... more Edaravone is clinically used in Japan for treatment of patients with acute cerebral infarction. To clarify the effect of edaravone on neurogenesis in the hippocampus following neuronal injury in the hippocampal dentate gyrus, we investigated the effect of in vitro and in vivo treatment with edaravone on the proliferation of neural stem/progenitor cells prepared from the mouse dentate gyrus damaged by trimethyltin (TMT). Histological assessment revealed the presence of large number of nestin(+) cells in the dentate gyrus on days 3-5 post-TMT treatment. We prepared cells from the dentate gyrus of naïve, TMT-treated mice or TMT/edaravone-treated mice. The cells obtained from the dentate gyrus of TMT-treated animals were capable of BrdU incorporation and neurosphere formation when cultured in the presence of growth factors. The TMT-treated group had a larger number of nestin(+) cells and nestin(+)GFAP(+) cells than the naïve one. Under the culture condition used, sustained exposure of the cells from the damaged dentate gyrus to edaravone at 10 −11 and 10 −8 M promoted the proliferation of nestin(+) cells. The systemic in vivo treatment with edaravone for 2 days produced a significant increase in the number of nestin(+) cells among the cells prepared from the dentate gyrus on day 4 post-TMT treatment, and as well as one in the number of neurospheres formed from these cells in the culture. Taken together, our data indicated that edaravone had the ability to promote the proliferation of neural stem/progenitor cells generated following neuronal damage in the dentate gyrus.
Journal of Pharmacological Sciences, 2014
Aripiprazole is used clinically as an atypical antipsychotic. We evaluated the effect of in vivo ... more Aripiprazole is used clinically as an atypical antipsychotic. We evaluated the effect of in vivo treatment with aripiprazole on the proliferation and differentiation of neural stem/ progenitor cells in a mouse model, trimethyltininduced neuronal loss/selfrepair in the hippo campal dentate gyrus (referred as "impaired animals") [Ogita et al., J Neurosci Res. 82, 609-621 (2005)]. In the impaired animals, an increased number of 5-bromo-2′-deoxyuridine (BrdU)-positive cells was seen in the dentate gyrus at the initial time window of the selfrepair stage. At the same time window, a single treatment with aripiprazole significantly increased the number of cells positive for both BrdU and nestin in the dentate gyrus of the impaired animals. Chronic treatment with aripiprazole promoted the proliferation/survival and neuronal differentiation of the cells newlygenerated following the neuronal loss in the dentate gyrus of the impaired animals. The chronic treatment with aripiprazole improved depressionlike behavior seen in the impaired animals. Taken together, our data suggest that aripiprazole had a beneficial effect on neuronal regeneration following neuronal loss in the dentate gyrus through indirectly promoted prolifera tion/survival and neuronal differentiation of neural stem/progenitor cells in the subgranular zone of the dentate gyrus.
Folia Pharmacologica Japonica, 2013
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Papers by Masanori Yoneyama