Masamitsu Shimazawa

Gifu Pharmaceutical University, Gihu, Gifu, Japan

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Publications (214)619.07 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is a common neurodegenerative disease characterized by cognitive dysfunction and neuronal cell death in the hippocampus and cerebral cortex. Glucagon-like peptide-1 (GLP-1) is an insulinotropic peptides. GLP-1-associated medicines are widely used as treatments for type 2 diabetes. In addition, they have been shown to ameliorate pathology in AD mouse models. Here, we investigated the effects of GLP-1 on different stressors in murine hippocampal HT22 cells. GLP-1 (7–36) prevented H2O2-, l-glutamate-, tunicamycin-, thapsigargin-, and amyloid β1–42-induced neuronal cell death in a concentration-dependent manner. GLP-1 (7–36) treatment for 1 h significantly increased phosphorylated Akt and extracellular signal-regulated kinase 1 and 2 (ERK1/2) when compared with vehicle-treatment. These results suggest that GLP-1 (7–36) is protective against these stressors via activation of survival signaling molecules, such as Akt and ERK1/2 in HT22 cells. In conclusion, GLP-1 and activators of the GLP-1 receptor might be useful targets for the treatment of AD.
    Biochemical and Biophysical Research Communications 02/2015; · 2.28 Impact Factor
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    ABSTRACT: Cutamesine dihydrochloride is an agonist of sigma-1 receptor, which is a ligand-operated receptor chaperone at the mitochondrion-associated endoplasmic reticulum (ER) membrane. ER stress plays a pivotal role in light irradiation-induced retinal damage. In the present study, we examined whether cutamesine is effective against experimental degenerative retinal damages in vitro and in vivo. The effects of cutamesine against white light-induced retinal photoreceptor damage were evaluated in vitro by measuring cell death. The expression of sigma-1 receptor after the light exposure was examined by immunoblot analysis. The disruption of the mitochondrial membrane potential and caspase-3/7 activation after excessive light exposure were also examined. In addition, retinal damage in mice induced by irradiation to white light was evaluated using histological staining and electroretinography. Cutamesine reduced the cell death rate induced by light exposure, and the protective effect was prevented by N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD-1047) dihydrobromide, a sigma-1 receptor antagonist. Sigma-1 receptor expression was decreased by light exposure, and cutamesine suppressed the decreased expression of sigma-1 receptor protein. Cutamesine also reduced the mitochondrial damage and reduced the elevated level of caspase 3/7 activity; this effect was attenuated by BD-1047. In in vivo studies, cutamesine suppressed the light-induced retinal dysfunction and thinning of the outer nuclear layer in the mouse retina. These findings indicate that cutamesine protects against retinal cell death in vitro and in vivo by the agonistic effect of sigma-1 receptor. Therefore, sigma-1 receptor may have a potential as a therapeutic target in retinal diseases mediated by photoreceptor degeneration. Copyright © 2015. Published by Elsevier Ltd.
    Experimental Eye Research 01/2015; · 3.02 Impact Factor
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    ABSTRACT: Excessive ferrous promoted light-induced cone cell death via hydroxyl radical.•Intracellular ferrous ion is changed on light exposed photoreceptor cell.•2,2′-bipyridyl might be a promising new therapeutic strategy for AMD.
    Experimental Eye Research 12/2014; 129. · 3.02 Impact Factor
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    ABSTRACT: Glycoprotein nonmelanoma protein B (GPNMB, alias osteoactivin), a type I transmembrane glycoprotein, is cleaved by extracellular proteases, resulting in release of an extracellular fragment (ECF). GPNMB is widely expressed by neurons within the CNS, including the hippocampus; however, its function in the brain remains unknown. Here, we investigated the role of GPNMB in memory and learning by using transgenic (Tg) mice overexpressing GPNMB (Tg mice on a BDF-1 background) and ECF-treated mice. In the hippocampus of both wild-type and Tg mice, GPNMB was highly expressed in neurons and astrocytes. Tg mice exhibited memory improvements in two types of learning tasks but were impaired in a passive-avoidance test. In Tg mice, the hippocampus displayed increased levels of the α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunit GluA1. Intracerebroventricular administration of ECF (50 ng) to Institute of Cancer Research (ICR) mice also improved memory in a passive-avoidance test and increased hippocampal GluA1 levels 24 h after treatment. In Tg mice and ECF (0.25 μg/mL)-treated hippocampal slices, long-term potentiation (LTP) was promoted. These findings suggest that GPNMB may be a novel target for research on higher-order brain functions.This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 12/2014; · 4.24 Impact Factor
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    ABSTRACT: Diacylglycerol kinase (DGK) is an enzyme that converts diacylglycerol to phosphatidic acid. Previously, we reported that DGKβ knockout (KO) mice showed mania-like behaviors such as hyperactivity, reduced anxiety, and cognitive impairment. Furthermore, lithium ameliorated the hyperactivity and reduced anxiety of DGKβ KO mice. In this study, we investigated the effects of the clinically active antimanic drugs valproate and olanzapine on the abnormal behaviors of DGKβ KO mice. Valproate (100mg/kg/day) and olanzapine (1mg/kg/day) were administered intraperitoneally. Following drugs treatments, behavioral tests were performed to investigate locomotor activity, anxiety levels, and cognitive function of the mice. A single treatment of valproate and olanzapine did not ameliorate the hyperactivity or abnormal anxiety level of DGKβ KO mice. Chronic treatment with valproate and olanzapine significantly decreased locomotor activity and abnormal anxiety levels of DGKβ KO mice. Additionally, valproate also ameliorated cognitive function of DGKβ KO mice. These results suggest that the abnormal behaviors of DGKβ KO mice is responsive to antimanic drugs, and that DGKβ KO mice are useful as an animal model of mania. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
    Pharmacological reports: PR 10/2014; 67(2). · 2.17 Impact Factor
  • Tomomi Masuda, Masamitsu Shimazawa, Hideaki Hara
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    ABSTRACT: Kallikrein is a serine protease involved in the kallikrein-kinnin system. Kallikrein is derived from the blood plasma or tissue, and is correlated with aggravation and improvement in eye diseases, such as, glaucoma, diabetic retinopathy, age-related macular degeneration, and ocular ischemic syndrome. The plasma kallikrein stimulates retinal vascular permeability and intraocular hemorrhage. On the other hand, we had reported that the tissue kallikrein normalizes retinal vasopermeability and inhibited retinal neovascularization and retinal ischemic injury. The protective mechanisms of the tissue-derived kallikrein include the cleavage of vascular endothelial growth factor (VEGF), which suggests that the tissue kallikrein could be potentially-effective against any disease involving the VEGF production. Copyright © 2014 Elsevier B.V. All rights reserved.
    European Journal of Pharmacology 10/2014; · 2.68 Impact Factor
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    ABSTRACT: Purpose:The incidence of blindness is increasing, in part, because of the abnormal ocular neovascularization. Anti-VEGF therapies have yielded impressive results; however, they are not a cure for blindness. Recently, metallothioneins (MTs) 1 and 2 have been implicated in the process of angiogenesis. Therefore, we investigated whether MT 1 and MT 2 were also involved in ocular neovascularization. Methods:The concentrations of MT 1 and MT 2 (hereafter MT-1/2) were observed by ELISA. We examined the role of MT-1/2 in ocular neovascularization by using both an oxygen-induced retinopathy (OIR) model and a laser-induced choroidal neovascularization (CNV) model. We investigated the localization of MT-1/2 in retina. Furthermore we investigated the expression of hypoxia-inducible factor (HIF)-1α and VEGF in OIR. In vitro, we investigated the degradation of HIF-1α. Results:The MT-1/2 were significantly elevated in proliferative diabetic retinopathy patients. Ocular neovascularization, which was induced in both the OIR model and the CNV model, was decreased in MT-1/2 knockout (KO) mice. We confirmed that although MT-1/2 was expressed throughout the murine retina, its expression levels were highest in the endothelial cells. Further, OIR enhanced MT-1/2 expression in the retina. Interestingly, in the OIR model, both HIF-1α and VEGF levels were significantly decreased in the retina of MT-1/2 KO mice. In addition, we found that knockdown of MT-1/2 accelerated ubiquitination of HIF-1α. Conclusions:These results indicate that MTs 1 and 2 are involved in retinal and choroidal neovascularization, and that MT-1/2 might be a new therapeutic target in diseases in which ocular angiogenesis is implicated.
    Investigative Ophthalmology &amp Visual Science 09/2014; · 3.66 Impact Factor
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    ABSTRACT: Zonisamide has been reported to have protective effects on epilepsy and Parkinson's disease and to work via various mechanisms of action, such as inhibition of monoamine oxidase-B and enhancement of tyrosine hydroxylase. Recently, it has been suggested that zonisamide itself shows neuroprotective actions. Therefore, in the present study we investigated the neuroprotective effects of zonisamide against endoplasmic reticulum (ER) stress. We used human neuroblastoma (SH-SY5Y) cells and investigated the protective effects of zonisamide against tunicamycin- and thapsigargin-induced neuronal cell death. In addition, we investigated the effect of zonisamide against 1-methyl-4-phenylpyridinium (MPP(+))-induced cell death and the mechanism of protection against ER stress. In vivo, we investigated the effect of zonisamide (20mg/kg, p.o.) in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson's disease. Zonisamide not only suppressed MPP(+)-induced cell death, but also inhibited ER stress-induced cell death and suppressed the expression of ER stress-related factors such as C/EBO homologous protein (CHOP) in vivo. Furthermore, zonisamide inhibited the activation of caspase-3 in vitro. These results suggest that zonisamide affected ER stress via caspase-3. We think that ER stress, particularly the mechanism via caspase-3, is involved in part of the neuroprotective effect of zonisamide against the experimental models of Parkinson's disease.
    European Journal of Pharmacology 09/2014; · 2.68 Impact Factor
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    ABSTRACT: Intracranial hemorrhage (ICH) remains a devastating disease, and heavy alcohol consumption is an underlying risk factor. The aim of this study was to study the mechanism of ethanol-induced endothelial cell damage and to evaluate the protective effect of cilostazol against ethanol-induced damage. We first evaluated transendothelial electrical resistance (TEER) and cell viability of human brain microvascular endothelial cells at the ethanol concentration shown to cause mild-to-moderate intoxication in the clinic. We also assessed the permeability of fluorescein isothiocyanate (FITC)-dextran and the change in tight junction proteins. Furthermore, we studied the potential of cilostazol to protect endothelial cells from ethanol-induced dysfunction. Concentration- and time-dependent effects of ethanol on cell viability and TEER showed that TEER was reduced at each concentration of ethanol tested during exposures of >2 h, but cell viability was not changed. Permeability of FITC-dextran was enhanced, and both tight junction and adherens junction proteins were reduced by 3-h ethanol treatment. The permeability of FITC-dextran was ameliorated by administration of cilostazol in a concentration-dependent manner. The protective effect of cilostazol was obstructed by administration of a protein kinase A inhibitor. Using gelatin zymography, we found that the protective effect of cilostazol was by reducing matrix metalloproteinase 9 (MMP-9) activation, but it had no effect on reactive oxygen spices (ROS). Our results indicate that cilostazol protected endothelial cells against ethanol-induced endothelial dysfunction by inhibiting ROS-mediated activation of MMP-9.
    Current Neurovascular Research 09/2014; · 2.74 Impact Factor
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    ABSTRACT: Diabetes is a crucial risk factor for stroke and is associated with increased frequency and poor prognosis. Although endothelial dysfunction is a known contributor of stroke, the underlying mechanisms have not been elucidated. The aim of this study was to elucidate the mechanism by which chronic hyperglycemia may contribute to the worsened prognosis following stroke, especially focusing on mitochondrial alterations. We examined the effect of hyperglycemia on hemorrhagic transformation at 24 hours after middle cerebral artery occlusion (MCAO) in streptozotocin (STZ) -induced diabetic mice. We also examined the effects of high-glucose exposure for 6 days on cell death, mitochondrial functions and morphology in human brain microvascular endothelial cells (HBMVECs) or human endothelial cells derived from induced pluripotent stem cells (iCell endothelial cells). Hyperglycemia aggravated hemorrhagic transformation, but not infarction following stroke. High-glucose exposure increased apoptosis, capase-3 activity, and release of apoptosis inducing factor (AIF) and cytochrome c in HBMVECs as well as affected mitochondrial functions (decreased cell proliferation, ATP contents, mitochondrial membrane potential, and increased matrix metalloproteinase (MMP)-9 activity, but not reactive oxygen species production). Furthermore, morphological aberration of mitochondria was observed in diabetic cells (a great deal of fragmentation, vacuolation, and cristae disruption). A similar phenomena were seen also in iCell endothelial cells. In conclusion, chronic hyperglycemia aggravated hemorrhagic transformation after stroke through mitochondrial dysfunction and morphological alteration, partially via MMP-9 activation, leading to caspase-dependent apoptosis of endothelial cells of diabetic mice. Mitochondria-targeting therapy may be a clinically innovative therapeutic strategy for diabetic complications in the future.
    PLoS ONE 08/2014; 9(8):e103818. · 3.53 Impact Factor
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    ABSTRACT: Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein reported to have neuroprotective effects in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We investigated whether GPNMB is also neuroprotective against brain ischemia reperfusion injury. Focal ischemia/reperfusion injury was induced via filament middle cerebral artery occlusion for 2 h, followed by reperfusion upon withdrawal of the filament. We assessed the neuroprotective effects of GPNMB using transgenic (Tg) mice which over expressing GPNMB or recombinant GPNMB which has the sequence of human extracellular GPNMB. The results showed that GPNMB was up-regulated after ischemia reperfusion injury, and that genomic over-expression of GPNMB significantly ameliorated infarct volume. Next, we investigated the protective mechanisms of GPNMB via western blotting and immunohistochemistry. Phosphorylation of Extracellular Signal-regulated Kinase 1 and 2 (ERK1/2), and protein kinase B (Akt), were increased in the GPNMB Tg group according to western blotting data. Immunohistochemistry analysis showed that GPNMB was expressed not only in neurons, but also in astrocytes, produced labelling patterns similar to that in human brain ischemia. Furthermore, recombinant GPNMB also decreased the infarction volume. These results indicate that GPNMB protected neurons against ischemia reperfusion injury, and phosphor-Akt and phosphor-ERK might be a part of the protective mechanisms, and that the neuroprotective effect of GPNMB was seemingly induced by the extracellular sequence of GPNMB. In conclusion, these findings indicate that GPNMB has neuroprotective effects against ischemia reperfusion injury, via phosphorylation of ERK1/2 and Akt, suggesting that GPNMB may be a therapeutic target for ischemia reperfusion injuries.
    Neuroscience 07/2014; · 3.33 Impact Factor
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    ABSTRACT: Our eyes are increasingly exposed to light from the emitting diode (LED) light of video display terminals (VDT) which contain much blue light. VDTs are equipped with televisions, personal computers, and smart phones. The present study aims to clarify the mechanism underlying blue LED light-induced photoreceptor cell damage. Murine cone photoreceptor-derived cells (661 W) were exposed to blue, white, or green LED light (0.38 mW/cm(2)). In the present study, blue LED light increased reactive oxygen species (ROS) production, altered the protein expression level, induced the aggregation of short-wavelength opsins (S-opsin), resulting in severe cell damage. While, blue LED light damaged the primary retinal cells and the damage was photoreceptor specific. N-Acetylcysteine (NAC), an antioxidant, protected against the cellular damage induced by blue LED light. Overall, the LED light induced cell damage was wavelength-, but not energy-dependent and may cause more severe retinal photoreceptor cell damage than the other LED light.
    Scientific Reports 06/2014; 4:5223. · 5.08 Impact Factor
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    ABSTRACT: Ocular ischemic syndrome is likely stem from retinal ischemia, and which causes visual disorder. The pathological mechanism of ocular ischemic syndrome is still unknown, therefore the optimal treatment for ocular ischemic syndrome remains to be established. Then, this study aimed to evaluate the effects of tissue-derived kallidinogenase in retinal ischemia protection in mice. In the present study, the effects of tissue-derived kallidinogenase (1 or 10μg/kg, i.v.) on ischemia/reperfusion-induced retinal damage in mice were examined by histological, electrophysiological, and permeability analyses. In addition, we assessed phosphorylation of endothelial nitric oxide synthase (eNOS) and nuclear factor-kappa B (NF-κB), which is closely-involved in ischemic injury and permeability. Moreover, the neuroprotective effect of kallidinogenase in an in vitro model of ischemia induced by oxygen-glucose deprivation or hypoxia was examined. The results indicated that kallidinogenase significantly prevented the decrease in ganglion cell number induced by ischemia/reperfusion. Electroretinogram measurements showed that kallidinogenase significantly prevented the ischemia/reperfusion-induced reductions in a- and b-wave amplitudes seen 5 days after ischemia/reperfusion. Moreover, kallidinogenase significantly inhibited the permeability increase induced by ischemia/reperfusion. Similar to the results in vivo, kallidinogenase significantly inhibited the retinal ganglion cell death induced by oxygen-glucose deprivation. Also, kallidinogenase significantly suppressed the hypoxia-induced increase in permeability. However, these effects observed in vitro disappeared when an eNOS inhibitor was used concurrently. These findings suggest that kallidinogenase may prevent ischemia/reperfusion-induced retinal damage, might be through eNOS activation.
    European Journal of Pharmacology 05/2014; · 2.68 Impact Factor
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    ABSTRACT: Oxidative stress plays a critical role in mediating tissue injury and neuron death during ischemia-reperfusion injury (IRI). The Keap1-Nrf2 defense pathway serves as a master regulator of endogenous antioxidant defense, and Nrf2 has been attracting attention as a target for the treatment of IRI. In the present study, we evaluated Nrf2 expression in IRI using OKD (Keap1-dependent Oxidative stress Detector) mice and investigated the neuroprotective ability of an Nrf2 activator. We demonstrated temporal changes of Nrf2 expression in the same mice with luciferase assays and the Nrf2 activity time course using western blotting. We also visualized Nrf2 expression in the ischemic penumbra and investigated Nrf2 expression in mice and humans using immunohistochemistry. Endogenous Nrf2 up-regulation was not detected early in IRI, but expression peaked 24h after ischemia. Nrf2 expression was mainly detected in the penumbra, and it was found in neurons and astrocytes in both mice and humans. Intravenous administration of the Nrf2 activator bardoxolone methyl (BARD) resulted in earlier up-regulation of Nrf2 and heme oxygenase-1. Furthermore, BARD decreased infarction volume and improved neurological symptoms after IRI. These findings indicate that earlier Nrf2 activation protects neurons, possibly via effects on astrocytes.
    Free Radical Biology and Medicine 04/2014; · 5.27 Impact Factor
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    ABSTRACT: Blue light is a high-energy or short-wavelength visible light, which induces retinal diseases such as age-related macular degeneration and retinitis pigmentosa. Bilberry (Vaccinium myrtillus L.) and lingonberry (Vaccinium vitis-idaea) contain high amounts of polyphenols (anthocyanins, resveratrol, and proanthocyanidins) and thus confer health benefits. This study aimed to determine the protective effects and mechanism of action of bilberry extract (B-ext) and lingonberry extract (L-ext) and their active components against blue light-emitting diode (LED) light-induced retinal photoreceptor cell damage. Cultured murine photoreceptor (661 W) cells were exposed to blue LED light following treatment with B-ext, L-ext, or their constituents (cyanidin, delphinidin, malvidin, trans-resveratrol, and procyanidin B2). 661 W cell viability was assessed using a tetrazolium salt (WST-8) assay and Hoechst 33342 nuclear staining, and intracellular reactive oxygen species (ROS) production was determined using CM-H2DCFDA after blue LED light exposure. Activation of p38 mitogen-activated protein kinase (p38 MAPK), nuclear factor-kappa B (NF-kappaB), and LC3, an ubiquitin-like protein that is necessary for the formation of autophagosomes, were analyzed using Western blotting. Caspase-3/7 activation caused by blue LED light exposure in 661 W cells was determined using a caspase-3/7 assay kit. B-ext, L-ext, NAC, and their active components improved the viability of 661 W cells and inhibited the generation of intracellular ROS induced by blue LED light irradiation. Furthermore, B-ext and L-ext inhibited the activation of p38 MAPK and NF-kappaB induced by blue LED light exposure. Finally, B-ext, L-ext, and NAC inhibited caspase-3/7 activation and autophagy. These findings suggest that B-ext and L-ext containing high amounts of polyphenols exert protective effects against blue LED light-induced retinal photoreceptor cell damage mainly through inhibition of ROS production and activation of pro-apoptotic proteins.
    BMC Complementary and Alternative Medicine 04/2014; 14(1):120. · 1.88 Impact Factor
    This article is viewable in ResearchGate's enriched format
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    ABSTRACT: Although dry age-related macular degeneration (AMD) is one of the major causes of blindness, no effective therapies are developed. In this study, we investigated the effects of SUN N8075, a radical scavenger with neuroprotective properties, against light-induced retinal damage used as the model of dry AMD in mice. After dark adaption for 24 h, we exposed the mice at 8000 lx for 3 h. We evaluated the retinal damage by recording the electroretinagram (ERG) and measuring the thickness of outer nuclear layer (ONL) at 5 d after the light exposure. Retinal apoptotic cells were also detected by terminal deoxynucleotidyl transeferase mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) staining, and the expression of 8-hydroxy-2-deoxyguanosine (8-OHdG) as an index for oxidative stress at 48 h after exposure to light. In ERG measurement, the intraperitoneal administration of SUN N8075 at 30 mg/kg improved the retinal dysfunction induced by the excess light exposure. In the histological evaluation, SUN N8075 inhibited the reduction of ONL thickness. In addition, SUN N8075 decreased in both numbers of TUNEL- and 8-OHdG-positive cells in ONL. These findings suggest that the systemic administration of SUN N8075 has protective effects on excess light-induced photoreceptor degeneration, via inhibition of oxidative stress.
    Biological & Pharmaceutical Bulletin 01/2014; 37(3):424-30. · 1.85 Impact Factor
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    ABSTRACT: Background. We investigated the effects of Brazilian green propolis and its constituents against white light- or UVA-induced cell damage in mouse retinal cone-cell line 661W or human skin-derived fibroblast cells (NB1-RGB). Methods. Cell damage was induced by 3,000lx white light for 24 h or 4/10 J/cm(2) UVA exposure. Cell viability was assessed by Hoechst33342 and propidium iodide staining or by tetrazolium salt (WST-8) cell viability assay. The radical scavenging activity of propolis induced by UVA irradiation in NB1-RGB cells was measured using a reactive-oxygen-species- (ROS-) sensitive probe CM-H2DCFDA. Moreover, the effects of propolis on the UVA-induced activation of p38 and extracellular signal-regulated kinase (ERK) were examined by immunoblotting. Results. Treatment with propolis and two dicaffeoylquinic acids significantly inhibited the decrease in cell viability induced by white light in 661W. Propolis and its constituents inhibited the decrease in cell viability induced by UVA in NB1-RGB. Moreover, propolis suppressed the intracellular ROS production by UVA irradiation. Propolis also inhibited the levels of phosphorylated-p38 and ERK by UVA irradiation. Conclusion. Brazilian green propolis may become a major therapeutic candidate for the treatment of AMD and skin damage induced by UV irradiation.
    Evidence-based Complementary and Alternative Medicine 12/2013; 2013:238279. · 2.18 Impact Factor
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Recently, it has been reported that a mutation in the sigma-1 receptor causes juvenile ALS. Therefore, the function of the sigma-1 receptor may be important in the pathology of ALS. In the present study, we investigated the effect of SA4503, a sigma-1 receptor agonist, against in in vitro and in vivo ALS models. We first investigated whether SA4503, a sigma-1 receptor agonist, prevented superoxide dismutase 1 (SOD1G93A) - and serum free-induced cell death of mice motor neuron cells (NSC34) in in vitro model of an ALS. At concentrations of 1 to 10μM, SA4503 reduced SOD1G93A-induced cell death in a concentration-dependent manner, and BD1047, a sigma-1 receptor antagonist, inhibited the protective effect of SA4503. Next, we investigated whether SA4503 affected the phosphorylation levels of Akt (Ser 473) and extracellular signal-regulated kinase (ERK1/2) and the expression of the sigma-1 receptor. SA4503 promoted the phosphorylation of Akt (Ser 473) and ERK1/2 in a time-dependent manner, but SA4503 did not affect the expression of the sigma-1 receptor. These results suggest that the protective effect of SA4503 might be involved in promoting the phosphorylation of Akt and ERK1/2. We then investigated whether SA4503 suppressed the progression of ALS in an SOD1G93A ALS mouse model. SA4503 did not affect the onset time of ALS. However, it significantly extended the survival time in the SOD1G93A mice compared with a vehicle-treated group. These findings indicate that SA4503 is effective in suppressing motor neuron degeneration and symptom progression in ALS.
    Neuroscience Letters 12/2013; · 2.06 Impact Factor
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    ABSTRACT: Placental growth factor (PlGF) is a member of the vascular endothelial growth factor family. Although it has been reported that PlGF protects against neuronal damage in the brain, little is known about the effects of PlGF in the retina. Therefore, we investigated the effects of PlGF on retinal neuronal cells. To evaluate the effects of PlGF against L-buthionine-(S,R)-sulfoximine (BSO)/glutamate cell death, oxygen-glucose deprivation (OGD)-induced cell death, and light-induced cell death, RGC-5 and 661W cells were used. We evaluated the mechanism responsible for the protective effects of PlGF against retinal neuronal cell death by performing the examinations with U1026, which is a mitogen-activated protein kinase (MEK) inhibitor, and LY294002, which is a phosphoinositide 3-kinase (PI3K) inhibitor. In addition, we measured caspase-3/7 activity in RGC-5 cells and 661W cells. PlGF protected against RGC-5 cell death induced by BSO/glutamate and OGD and against 661W cell death induced by light irradiation. Moreover, an anti-PlGF antibody negated these protective effects. The protective effects of PlGF against OGD-induced RGC-5 cell death and light-induced 661W cell death were suppressed by using an anti-PlGF antibody, U1026, and LY294002. Treatment with PlGF suppressed caspase-3/7 activity in both cell lines. We demonstrated for the first time that PlGF exerts a protective effect by inhibiting the activation of caspase-3/7 through the MEK and PI3K pathway in retinal neuronal cells. These data suggest that PlGF may be an important protective factor in the retina. © 2013 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 11/2013; · 2.73 Impact Factor
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    ABSTRACT: Adipose tissue stromal vascular fraction contains mesenchymal stem cells, which show protective effects when administered to damaged tissues, mainly through secreted trophic factors. We examined the protective effects of adipose-derived stem cells (ASCs) and ASC-conditioned medium (ASC-CM) against retinal damage and identified the neuroprotective factors in ASC-CM. ASCs and mature adipocytes were isolated from mouse subcutaneous tissue. ASCs were injected intravitreally in a mouse model of light-induced retinal damage, and ASC injection recovered retinal function as measured by electroretinogram and inhibited outer nuclear layer, thinning, without engraftment of ASCs. ASC-CM and mature adipocyte-conditioned medium were collected after 72 hours of culture. In vitro, H2O2- and light-induced cell death was reduced in a photoreceptor cell line with ASC-CM but not with mature adipocyte-conditioned medium. In vivo, light-induced photoreceptor damage was evaluated by measurement of outer nuclear layer thickness at 5 days after light exposure and by electroretinogram recording. ASC-CM significantly inhibited photoreceptor degeneration and retinal dysfunction after light exposure. Progranulin was identified as a major secreted protein of ASCs that showed protective effects against retinal damage in vitro and in vivo. Furthermore, progranulin phosphorylated extracellular signal-regulated kinase, cAMP response element binding protein, and hepatocyte growth factor receptor, and protein kinase C signaling pathways were involved in the protective effects of progranulin. These findings suggest that ASC-CM and progranulin have neuroprotective effects in the light-induced retinal-damage model. Progranulin may be a potential target for the treatment of the degenerative diseases of the retina.
    STEM CELLS TRANSLATIONAL MEDICINE 11/2013; · 3.60 Impact Factor

Publication Stats

2k Citations
619.07 Total Impact Points

Institutions

  • 2004–2015
    • Gifu Pharmaceutical University
      • • Department of Biofunctional Evaluation
      • • Department of Biofunctional Molecules
      Gihu, Gifu, Japan
  • 2010
    • Kobe University
      • Laboratory of Molecular Pharmacology
      Kōbe, Hyōgo, Japan
    • Gifu University
      • Department of Ophthalmology
      Gihu, Gifu, Japan
  • 2008
    • Kyoto University
      • Primate Research Institute
      Kyoto, Kyoto-fu, Japan
  • 2004–2006
    • Santen Pharmaceutical Co., Ltd.
      Ōsaka, Ōsaka, Japan
  • 1996–2005
    • Hamamatsu University School of Medicine
      • Division of Pharmacology
      Hamamatu, Shizuoka, Japan
  • 1999
    • Osaka Medical College
      • Department of Ophthalmology
      Takatuki, Ōsaka, Japan