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Judith Thomas Tayra,
Masahiro Kameda,
Takao Yasuhara,
Takashi Agari,
Tomohito Kadota,
Feifei Wang, Yoichiro Kikuchi,
Hanbai Liang,
Aiko Shinko,
Takaaki Wakamori,
Brigitta Vcelar,
Robert Weik,
Isao Date
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ABSTRACT: Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons. Thus the development of therapeutic neuroprotection and neurorescue strategies to mitigate disease progression is important. In this study we evaluated the neuroprotective/rescue effects of erythropoietin Fc fusion protein (EPO-Fc) and carbamylated erythropoietin Fc fusion protein (CEPO-Fc) in a rat model of Parkinson's disease. Adult female Sprague-Dawley rats received intraperitoneal injection of EPO-Fc, CEPO-Fc or PBS. Behavioral evaluations consisted of rota-rod, cylinder and amphetamine-induced rotation tests. In the neuroprotection experiment, the CEPO-Fc group demonstrated significant improvement compared with the EPO-Fc group on the amphetamine-induced rotation test throughout the four-week follow-up period. Histologically, significantly more tyrosine hydroxylase (TH)-positive neurons were recognized in the substantia nigra (SN) pars compacta in the CEPO-Fc group than in the PBS and EPO-Fc groups. In the neurorescue experiment, rats receiving CEPO-Fc showed significantly better behavioural scores than those receiving PBS. The histological data concerning striatum also showed that the CEPO-Fc group had significantly better preservation of TH-positive fibers compared to the PBS and EPO-Fc groups. Importantly, there were no increases in hematocrit or hemoglobin levels in the CEPO-Fc group in either the neuroprotection or the neurorescue experiments. In conclusion, the newly developed CEPO-Fc might confer neuroprotective and neurorescue benefits in a rat model of Parkinson's disease without the side effects associated with polycythemia. CEPO-Fc might be a therapeutic tool for patients with Parkinson's disease.
Brain research 02/2013; · 2.46 Impact Factor
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Yoichiro Kikuchi,
Takao Yasuhara,
Takashi Agari,
Akihiko Kondo,
Satoshi Kuramoto,
Masahiro Kameda,
Tomohito Kadota,
Tanefumi Baba,
Naoki Tajiri,
Feifei Wang,
Judith T. Tayra,
Hanbai Liang,
Yasuyuki Miyoshi,
Cesario V. Borlongan,
Isao Date
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ABSTRACT: Increased oxidative stress contributes to pathogenesis of Parkinson's disease (PD). 8-hydroxy-2'-deoxyguanosine (8-OHdG) is the oxidation product most frequently measured as an indicator of oxidative DNA damage. Several studies have shown increased 8-OHdG in PD patients. There are few basic laboratory data examining 8-OHdG levels in animal models of PD. In this study, we utilized hemiparkinsonian model of rats induced by intrastriatal injection of 6-hydroxydopamine (6-OHDA). The urinary 8-OHdG level was measured in relation to behavioral and pathological deficits arising from 6-OHDA-induced neurotoxic effects on the nigrostriatal dopaminergic pathway. All rats were subjected to a series of behavioral tests for 42 days after 6-OHDA injection. We collected urine samples with subsequent measurement of 8-OHdG level using ELISA kits. For immunohistochemical evaluation, tyrosine hydroxylase (TH) staining was performed. Significant increments in urinary 8-OHdG level were observed continuously from day 7 until day 35 compared to control group, which showed a trend of elevation as early as day 3. Such elevated urinary 8-OHdG level significantly correlated with all of the behavioral deficits measured here, suggesting that urinary 8-OHdG level provides a good index of severity of parkinsonism. Urinary 8-OHdG level also had a significant positive correlation with the survival rate of dopaminergic fibers or neurons, advancing the concept that oxidative stress during the early phase of 6-OHDA neurotoxicity may correspond to disease progression closely approximating neuronal degeneration in the nigrostriatal dopaminergic system. The present results demonstrate that alterations in urinary 8-OHdG level closely approximate onset and disease progression in PD. J. Cell. Physiol. 226: 1390–1398, 2011. © 2010 Wiley-Liss, Inc.
Journal of Cellular Physiology 02/2011; 226(5):1390 - 1398. · 3.87 Impact Factor
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Satoshi Kuramoto,
Takao Yasuhara,
Takashi Agari,
Akihiko Kondo,
Meng Jing, Yoichiro Kikuchi,
Aiko Shinko,
Takaaki Wakamori,
Masahiro Kameda,
Feifei Wang,
Kyohei Kin,
Satoru Edahiro,
Yasuyuki Miyoshi,
Isao Date
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ABSTRACT: Brain-derived neurotrophic factor (BDNF) is a well neurotrophic factor with neuroprotective potentials for various diseases in the central nervous system. However several previous studies demonstrated that BDNF might deteriorate symptoms for epilepsy model of animals by progression of abnormal neurogenesis. We hypothesized that continuous administration of BDNF at low dose might be more effective for epilepsy model of animals because high dose of BDNF was used in many studies. BDNF-secreting cells were genetically made and encapsulated for transplantation. Rats receiving BDNF capsule showed significant amelioration of seizure stage and reduction of the number of abnormal spikes at 7 days after kainic acid administration, compared to those of control group. The number of BrdU and BrdU/doublecortin positive cells in the hippocampus of BDNF group significantly increased, compared to that of control group. NeuN positive cells in the CA1 and CA3 of BDNF group were significantly preserved, compared to control group. In conclusion, low dose administration using encapsulated BDNF-secreting cells exerted neuroprotective effects with enhanced neurogenesis on epilepsy model of rats. These results might suggest the importance of the dose and administrative way of this neurotrophic factor to the epilepsy model of animals.
Brain research 10/2010; 1368:281-9. · 2.46 Impact Factor
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ABSTRACT: Progressive multifocal leukoencephalopathy (PML) is caused by opportunistic infection by JC virus and presents with progressive demyelinating lesions in the central nervous system. A 59-year-old man with a history of alcoholic liver dysfunction presented with progressive weakness of his left leg over a period of one month. MRI showed multiple white matter lesions that were of low intensity on the T1 image and high intensity on the T2 image, heterogeneously high intensity on the diffusion image, and were not enhanced with contrast media. The patient underwent open biopsy of the right parietal lesion. The histological findings were the demyelination and the enlargement of nuclei of oligodendrocytes. Electron microscopic examination showed numerous viral particles in the nuclei of the oligodendrocytes. Infection by JC virus in the central nervous system was diagnosed with the polymerase chain reaction (PCR) products sampled from the cerebrospinal fluid. The incidence of PML has significantly increased in immunosuppressive patients, such as AIDS (acquired immunodeficiency syndrome). We presented the first case of PML in an immune-compromised state with alcoholic liver dysfunction.
No shinkei geka. Neurological surgery 06/2010; 38(6):569-74. · 0.13 Impact Factor
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Feifei Wang,
Takao Yasuhara,
Tetsuro Shingo,
Masahiro Kameda,
Naoki Tajiri,
Wen Yuan,
Akihiko Kondo,
Tomohito Kadota,
Tanefumi Baba,
Judith Tayra, Yoichiro Kikuchi,
Yasuyuki Miyoshi,
Isao Date
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ABSTRACT: Abstract
Background
Mesenchymal stem cells (MSCs) are pluripotent stem cells derived from bone marrow with secretory functions of various neurotrophic factors. Stromal cell-derived factor-1α (SDF-1α) is also reported as one of chemokines released from MSCs. In this research, the therapeutic effects of MSCs through SDF-1α were explored. 6-hydroxydopamine (6-OHDA, 20 μg) was injected into the right striatum of female SD rats with subsequent administration of GFP-labeled MSCs, fibroblasts, (i.v., 1 × 10<sup>7 </sup>cells, respectively) or PBS at 2 hours after 6-OHDA injection. All rats were evaluated behaviorally with cylinder test and amphetamine-induced rotation test for 1 month with consequent euthanasia for immunohistochemical evaluations. Additionally, to explore the underlying mechanisms, neuroprotective effects of SDF-1α were explored using 6-OHDA-exposed PC12 cells by using dopamine (DA) assay and TdT-mediated dUTP-biotin nick-end labeling (TUNEL) staining.
Results
Rats receiving MSC transplantation significantly ameliorated behaviorally both in cylinder test and amphetamine-induced rotation test compared with the control groups. Correspondingly, rats with MSCs displayed significant preservation in the density of tyrosine hydroxylase (TH)-positive fibers in the striatum and the number of TH-positive neurons in the substantia nigra pars compacta (SNc) compared to that of control rats. In the in vitro study, SDF-1α treatment increased DA release and suppressed cell death induced by 6-OHDA administration compared with the control groups.
Conclusions
Consequently, MSC transplantation might exert neuroprotection on 6-OHDA-exposed dopaminergic neurons at least partly through anti-apoptotic effects of SDF-1α. The results demonstrate the potentials of intravenous MSC administration for clinical applications, although further explorations are required.
BMC Neuroscience. 01/2010;
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Feifei Wang,
Takao Yasuhara,
Tetsuro Shingo,
Masahiro Kameda,
Naoki Tajiri,
Wen Ji Yuan,
Akihiko Kondo,
Tomohito Kadota,
Tanefumi Baba,
Judith Thomas Tayra, Yoichiro Kikuchi,
Yasuyuki Miyoshi,
Isao Date
[show abstract]
[hide abstract]
ABSTRACT: Mesenchymal stem cells (MSCs) are pluripotent stem cells derived from bone marrow with secretory functions of various neurotrophic factors. Stromal cell-derived factor-1alpha (SDF-1alpha) is also reported as one of chemokines released from MSCs. In this research, the therapeutic effects of MSCs through SDF-1alpha were explored. 6-hydroxydopamine (6-OHDA, 20 microg) was injected into the right striatum of female SD rats with subsequent administration of GFP-labeled MSCs, fibroblasts, (i.v., 1 x 107 cells, respectively) or PBS at 2 hours after 6-OHDA injection. All rats were evaluated behaviorally with cylinder test and amphetamine-induced rotation test for 1 month with consequent euthanasia for immunohistochemical evaluations. Additionally, to explore the underlying mechanisms, neuroprotective effects of SDF-1alpha were explored using 6-OHDA-exposed PC12 cells by using dopamine (DA) assay and TdT-mediated dUTP-biotin nick-end labeling (TUNEL) staining.
Rats receiving MSC transplantation significantly ameliorated behaviorally both in cylinder test and amphetamine-induced rotation test compared with the control groups. Correspondingly, rats with MSCs displayed significant preservation in the density of tyrosine hydroxylase (TH)-positive fibers in the striatum and the number of TH-positive neurons in the substantia nigra pars compacta (SNc) compared to that of control rats. In the in vitro study, SDF-1alpha treatment increased DA release and suppressed cell death induced by 6-OHDA administration compared with the control groups.
Consequently, MSC transplantation might exert neuroprotection on 6-OHDA-exposed dopaminergic neurons at least partly through anti-apoptotic effects of SDF-1alpha. The results demonstrate the potentials of intravenous MSC administration for clinical applications, although further explorations are required.
BMC Neuroscience 01/2010; 11:52. · 3.04 Impact Factor
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Naoki Tajiri,
Takao Yasuhara,
Tetsuro Shingo,
Akihiko Kondo,
Wenji Yuan,
Tomohito Kadota,
Feifei Wang,
Tanefumi Baba,
Judith Thomas Tayra,
Takamasa Morimoto,
Meng Jing, Yoichiro Kikuchi,
Satoshi Kuramoto,
Takashi Agari,
Yasuyuki Miyoshi,
Hidemi Fujino,
Futoshi Obata,
Isao Takeda,
Tomohisa Furuta,
Isao Date
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ABSTRACT: Recent studies demonstrate that rehabilitation ameliorates physical and cognitive impairments of patients with stroke, spinal cord injury, and other neurological diseases and that rehabilitation also has potencies to modulate brain plasticity. Here we examined the effects of compulsive exercise on Parkinson's disease model of rats. Before 6-hydroxydopamine (6-OHDA, 20 microg) lesion into the right striatum of female SD rats, bromodeoxyuridine (BrdU) was injected to label the proliferating cells. Subsequently, at 24 h after the lesion, the rats were forced to run on the treadmill (5 days/week, 30 min/day, 11 m/min). As behavioral evaluations, cylinder test was performed at 1, 2, 3, and 4 weeks and amphetamine-induced rotational test was performed at 2 and 4 weeks with consequent euthanasia for immunohistochemical investigations. The exercise group showed better behavioral recovery in cylinder test and significant decrease in the number of amphetamine-induced rotations, compared to the non-exercise group. Correspondingly, significant preservation of tyrosine hydroxylase (TH)-positive fibers in the striatum and TH-positive neurons in the substantia nigra pars compacta (SNc) was demonstrated, compared to the non-exercise group. Additionally, the number of migrated BrdU- and Doublecortin-positive cells toward the lesioned striatum was increased in the exercise group. Furthermore, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor increased in the striatum by exercise. The results suggest that exercise exerts neuroprotective effects or enhances the neuronal differentiation in Parkinson's disease model of rats with subsequent improvement in deteriorated motor function.
Brain research 11/2009; 1310:200-7. · 2.46 Impact Factor
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Akihiko Kondo,
Tetsuro Shingo,
Takao Yasuhara,
Satoshi Kuramoto,
Masahiro Kameda, Yoichiro Kikuchi,
Toshihiro Matsui,
Yasuyuki Miyoshi,
Takashi Agari,
Cesario V Borlongan,
Isao Date
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[hide abstract]
ABSTRACT: We explored the effects of exogenous and endogenous erythropoietin (EPO) in a seizure model of rat. Adult male Fischer 344 rats received continuous intraventricular infusion of EPO dissolved in saline containing 1mg/ml of rat serum albumin, anti-EPO antibody, saline containing 1mg/ml of rat serum albumin or combined EPO and neuropeptide Y (NPY) Y2-receptor antagonist. Animals were behaviorally evaluated for seizure development over 6h after kainic acid injection followed by immunohistochemical assays. Mortality rate, seizure severity, apoptotic cell death and abnormal cell proliferation in the hippocampus of EPO-treated epileptic rats were significantly attenuated, compared to control rats. Anti-EPO antibody in non-EPO-treated animals worsened seizures and CA1 neuronal cell death, while NPY Y2-receptor antagonist cancelled the therapeutic effects of exogenous EPO. Both exogenous and endogenous EPO might modulate seizure severity and protect the hippocampal neurons in epileptic rats, via novel mechanistic pathways involving blockade of epileptogenic cell formation coupled with NPY receptor modulation in the hippocampus.
Brain research 09/2009; 1296:127-36. · 2.46 Impact Factor
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ABSTRACT: A 35-year-old male experienced a sudden onset of severe headache. A CT scan revealed subarachnoid hemorrhage. By cerebral angiography, he was diagnosed as having a ruptured right vertebral artery dissecting aneurysm (VADA). It was successfully treated by endovascular occlusion of the affected site, including the aneurysm and parent artery, by using detachable coils. A follow-up angiography obtained seven months after the first treatment revealed the recanalization of the right vertebral artery and dissected aneurysm in an antegrade fashion. A skull X-ray image was useful for detecting the change in appearance of the coils. The second embolization was successfully performed in the same manner. Based on this rare case, the authors emphasize that a careful angiographic analysis and complete internal trapping of the dissecting site are important in the treatment of the ruptured VADA.
No shinkei geka. Neurological surgery 09/2007; 35(8):813-9. · 0.13 Impact Factor
