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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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ABSTRACT: We report on a case of successful surgical treatment of drug-resistant epilepsy associated with a solitary lesion of periventricular nodular heterotopia (PNH). In the reported patient, intracranial ictal electroencephalography disclosed that seizures did not originate from the heterotopic nodules. However, the seizures were completely suppressed by lesionectomy of PNH alone. Epileptogenesis associated with PNH likely involves a very complex network between PNH and the surrounding cortex, and the disruption of this network may be an effective means of curing intractable, PNH-associated epilepsy.
Acta medica Okayama 12/2012; 66(6):487-92. · 0.84 Impact Factor
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ABSTRACT: We report on a male patient who experienced a previously unreported sequence of cryptogenic West syndrome in infancy and subsequent mesial temporal lobe epilepsy. His complex partial seizures were consistently characterised by motionless staring with brief right eye blinking. Scalp electroencephalography (EEG) showed bilateral temporal spikes which were dominant on the right side. Magnetic resonance imaging (MRI) revealed no organic brain lesion. Invasive EEG recording captured seizures with right hippocampal onset. The patient became seizure-free following right temporal lobectomy at 27 years, 8 months of age. Pathological examination of the resected specimen revealed corpora amylacea and gliosis in the temporal cortex but no clear findings of hippocampal sclerosis. It is suggested that an epileptogenic lesion causing MRI-negative mesial temporal lobe epilepsy may give rise to apparent cryptogenic West syndrome in infancy.
Epileptic disorders: international epilepsy journal with videotape 09/2012; 14(3):334-9. · 1.50 Impact Factor
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ABSTRACT: Patients with advanced Parkinson's disease (PD) often present with axial symptoms, including abnormal posture, postural instability, and gait disorder. Although spinal cord stimulation (SCS) is effective for pain, little is known about the effect of SCS on motor function in PD patients. The present study investigated the effect of SCS on posture and gait in 15 PD patients, 5 men and 10 women aged 63-79 years (mean 71.1 years), with low back pain and leg pain who received SCS. A visual analog scale (VAS) was used for pain evaluation pre- and postoperatively. The Unified Parkinson's Disease Rating Scale, Timed Up and Go tests, and Timed 10-Meter Walk tests were used to evaluate motor function and activities of daily living of patients. Preoperative mean VAS score was 8.9 (range 7.8-10), which showed significant postoperative improvement at 3 months to mean VAS score of 2.0 (range 0-3.3). The improvements in VAS scores persisted at 12 months after surgery with mean VAS score of 2.3 (range 0-4). Posture and postural stability motor subscores were improved at 3 months after SCS, and gait had significantly improved at 3 months and 1 year after surgery. Timed 10-Meter Walk tests also demonstrated that patient gait was significantly improved at 3 months and 12 months after surgery. Most advanced stage PD patients suffer considerable pain that causes abnormal posture and gait disturbance. SCS is expected to lead to both amelioration of pain and improvement of motor function in such patients.
Neurologia medico-chirurgica 01/2012; 52(7):470-4. · 0.61 Impact Factor
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ABSTRACT: Severe hemifacial spasm caused by compression by a tortuous vertebral artery (VA) often is encountered and is difficult to treat. We describe a patient with hemifacial spasm caused by compression of the facial nerve by a tortuous VA. A simple and effective transposition approach, a "double-stick tape" technique, to the offending artery using a fibrin tissue-adhesive collagen fleece product (TachoComb) is reported.
A 65-year-old woman presented with an 8-year history of right-sided facial spasms, including the orbicularis oculi and orbicularis oris muscles. MRI revealed a tortuous right VA indented into the pontomedullary junction. The right anterior inferior cerebellar artery (AICA) also contacted the proximal portion of the facial nerve. Surgical exploration with standard retrosigmoid craniotomy was performed. The offending VA was dissected away from the pontomedullary junction toward the cranial base. A small piece of TachoComb, with fibrin glue applied on the non-coated side of the fleece to make a "double-stick tape," was then placed on the ventral surface of the VA. Until the glue hardened, the VA was held away from the brainstem onto the dura of the petrous pyramid. After this procedure, AICA transposition was performed. The patient's symptoms were completely resolved immediately after surgery, and she remained asymptomatic at her 1 year follow-up visit.
The advantage of our "double-stick tape" technique is the simplicity of the procedure. The present technique is a feasible alternative for the treatment of hemifacial spasm caused by a tortuous VA.
Neurosurgery 03/2011; 68(2 Suppl Operative):377-82; discussion 382. · 2.79 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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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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ABSTRACT: High-frequency oscillations (HFOs) of up to 500Hz in EEG are considered to have close relation with ictogenesis. We had the unique opportunity to record a seizure in EEG with intracerebral macroelectrodes and a sampling frequency of 10kHz. Considering the notion that faster HFOs are likely more ictogenic, we investigated this ictal EEG data to find if even faster HFOs were present. HFOs were investigated in interictal spikes and seizure activity using time-frequency spectra: t values corresponding to frequencies from 100 to 1000Hz were obtained by comparison to the background and controlled by the false discovery rate (FDR). The seizure had a right hippocampal onset. HFOs up to 800Hz as well as HFOs below 500Hz built up in the hippocampal discharges more at the beginning of the seizure and during the preictal period than in the interictal period. These HFOs were visually confirmed in temporally expanded EEG traces. We demonstrated for the first time the existence of HFOs above 500Hz and up to 800Hz with intracerebral macroelectrodes in an epileptic patient; they occurred primarily in association with the seizure discharge. HFOs above 500Hz possibly reflect facilitation of ictogenic neuronal hypersynchronization.
Epilepsy research 11/2009; 88(2-3):139-44. · 2.48 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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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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No shinkei geka. Neurological surgery 07/2009; 37(6):597-607. · 0.13 Impact Factor
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ABSTRACT: We attempted to clarify functional interhemispheric connections of motor cortex (MC) by investigating cortico-cortical evoked potentials from human brains in vivo. Three patients with intractable epilepsy who underwent invasive EEG monitoring with subdural electrodes as presurgical evaluation were studied. Electric pulse stimuli were delivered in a bipolar fashion to two adjacent electrodes on and around MC. Cortico-cortical evoked potentials were recorded by averaging electrocorticograms from the contralateral hemisphere. An initial positive triphasic or an initial negative biphasic wave was recorded when the contralateral MCs were stimulated. When the non-MC electrodes were stimulated, no response was recorded. The latencies ranged from 9.2 to 23.8 ms for the initial positive peak, and 25.4 to 39.4 ms for the initial or the second negative peak. The cortico-cortical evoked potentials responses were maximal around the homonymous electrodes with the stimulated electrodes. Our results directly demonstrate the presence of the functional interhemispheric connections originating in MC. The interhemispheric transit time is indicated. The homotopic distribution of the responses indicates that motor coordination of the bilateral bodies is, at least partially, controlled within MC.
Journal of clinical neurophysiology: official publication of the American Electroencephalographic Society 12/2008; 25(6):351-6. · 1.47 Impact Factor
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ABSTRACT: The relationship between neurogenesis and epilepsy remains to be solved so far, although aberrant electric circuit recognized in epilepsy might be involved in neurogenesis. In this study, neurogenesis and the proliferation of astrocytes in the subgranular zone of the hippocampus were explored using unilateral amygdala-kindled rats with or without muscimol, a gamma-aminobutyric acid a (GABAa) agonist injection into the bilateral anterior thalamic nuclei (AN). Muscimol injection significantly ameliorated the behavioral scores of epilepsy without any significant alteration on the electroencephalography recorded at the stimulated basolateral amygdala, thus suggesting that muscimol injection might affect the secondary generalization, but not the initial discharge itself. The number of bromodeoxyuridine (BrdU), BrdU/doublecortin and BrdU/glial fibrillary acidic protein-positive cells in the subgranular zone of kindled animals increased markedly. Muscimol injection significantly suppressed neurogenesis, but not the proliferation of astrocyte, in the subgranular zone of the non-stimulated side, probably through the suppression of secondary generalization via AN. The results might indicate the underlying relationships between neurogenesis and epilepsy, that epileptic propagation in unilateral amygdala-kindled rats might go through AN into the contralateral side with subsequent neurogenesis, although further studies need to clarify the hypothesis.
Neurological Research 10/2008; 31(4):407-13. · 1.52 Impact Factor
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Wen Ji Yuan,
Takao Yasuhara,
Tetsuro Shingo,
Kenichiro Muraoka, Takashi Agari,
Masahiro Kameda,
Takashi Uozumi,
Naoki Tajiri,
Takamasa Morimoto,
Meng Jing,
Tanefumi Baba,
Feifei Wang,
Hanbai Leung,
Toshihiro Matsui,
Yasuyuki Miyoshi,
Isao Date
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ABSTRACT: Parkinson's disease (PD) is a neurological disorder characterized by the degeneration of nigrostriatal dopaminergic systems. Free radicals induced by oxidative stress are involved in the mechanisms of cell death in PD. This study clarifies the neuroprotective effects of edaravone (MCI-186, 3-methyl-1-phenyl-2-pyrazolin-5-one), which has already been used for the treatment of cerebral ischemia in Japan, on TH-positive dopaminergic neurons using PD model both in vitro and in vivo. 6-hydroxydopamine (6-OHDA), a neurotoxin for dopaminergic neurons, was added to cultured dopaminergic neurons derived from murine embryonal ventral mesencephalon with subsequet administration of edaravone or saline. The number of surviving TH-positive neurons and the degree of cell damage induced by free radicals were analyzed. In parallel, edaravone or saline was intravenously administered for PD model of rats receiving intrastriatal 6-OHDA lesion with subsequent behavioral and histological analyses.
In vitro study showed that edaravone significantly ameliorated the survival of TH-positive neurons in a dose-responsive manner. The number of apoptotic cells and HEt-positive cells significantly decreased, thus indicating that the neuroprotective effects of edaravone might be mediated by anti-apoptotic effects through the suppression of free radicals by edaravone. In vivo study demonstrated that edaravone-administration at 30 minutes after 6-OHDA lesion reduced the number of amphetamine-induced rotations significantly than edaravone-administration at 24 hours. Tyrosine hydroxylase (TH) staining of the striatum and substantia nigra pars compacta revealed that edaravone might exert neuroprotective effects on nigrostriatal dopaminergic systems. The neuroprotective effects were prominent when edaravone was administered early and in high concentration. TUNEL, HEt and Iba-1 staining in vivo might demonstrate the involvement of anti-apoptotic, anti-oxidative and anti-inflammatory effects of edaravone-administration.
Edaravone exerts neuroprotective effects on PD model both in vitro and in vivo. The underlying mechanisms might be involved in the anti-apoptotic effects, anti-oxidative effects, and/or anti-inflammatory effects of edaravone. Edaravone might be a hopeful therapeutic option for PD, although the high therapeutic dosage remains to be solved for the clinical application.
BMC Neuroscience 09/2008; 9:75. · 3.04 Impact Factor
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Kazuya Takahashi,
Takao Yasuhara,
Tetsuro Shingo,
Kenichiro Muraoka,
Masahiro Kameda,
Akira Takeuchi,
Akimasa Yano,
Kazuhiko Kurozumi, Takashi Agari,
Yasuyuki Miyoshi,
Kazushi Kinugasa,
Isao Date
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ABSTRACT: Cell therapy using stem cells is awaited by stroke patients with impaired movement and cognitive functions, although intravenous alteplase-administration ameliorated outcomes of patients receiving the therapy within 3 h of onset. In this study, we explored the therapeutic effects of neural progenitor cells (NPC) upon middle cerebral artery occlusion (MCAO) model of rats with exploration of the differences between adult and embryonic NPCs in therapeutic effects. GFP-labeled adult or embryonic NPCs were transplanted for transient MCAO model of rats at 1h after reperfusion. Rats were examined behaviorally using limb placement test, rotarod test and cylinder test with neuroradiological assessment using magnetic resonance imaging (MRI). Consequently after euthanasia, rats were immunohistochemically investigated to explore graft survival and immune reaction. MRI of rats receiving NPCs revealed significant reduction of infarct volumes, compared to vehicle-treated rats with corresponding behavioral amelioration. The transplanted cells were surviving in rats receiving NPCs, although the number of embryonic NPCs was significantly higher than that of adult NPCs. Iba-1-positive inflammatory cells of rats receiving adult NPCs were prominent, compared to those receiving embryonic NPCs, which might be a rationale for the differences between rats receiving adult and embryonic NPCs in the number of surviving NPCs. On the contraries, adult NPCs surely demonstrated therapeutic effects with a few surviving cells, thus indicating that the therapeutic effects might be due to trophic/growth factor-secretion from transplanted NPCs, rather than replacement of damaged host neurons. Therapeutic effects of NPCs for MCAO model of rats were clarified in this study. Transplantation of NPCs will be a hopeful strategy for stroke patients, although further studies are required for the patient safety and underlying mechanisms.
Brain Research 08/2008; 1234:172-82. · 2.73 Impact Factor
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ABSTRACT: Metabotropic glutamate receptors (mGluRs) have been recently implicated as robust therapeutic targets for Parkinson's disease (PD). Here, we explored how activation of mGluRs in globus pallidus (GP) affected the amphetamine-induced rotational behavior in the unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of PD. The amphetamine-induced rotations were completely suppressed by the ipsilateral intrapallidal injection of the non-selective mGluR agonist, 1-aminocyclopentane-1S,3R-dicarboxylic acid (ACPD) and the selective group I mGluR agonist, (R,S)-3,5-dihydroxyphenylglycine (DHPG), but not the selective group III mGluR agonist, l-2-amino-4-phosphonobutyric acid (l-AP4). The suppressive effects were detected at 2, 4, 6, 8, and 12 h after ACPD injection, but returned to the control level at 24 h. A remarkable c-fos expression was found in the lesioned side of GP, subthalamic nucleus (STN), and substantia nigra pars reticulata (SNr) of rats that received the ACPD or DHPG injection, compared to rats treated with L-AP-4 or phosphate buffer-injection. The results indicate that the blockade of amphetamine-induced rotations might be at least partially mediated by group I mGluR activation. This study advances the use of selective group I mGluRs directed toward the GP for PD treatment.
Brain Research 05/2008; 1203:189-96. · 2.73 Impact Factor
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ABSTRACT: Microvascular decompression (MVD) is an effective form of surgery for the treatment of trigeminal neuralgia (TN), and is superior to other procedures utilized in the treatment of this condition. TN is commonly seen in the elderly, but there is debate regarding the use of MVD in elderly patients. This report presents a retrospective review of the clinical features and surgical outcomes in elderly patients with TN. We divided TN patients into two groups: an elderly group more than 70 years old and a younger group under 70 years old. There were no serious complications in either group, and the length of hospital stay was not influenced by the age of the patients. Surgical outcome was excellent in both groups. The surgical findings in the elderly group were atrophy of the cerebellum and segmental sclerotic changes in the affected artery. In cases of trigeminal neuralgia in which medical therapy has failed to produce beneficial results, we encourage elderly patients to undergo MVD if their general condition is stable. However, this procedure should be performed with great care in elderly patients to avoid the onset of complications.
No shinkei geka. Neurological surgery 02/2008; 36(1):45-9. · 0.13 Impact Factor
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Kazuki Kobayashi,
Takao Yasuhara, Takashi Agari,
Kenichiro Muraoka,
Masahiro Kameda,
Wen Ji Yuan,
Hitoshi Hayase,
Toshihiro Matsui,
Yasuyuki Miyoshi,
Tetsuro Shingo,
Isao Date
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ABSTRACT: We established a PC12 cell line (PC12TH Tet-Off) in which human tyrosine hydroxylase (TH) expression can be negatively controlled by Doxycycline (Dox). First, dopamine (DA)-secretion from PC12TH Tet-Off cells was controlled by Dox-administration in a dose-responsive manner ranging from 0 to 100 ng/ml for 70 days in vitro. Furthermore, Parkinson's disease model of rats receiving encapsulated PC12TH Tet-Off cells displayed a significant decrease of dopamine concentration in the cerebrospinal fluid (CSF) and increase of the number of apomorphine-induced rotations by Dox-administration, as compared to transplanted rats without Dox-administration, although the significant decrease of the reduction ratio of DA concentration in the CSF with Dox-administration was recognized over time. At 2 months post-implantation, concentration of dopamine in the implanted striatum and from the retrieved capsules demonstrated that the control of DA-secretion could be partially achieved for 2 months in vivo. Our results support both the value of cell therapy using Tet-Off system and the technique of encapsulation might be a feasible option for Parkinson's disease especially in resolving the problem of dopamine oversupply in the future, although a more efficient way to control DA-secretion with quicker regulation and much titration of dose should be explored before clinical application.
Brain Research 09/2006; 1102(1):1-11. · 2.73 Impact Factor
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ABSTRACT: Vascular endothelial growth factor (VEGF) has been shown to display neuroprotective effects on dopaminergic (DA) neurons. Here, we investigated the neurorescue effects of VEGF on 6-hydroxydopamine (6-OHDA)-treated DA neurons in vitro and in vivo. Initially, we examined in vitro whether 1, 10, or 100 ng/ml of VEGF administration at 2 or 4 h after 6-OHDA treatment rescued DA neurons derived from E14 murine ventral mesencephalon. The earlier treatment of VEGF suppressed 6-OHDA-induced loss of DA neurons more than the delayed treatment. Next, we examined whether the continuous infusion of VEGF had neurorescue effects in a rat model of Parkinson's disease. We established a human VEGF secreting cell line (BHK-VEGF) and encapsulated the cells into hollow fibers. The encapsulated cells were unilaterally transplanted into the striatum of adult rats at 1 or 2 weeks after 6-OHDA lesions, and animals subsequently underwent behavioral and immunohistochemical evaluations. Compared to lesioned rats that received BHK-Control capsules, lesioned rats transplanted with BHK-VEGF capsules showed a significant reduction in the number of amphetamine-induced rotations, a significant preservation of TH-positive neurons in the substantia nigra pars compacta, and a remarkable glial proliferation in the striatum, with the earlier transplantation exerting much more benefits than the delayed transplantation. Parallel studies revealed that the observed in vitro and in vivo neurorescue effects were likely mediated by VEGF's angiogenic and glial proliferative effects, as well as its direct effects on the neurons. Our results suggest that VEGF is a highly potent neurorescue molecule for Parkinson's disease therapy.
Brain Research 09/2005; 1053(1-2):10-8. · 2.73 Impact Factor
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Takao Yasuhara,
Tetsuro Shingo,
Kenichiro Muraoka,
Masahiro Kameda, Takashi Agari,
Yuan Wenji,
Tomohito Hishikawa,
Toshihiro Matsui,
Yasuyuki Miyoshi,
Toru Kimura,
Cesario V Borlongan,
Isao Date
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ABSTRACT: Semaphorin3A (Sema3A) is known to cause neuronal apoptosis and serves as a chemorepellent factor for axonal growth. In our previous report, we found that Sema3A was up-regulated in the 6-OHDA-injected striatum of rats, suggesting that Sema3A was likely involved in dopaminergic (DA) depletion. In this study, we investigated whether Sema3A directly worked as a neurotoxin to DA neurons both in vitro and in vivo. First, effects of various dosages of Sema3A administration on the DA neurons of the E14 murine ventral mesencephalon were examined in vitro. Sema3A at a dose over 500 ng/ml induced apoptosis to DA neurons. Next, we examined whether the continuous infusion of Sema3A exerted degeneration of DA neurons in rats. We established a Sema3A-secreting cell line (BHK-Sema3A), confirming the secreting functions by immunocytochemical and Western blot assays. Adult Sprague-Dawley rats were unilaterally implanted into the striatum with BHK-Sema3A or BHK non-Sema3A control cells, and subsequently underwent behavioral and immunohistochemical evaluations. Rats that received BHK-Sema3A did not show significant differences in the number of amphetamine- and apomorphine-induced rotations and TH-positive neurons in the substantia nigra pars compacta compared to the control group. Our results revealed that Sema3A was toxic to cultured DA neurons at very high dosages, but the continuous secretion of Sema3A at modest dosage in vivo did not produce Parkinsonian pathophysiologic symptoms. Optimizing the dosage and infusion location (i.e., nigra) and timing (more than 1 week post-transplantation) might further reveal the contribution of Sema3A to the pathogenesis of Parkinson's disease.
Neuroscience Letters 382(1-2):61-5. · 2.11 Impact Factor
