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Featured researches published by Tadao Morino.


Annals of the New York Academy of Sciences | 2000

Cascading glia reactions: a common pathomechanism and its differentiated control by cyclic nucleotide signaling.

Peter Schubert; Tadao Morino; Hirofumi Miyazaki; Tadanori Ogata; Yoichi Nakamura; Cristina Marchini; Stefano Ferroni

Abstract: A pathological glia activation, stimulated by inflammatory proteins, β‐amyloid, or brain ischemia, is discussed as a common pathogenic factor for progressive nerve cell damage in vascular and Alzheimer dementia. A critical point seems to be reached, if the cytokine‐controlled microglial upregulation causes a secondary activation of astrocytes which loose the negative feedback control, are forced to give up their physiological buffering function, and may add to neuronal damage by the release of nitric oxide (NO) and by promoting toxic β‐amyloid formation. A strengthening of the cyclic adenosine‐5′,3′‐monophosphate (cAMP) signaling exerted a differential inhibition of the stimulatory cytokines tumor necrosis factor‐α (TNF‐α and interleukin‐1β (IL‐1β) released from cultured rat microglia, but maintained the negative feedback signal IL‐6; cAMP inhibited also the release of free oxygen radicals (OR) but not of NO. Reinforcement of the NO‐induced cyclic guanosine monophosphate (cGMP) increase by blockade of the phosphodiesterase (PDE) subtype‐5 with propentofylline counterbalanced the toxic NO action that causes with OR neuronal damage by peroxynitrate formation. In rat cultured astrocytes, a prolonged cAMP elevation favored cell differentiation, the expression of a mature ion channel patter, and an improvement of the extracellular glutamate uptake. Cyclic AMP signaling could be strengthened by PDE blockade and by raising extracellular adenosine, which stimulates A2 receptor‐mediated cAMP synthesis. Via an A1 receptor‐mediated effect, elevated adenosine was found to overcome a deficient intracellular calcium mobilization resulting from an impaired muscarinic signaling at pathologically decreased acetylcholine concentrations. We suggest that pharmaca, which elevate extracellular adenosine and/or block the degradation of cyclic nucleotides, may be used to counteract glia‐related neuronal damage in dementing processes.


Brain Research | 2003

Adenosine triphosphate inhibits cytokine release from lipopolysaccharide-activated microglia via P2y receptors.

Tadanori Ogata; Miao Chuai; Tadao Morino; Haruyasu Yamamoto; Yoichi Nakamura; Peter Schubert

Microglial proliferation and activation have been reported to occur after several central nervous system injuries. In this study, we tested the effects of adenosine triphosphate (ATP) on cultured microglia obtained from the spinal cord of rat embryos. The amounts of tumor necrosis factor alpha (TNF-alpha), interleukin 1beta and interleukin 6 released from the microglia, which were stimulated by lipopolysaccharide (LPS; 100 ng/ml), were inhibited by the simultaneous addition of ATP in a dose dependent manner (10-300 microM). We examined the effect of several endogenous purines (ATP, ADP, CTP, UDP, UTP) and P(2)y receptor agonists (ADPbetaS and 2-methylthio-ATP) on LPS-induced TNF-alpha release. The rank order of inhibitory potency of endogenous purines on TNF-alpha release was: ATP>ADP>>UTP>UDP>CTP. The latter three were much less potent than the former two. The addition of 10 microM 2-methylthio-ATP showed a potency similar to 100 microM ATP. The addition of ADPbetaS, however, showed less effect. These endogenous purines and selective ATP receptor agonists showed a similar inhibitory effect in their rank order on LPS-induced interleukin 6 release. We demonstrate that ATP inhibits cytokine release from LPS-activated microglia via metabotropic receptors. The application of P(2)y receptor agonists might be considered as a pharmacological treatment of several pathological conditions of the spinal cord, including toxic immunoreactions.


Spine | 2007

Real-time direct measurement of spinal cord blood flow at the site of compression: relationship between blood flow recovery and motor deficiency in spinal cord injury.

Yuichiro Hamamoto; Tadanori Ogata; Tadao Morino; Masayuki Hino; Haruyasu Yamamoto

Study Design. An in vivo study to measure rat spinal cord blood flow in real-time at the site of compression using a newly developed device. Objectives. To evaluate the change in thoracic spinal cord blood flow by compression force and to clarify the association between blood flow recovery and motor deficiency after a spinal cord compression injury. Summary of Background Data. Until now, no real-time measurement of spinal cord blood flow at the site of compression has been conducted. In addition, it has not been clearly determined whether blood flow recovery is related to motor function after a spinal cord injury. Methods. Our blood flow measurement system was a combination of a noncontact type laser Doppler system and a spinal cord compression device. The rat thoracic spinal cord was exposed at the 11th vertebra and spinal cord blood flow at the site of compression was continuously measured before, during, and after the compression. The functioning of the animal’s hind-limbs was evaluated by the Basso, Beattie and Bresnahan scoring scale and the frequency of voluntary standing. Histologic changes such as permeability of blood-spinal cord barrier, microglia proliferation, and apoptotic cell death were examined in compressed spinal cord tissue. Results. The spinal blood flow decreased on each increase in the compression force. After applying a 5-g weight, the blood flow decreased to <40% of the precompression level. Complete ischemia was reached using a 20-g weight. After decompression, the blood flow level in the 20-minute complete ischemia group was significantly higher than that in the 40-minute complete ischemia group. The hind-limb motor function in the 40-minute complete ischemia group was significantly less than that in the sham group (without compression), while no significant difference was observed between the 20-minute ischemia group and the sham group. In the 20-minute ischemia group, the rats whose spinal cord blood flow recovery was incomplete showed significant motor function loss compared with rats that completely recovered blood flow. Extensive breakdown of blood-spinal cord barrier integrity and the following microglia proliferation and apoptotic cell death were detected in the 40-minute complete ischemia group. Conclusion. Duration of ischemia/compression and blood flow recovery of the spinal cord are important factors in the recovery of motor function after a spinal cord injury.


Spinal Cord | 2008

Microglia inhibition is a target of mild hypothermic treatment after the spinal cord injury.

Tadao Morino; Tadanori Ogata; Jun Takeba; Haruyasu Yamamoto

Study Design:A basic study using a spinal cord injury (SCI) model in rats.Objectives:The effect of mild hypothermic treatment on histological changes and motor function after a rat spinal cord compression injury was assessed.Methods:Mild spinal cord compression was performed at the eleventh thoracic vertebral level by a 20 g weight for 20 min. Rats in the mild hypothermic model were kept at a body temperature of 33 °C and rats in the normothermic group were kept at 37 °C for 1 h from beginning of compression. Motor function was evaluated by measuring the frequency of standing. Microglia were stained by isolectin B4 and observed in the compressed portion of the spinal cord. The amount of tumor necrosis factor-α (TNF-α) in the compressed spinal cord was measured by the ELISA method.Results:In the normothermic rats, microglia proliferated up to 72 h after the compression. Proliferation was substantially inhibited at 48 and 72 h after compression in the hypothermic rats. The motor function of the hypothermic rats improved at 48 and 72 h after the compression, whereas no improvement was seen in the normothermic rats. The amount of TNF-α in the compressed portion of the spinal cord was lower in hypothermic rats compared with normothermic rats throughout the experiment.Conclusions:These results suggest that hypothermic treatment is effective for the amelioration of delayed motor dysfunction via inhibition of microglial inflammatory responses.


Neuroscience Research | 2012

A novel thermoelectric cooling device using Peltier modules for inducing local hypothermia of the spinal cord: The effect of local electrically controlled cooling for the treatment of spinal cord injuries in conscious rats

Kei Morizane; Tadanori Ogata; Tadao Morino; Hideki Horiuchi; Gotaro Yamaoka; Masayuki Hino; Hiromasa Miura

We developed a novel thermoelectric cooling device using Peltier modules for the treatment of spinal cord injury in rats. The extracorporeal electrically cooling component was attached to the aluminum arched plate which was placed on the surface of the spinal cord after the contusion injury in the 11th thoracic spinal cord. During the hypothermic treatment, rats were awake and could move in the cage. Hind limb motor function, evaluated using a BBB scale, in the hypothermic animals (33°C for 48 h) was significantly higher than that in the normothermic animals from 2 weeks to 8 weeks after the injury.


Spinal Cord | 2010

Adenosine A1 receptor agonists reduce hyperalgesia after spinal cord injury in rats

Hideki Horiuchi; Tadanori Ogata; Tadao Morino; Haruyasu Yamamoto

Study design:An in vivo study using a spinal cord compression model in rats.Objectives:To evaluate the effect of adenosine on thermal hyperalgesia after spinal cord injury (SCI).Summary of background data:After SCI, some patients suffer dysesthesia that is unresponsive to conventional treatments. We previously established a rat thoracic spinal cord mild-compression model by which we were able to induce thermal hyperalgesia in the hind limbs.Methods:The thoracic spinal cord was compressed gently using a 20-g weight for 20 min. The withdrawal latency in response to thermal stimulation was monitored bilaterally in the hind limbs using Hargreaves’ Plantar test apparatus.Results:SCI-induced thermal hyperalgesia was mimicked by the intrathecal application of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A1 receptor antagonist. Hyperalgesia induced by SCI was significantly inhibited by the intrathecal application of 10–30 nmol chloro-adenosine (Cl-adenosine), a nonselective adenosine receptor agonist. The effect of Cl-adenosine (10 nmol) on hyperalgesia after SCI was blocked by the simultaneous application of DPCPX. Intrathecal application of R(−)N6-(2phenylisopropyl) adenosine (R-PIA; 10 nmol), a selective A1 receptor agonist, also inhibited SCI-induced hyperalgesia. In contrast, intrathecal application of CGS21680, a selective adenosine A2a receptor agonist, did not inhibit SCI-induced hyperalgesia.Conclusions:These results suggest that adenosine inhibits hyperalgesia through the stimulation of A1 receptors. Adenosine or adenosine A1 receptor agonists should be considered as candidates for new therapeutic methods for treating post-SCI dysesthesia.


Neuroscience Research | 2009

Intrathecal transplantation of autologous macrophages genetically modified to secrete proenkephalin ameliorated hyperalgesia and allodynia following peripheral nerve injury in rats.

Masayuki Hino; Tadanori Ogata; Tadao Morino; Hideki Horiuchi; Haruyasu Yamamoto

To develop a novel genetic approach for the treatment of pain, we tested the transplantation of gene-transferred autologous macrophages by lumbar puncture. A rat neuropathic pain model was produced by chronic constriction of the sciatic nerve. Autologous macrophages were collected from the intraperitoneal space. Then human proenkephalin gene was transferred into the macrophages by electroporation. The gene-transferred macrophages were transplanted into the subarachnoid space by lumbar puncture. One week after transplantation, the heat hyperalgesia and allodynia induced by sciatic nerve constriction completely remitted. The analgesic action continued until at least 4 weeks after transplantation. The transplanted macrophages migrated into the spinal cord and expressed proenkephalin mRNA and Met-enkephalin protein. The method we tested in the present study may be a safe, simple and effective way to inhibit pain sensation after peripheral nerve injuries.


Foot & Ankle International | 2007

Intraosseous gouty tophus of the talus, treated by total curettage and calcium phosphate cement filling: a case report.

Tadao Morino; Masaru Fujita; Kenji Kariyama; Hisahide Yamakawa; Tadanori Ogata; Haruyasu Yamamoto

Long-term untreated hyperuricemia induces repeatable arthritis that results in chronic arthritis.7 Under continuous hyperuricemia condition, monosodium urate crystal deposition occurs not only in joints but also in connective tissue or interosseous spaces.4,9 Intraosseous gouty invasion, a relatively rare condition, has been reported to occur in the femoral condyle,6 the clavicle,12 the patella,3 the vertebral body,17 and the talus.16 Gouty invasion in the talus is an especially rare condition. Only three reports describing a lesion in the talus were available.5,13,16 The established operative procedure for large intraosseous gouty invasion is curettage and bone grafting.6,17 We present a patient in whom an intraosseous gouty tophus in the talus was treated by total curettage and filling the defect with calcium phosphate cement (CPC: alpha-tricalcium phosphate; Biopex-R, Mitsubishi Material, Osaka, Japan).


Journal of Spinal Disorders & Techniques | 2009

Resolution of intraspinal retro-odontoid cyst associated with os odontoideum after posterior fixation.

Tadanori Ogata; Yoshiyuki Kawatani; Tadao Morino; Haruyasu Yamamoto

Study Design A case report and review of previous literature. Objectives To describe the diagnosis and successful treatment of an intraspinal retro-odontoid cyst associated with an os odontoideum. Summary of Background Data Retro-odontoid cysts associated with atlantoaxial instability are extremely rare. Direct excision of the cysts has commonly been performed for the surgical treatment of myelopathy. Methods A retro-odontoid cyst in a 58-year-old woman with os odontoideum was treated surgically by posterior fixation between C1 and C3 without resection of the retro-odontoid mass. The patients history, clinical examination, imaging findings, and treatment are reported. Results The patient experienced walking difficulty, numbness in the upper and lower limbs, and hypesthesia in both hands. Congenital C2/3 fusion and atlantoaxial instability associated with an os odontoideum were found in the radiographs. Magnetic resonance imaging detected a round retro-odontoid mass, which compressed the spinal cord. The mass showed uniform low intensity on T1-weighted images and uniform high signal intensity on T2-weighted images. Gadolinium-diethylenetriaminepenta-acetic acid–enhanced T1-weighted images showed rim enhancement of the mass with no internal enhancement. Three months after the operation, the mass was no longer visible in a magnetic resonance imaging examination and the patient completely recovered motor function in her extremities. Conclusions Posterior fixation without resection was successfully used to eliminate a retro-odontoid cyst associated with atlantoaxial instability.


Skeletal Radiology | 2010

3-D MRI/CT fusion imaging of the lumbar spine

Yuki Yamanaka; Junji Kamogawa; Ryosuke Katagi; Kazuaki Kodama; Hiroshi Misaki; Kazuo Kamada; Shunsuke Okuda; Tadao Morino; Tadanori Ogata; Haruyasu Yamamoto

ObjectiveThe objective was to demonstrate the feasibility of MRI/CT fusion in demonstrating lumbar nerve root compromise.Materials and methodsWe combined 3-dimensional (3-D) computed tomography (CT) imaging of bone with 3-D magnetic resonance imaging (MRI) of neural architecture (cauda equina and nerve roots) for two patients using VirtualPlace software.ResultsAlthough the pathological condition of nerve roots could not be assessed using MRI, myelography or CT myelography, 3-D MRI/CT fusion imaging enabled unambiguous, 3-D confirmation of the pathological state and courses of nerve roots, both inside and outside the foraminal arch, as well as thickening of the ligamentum flavum and the locations, forms and numbers of dorsal root ganglia. Positional relationships between intervertebral discs or bony spurs and nerve roots could also be depicted.ConclusionUse of 3-D MRI/CT fusion imaging for the lumbar vertebral region successfully revealed the relationship between bone construction (bones, intervertebral joints, and intervertebral disks) and neural architecture (cauda equina and nerve roots) on a single film, three-dimensionally and in color. Such images may be useful in elucidating complex neurological conditions such as degenerative lumbar scoliosis(DLS), as well as in diagnosis and the planning of minimally invasive surgery.

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