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Maeda N.,Tokyo Metropolitan Institute for Neuroscience
Central Nervous System Agents in Medicinal Chemistry | Year: 2010

Chondroitin sulfate is popular in the field of neuroscience, because the treatment of nervous tissues with chondroitinase ABC, which degrades chondroitin sulfate up to unsaturated disaccharides, causes severe changes in various aspects of neural development and functions. Chondroitinase ABC treatments of developing nervous tissue impair the growth and differentiation of neural progenitor cells, and cause various pathfinding errors of axons. After injury to the adult central nervous system, axon regeneration fails at scar regions expressing large amounts of chondroitin sulfate proteoglycans. However, after chondroitinase ABC treatment, many axons regenerate and traverse the damaged areas. Furthermore, it was revealed that chondroitin sulfate proteoglycans are involved in neural plasticity. These observations indicated that chondroitin sulfate proteoglycans as major components of the extracellular matrix and cell surface play pivotal roles in the development, regeneration, and plasticity of neuronal networks. Chondroitin sulfate shows highly diverse structural variation, and recent studies indicated that this glycosaminoglycan binds with various growth factors, chemokines and axon guidance molecules in a structure-dependent manner and regulates their activities. Notably, oversulfated structures such as D (GlcA(2-O-sulfate)β1-3GalNAc(6-O-sulfate)) and E (GlcAβ1-3GalNAc(4,6-O-disulfate)) units constitute the binding sites for many proteins, and play important roles in regulation of the growth of neural progenitors, neurite extension, and neuronal migration. The synthesis of these structures is strictly regulated by the chondroitin sulfate synthase family and many sulfotransferases, which should be useful therapeutic targets in neurological disorders. © 2010 Bentham Science Publishers Ltd.


Shishido-Hara Y.,Kyorin University | Shishido-Hara Y.,Tokyo Metropolitan Institute for Neuroscience
Acta Neuropathologica | Year: 2010

Progressive multifocal leukoencephalopathy is a fatal viral-induced demyelinating disease that was once rare but has become more prevalent today. Over the past decades, much has been learned about the disease from molecular study of the etiological agent of the disease, JC virus. Recently, promyelocytic leukemia nuclear bodies (PML-NBs), punctuate structures for important nuclear functions in eukaryotic cells, were identified as an intranuclear target of JC virus infection. Neuropathologically, JC virus-infected glial cells display diffuse amphophilic viral inclusions by hematoxylin-eosin staining (full inclusions), a diagnostic hallmark of this disease. Recent results using immunohistochemistry, however, revealed the presence of punctate viral inclusions preferentially located along the inner nuclear periphery (dot-shaped inclusions). Dot-shaped inclusions reflect the accumulation of viral progeny at PML-NBs, which may be disrupted after viral replication. Structural changes to PML-NBs have been reported for a variety of human diseases, including cancers and neurodegenerative disorders. Thus, PML-NBs may provide clues to the further pathogenesis of JC virus-induced demyelinating disease. Here, we review what we have learned since the disease entity establishment, including a look at recent progress in understanding the relationship between JC virus, etiology and PML-NBs. © 2010 Springer-Verlag.


Uchida S.,Tokyo Metropolitan Institute for Neuroscience
JAMS Journal of Acupuncture and Meridian Studies | Year: 2014

This article presents a review of our studies on the cholinergic vasodilative system in the cerebral cortex in relation to the effects of acupuncture and aging. In anesthetized rats, manual acupuncture-like stimulation of the cheek, forepaw, upper arm, and hindpaw increases the cortical cerebral blood flow (CBF). The mechanism for the increased response of CBF due to forepaw stimulation has been found to be a reflex response whose afferents are Groups III and IV somatic afferent fibers and whose efferents are cholinergic fibers that originate in the nucleus basalis of Meynert. Although the cholinergic cortical vasodilation to nucleus basalis of Meynert stimulation at high intensities declines with age, the increased response of CBF induced by natural somatic afferent stimulation, such as an acupuncture-like stimulation of a forepaw, is well maintained even in very old rats (approximately 3 years of age). These findings in anesthetized rats may support the application of acupuncture to elderly people and patients with disturbances in the CBF by activating the intracranial cholinergic vasodilative system. © 2014.


Uchihara T.,Tokyo Metropolitan Institute for Neuroscience
Neuropathology | Year: 2011

One of the challenges in neuropathology is to clarify how molecules, functional carriers of uni-dimensional sequence of amino acid or nucleic acid, behave to engender disease-specific pathological processes in complex three-dimensional (3D) structures such as the human brain in an ordered chronological sequence (four-dimensional extension as a whole). Along with expanding molecular explanations for brain diseases, parallel and independent hypotheses based on morphological observations are particularly useful and necessary for reasonable understanding of the brain and its dysfunction. For example, with classical methods such as silver impregnations, it is possible to differentiate underlying molecular pathologies (three-repeat tau/Campbell-Switzer vs. four-repeat tau/Gallyas silver impregnation) for improved histological diagnosis. Innovations with 3D reconstruction not only provide more realistic reproduction of the targets but also allow quantitative measurement on a 3D basis (3D volumetry). Contrary to the prevailing impression that pathological deposits are generally toxic to cells, quantification demonstrated possible countertoxic potentials of ubiquitin-positive intranuclear inclusions in CAG-repeat disorders on a two-dimensional basis and of glial cytoplasmic inclusions of multiple system atrophy on 3D volumetry. Furthermore, 3D extension of neurites around target lesions is now traceable in relation to the relevant clinical consequences. This neurite neuropathology may pave the way for early specific diagnosis of neurodegenerative disorders, as established through 123I-metaiodobenzylguanidine cardiac scintigraphy for Parkinson disease, aiming at therapeutic intervention before depletion of mother neurons is feasible. For appropriate translation of sequence biology into the frame of human neuropathology, it is necessary to expand further the morphological dimensions so that comprehensive understanding of these disorders leads to specific diagnosis and treatment as early as possible. © 2011 Japanese Society of Neuropathology.


Recently, we found that gentle mechanical skin stimulation inhibits the micturition reflex in anesthetized rats. However, the central mechanisms underlying this inhibition have not been determined. This study aimed to clarify the central neural mechanisms underlying this inhibitory effect. In urethane-anesthetized rats, cutaneous stimuli were applied for 1 min to the skin of the perineum using an elastic polymer roller with a smooth, soft surface. Inhibition of rhythmic micturition contractions by perineal stimulation was abolished by naloxone, an antagonist of opioidergic receptors, administered into the intrathecal space of the lumbosacral spinal cord at doses of 2-20 μg but was not affected by the same doses of naloxone administered into the subarachnoid space of the cisterna magna. Next, we examined whether perineal rolling stimulation inhibited the descending and ascending limbs of the micturition reflex. Perineal rolling stimulation inhibited bladder contractions induced by electrical stimulation of the pontine micturition center (PMC) or the descending tract of the micturition reflex pathway. It also inhibited the bladder distension-induced increase in the blood flow of the dorsal cord at L5-S1, reflecting the neural activity of this area, as well as pelvic afferent-evoked field potentials in the dorsal commissure at the lumbosacral level; these areas contain long ascending neurons to the PMC. Neuronal activities in this center were also inhibited by the rolling stimulation. These results suggest that the perineal rolling stimulation activates the spinal opioidergic system and inhibits both ascending and descending transmissions of the micturition reflex pathway in the spinal cord. These inhibitions would lead to the shutting down of positive feedback between the bladder and the PMC, resulting in inhibition of the micturition reflex. Based on the central neural mechanisms we show here, gentle perineal stimulation may be applicable to several different types of overactive bladder. © 2015 Hotta, Watanabe.

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