研究者詳細 - 岡野　栄之

論文 - 岡野　栄之

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Human neural stem/progenitor cells, expanded in long-term neurosphere culture, promote functional recovery after focal ischemia in Mongolian gerbils

Ishibashi Satoru, Sakaguchi Masanori, Kuroiwa Toshihiko, Yamasaki Mami, Kanemura Yonehiro, Shizuko Ichinose, Shimazaki Takuya, Onodera Masafumi, Okano Hideyuki, Mizusawa Hidehiro

Journal of Neuroscience Research 78 （ 2 ） 215 - 223 2004年10月

ISSN 0360-4012

Transplantation of human neural stem cells (NSCs) is a promising potential therapy for neurologic dysfunctions after the hyperacute stage of stroke in humans, but large amounts of human NSCs must be expanded in long-term culture for such therapy. To determine their possible therapeutic potential for human stroke, human fetal neural stem/progenitor cells (NSPCs) (i.e., neurosphere-forming cells) were isolated originally from forebrain tissues of one human fetus, and expanded in long-term neurosphere culture (exceeding 24 weeks), then xenografted into the lesioned areas in the brains of Mongolian gerbils 4 days after focal ischemia. Sensorimotor and cognitive functions were evaluated during the 4 weeks after transplantation. The total infarction volume in the NSPC-grafted animals was significantly lower than that in controls. Approximately 8% of the grafted NSPCs survived, mainly in areas of selective neuronal death, and were costained with antibodies against neuronal nuclei antibody (NeuN), microtubule associated protein (MAP-2), glial fibrillary acidic protein (GFAP), and anti-2′3′ cyclic nucleotide 3′-phosphodiesterase (CNPase). Synaptic structures between NSPCs-derived neurons and host neurons were observed. Furthermore, gradual improvement of neurologic functions was observed clearly in the NSPC-grafted animals, compared to that in controls. Human NSPCs, even from long-term culture, remarkably improved neurologic functions after focal ischemia in the Mongolian gerbil, and maintained their abilities to migrate around the infarction, differentiate into mature neurons, and form synapses with host neuronal circuits. These results indicate that in vitro-expanded human neurosphere cells are a potential source for transplantable material for treatment of stroke. © 2004 Wiley-Liss, Inc.

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Human amnion mesenchyme cells express phenotypes of neuroglial progenitor cells

Sakuragawa Norio, Kakinuma Kenichi, Kikuchi Aiko, Okano Hideyuki, Uchida Saiko, Kamo Isao, Kobayashi Mamoru, Yokoyama Yasunobu

Journal of Neuroscience Research 78 （ 2 ） 208 - 214 2004年10月

ISSN 0360-4012

Previous studies from our laboratory showed that human amnion epithelial cells (AECs) have multiple functions, such as synthesis and release of catecholamines, acetylcholine, neurotrophic factors, activin, and noggin. In this study, we investigated the identity of neural progenitor cells in human amnion mesenchyme cells (AMCs), which lie immediately adjacent to the AECs. Cryostat sections revealed that vimentin expression was detected in the AMCs and CK19 in AECs. Vimentin-positive cells made up 97.5% of total cells tested in cultured AMCs. Interestingly, 3.6% of total AMCs expressed the phenotype CK19+/vimentin +, indicating coexpression of epithelial and mesenchyme cell markers. In culturing with bromodeoxyuridine (BrdU) for 24 hr, 66-82% of cells were found to be BrdU positive, suggesting that they have proliferating potency. By using RT-PCR, AMCs express mRNA of nestin and Musashi1. With a neural cell differentiating protocol, cell bodies extended long bipolar or complex multipolar processes. Nestin (87.7% of total cells tested) and Musashi1 (93.1%) were expressed in undifferentiated cells, and their positively stained cells increased in number slightly after induction. Undifferentiated cells were stained by anti-Tuj1 and NF-M, and their positively stained cells increased significantly in number after induction, to 72.8% and 46.0%, respectively. Meanwhile, glial fibrillary acidic protein-positive cells increased from 25.4% to 43.2% after induction. These studies demonstrate that AMCs have phenotypes of neuroglial progenitor cells and can be differentiated into neuroglial phenotypes by optimal differentiation protocol. Eventually, AMC-derived stem cells may be a favorable cell vehicle in regenerative medicine. © 2004 Wiley-Liss, Inc.

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Possible oncogenicity of subventricular zone neural stem cells

Uchida Koichi, Mukai Makio, Okano Hideyuki, Kawase Takeshi

Neurosurgery 55 （ 4 ） 977 - 978 2004年10月

ISSN 0148-396X

OBJECTIVE: The origin of brain tumors has attracted much controversy. Recent advances in neural stem cell biology coupled with the new concepts of central nervous system development have raised interesting possibilities regarding the oncogenic properties of neural stem/progenitor cells. To elucidate these putative properties further, the clinical materials from an infant brain tumor were analyzed, focusing on the relation with the neural stem/progenitor cells. METHODS: The expression of neural stem/progenitor cell markers in the tumor cells and the cellular components of the infant brain tumor were examined using immunohistochemistry. The tumor cell biology was analyzed both in culture and in the grafted brain environment. RESULTS: Three main bodies of evidence were demonstrated indicating that the tumor was of possible subventricular zone postnatal or adult normal neural stem cell origin. First, in the tumor specimen we demonstrated the strong positive expression of the neural stem/progenitor cell markers, nestin and Musashi-1. Second, immunohistochemistry revealed the presence of neuronal, astrocytic, and immature precursor cells in the tumor tissue, similar to the cellular components of the subventricular zone, thereby pointing to the subventricular zone as the possible origin of the tumor. The subventricular zone also is one of the strong candidates for the location of postnatal/adult neural stem cells. This cellular evidence was strengthened further by the clinicoradiological findings that demonstrated the involvement of the subventricular zone of the lateral ventricle by the tumor. Third, in the in vitro and in vivo experiments, a dynamic shift in expression patterns between neural stem cells (nestin, Musashi-1) and differentiated cells (glial fibrillary acidic protein, neuron-specific Class III β-tubulin) markers was seen, similar to the proposed behavior of postnatal/adult neural stem cells in situ. CONCLUSION: These findings suggest that this brain tumor originated from neural stem cells located in the subventricular zone, and the further possibility of the general oncogenic potential of neural stem cells.

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Characterization of the isoforms of MOVO zinc finger protein, a mouse homologue of Drosophila Ovo, as transcription factors

Unezaki Sawako, Nishizawa Mikio, Okuda-Ashitaka Emiko, Masu Yasuo, Mukai Masanori, Kobayashi Satoru, Sawamoto Kazunobu, Okano Hideyuki, Ito Seiji

Gene 336 （ 1 ） 47 - 58 2004年07月

ISSN 0378-1119

We previously described two isoforms (MOVO-A and -B) of a novel zinc finger protein MOVO, a mouse homologue of Drosophila Ovo protein. Here, we isolated cDNA encoding the third isoform MOVO-C, which had a transactivation domain and zinc finger domain, but lacked an N-terminal potential repression domain that was present in MOVO-A. Three isoform mRNAs were expressed highly in mouse testis and also in the ovary at lower levels. The structural analyses of the isolated Movo gene and mRNAs demonstrated that three different Movo transcripts were differentially processed to generate three isoforms. Major mRNA species encoded MOVO-B with a zinc finger domain alone, and minor mRNA species encoded MOVO-A (potential repressor) and MOVO-C (potential activator). To assign MOVO to a transcriptional factor, we characterized DNA-binding and transactivation properties. Random oligonucleotide selection, electrophoretic mobility shift assay and footprinting indicated that MOVO bound to the sequence, 5′-G(G/C/T)GGGGG-3′. These motifs were found in the 5′-flanking regions of Movo and other testis-specific genes. Nuclear proteins binding to this motif were detected in mouse testis, and the expression of MOVO mRNA was restricted in spermatocytes. The luciferase assay demonstrated that MOVO-C activated Movo promoter and MOVO-A repressed it, but MOVO-B had no effects. Mutated MOVO-binding motifs in the Movo promoter reduced the luciferase activity. All the isoforms had no effects on SV40 promoter without MOVO-binding motifs. MOVO-A partially rescued oogenesis of a Drosophila ovo mutant. These results suggest that MOVO isoforms are transcription factors to regulate genes carrying the MOVO-binding motifs in the testis. © 2004 Elsevier B.V. All rights reserved.

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Mapping spatio-temporal activation of Notch signaling during neurogenesis and gliogenesis in the developing mouse brain

Tokunaga Akinori, Kohyama Jun, Yoshida Tetsu, Nakao Keiko, Sawamoto Kazunobu, Okano Hideyuki

Journal of Neurochemistry 90 （ 1 ） 142 - 154 2004年07月

ISSN 0022-3042

Notch1 plays various important roles including the maintenance of the stem cell state as well as the promotion of glial fates in mammalian CNS development. However, because of the very low amount of the activated form of Notch1 present in vivo, its precise activation pattern has remained unknown. In this study, we mapped the active state of this signaling pathway in situ in the developing mouse brain using a specific antibody that recognizes the processed form of the intracellular domain of Notch1 cleaved by presenilin/γ-secretase activity. By using this antibody, active state of Notch1 came to be detectable with a higher sensitivity than using conventional antibody against Notch1. We found that activated Notch1 was mainly detected in the nuclei of a subpopulation of radial glial cells, the majority of proliferating precursor cells in the ventricular zone (VZ). However, Notch1 activation was not detected in neuronal precursor cells positive for neuronal basic helix-loop-helix proteins or in differentiating neurons in the embryonic forebrain. Interestingly, we found that Notch1 was transiently activated in the astrocytic lineage during perinatal CNS development. Taken together, the present method has enabled us to determine the timing, gradients, and boundaries of the activation of Notch signaling.

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Isolation and transplantation of dopaminergic neurons generated from mouse embryonic stem cells

Yoshizaki Takahito, Inaji Motoki, Kouike Hiroko, Shimazaki Takuya, Sawamoto Kazunobu, Ando Kiyoshi, Date Isao, Kobayashi Kazuto, Suhara Tetsuya, Uchiyama Yasuo, Okano Hideyuki

Neuroscience Letters 363 （ 1 ） 33 - 37 2004年06月

ISSN 0304-3940

Embryonic stem (ES) cells differentiate into dopamine (DA)-producing neurons when co-cultured with PA6 stromal cells, but the resulting cultures contain a variety of unidentified cells. In order to label live DA neurons in mixed populations, we introduced a GFP reporter under the control of the tyrosine hydroxylase (TH) gene promoter into ES cells. GFP expression was observed in TH-immunoreactive cells that differentiated from the ES cells that carried the TH-GFPreporter gene. DA neurons expressing GFP were sorted from the mixed cell population by fluorescence-activated cell sorting of cells exhibiting GFP fluorescence, and the sorted GFP⁺ cells obtained were transplanted into a rat model of Parkinson's disease. Some of these cells survived and innervated the host striatum, resulting in a partial recovery from parkinsonian behavioral defects. This strategy of isolation and transplantation of ES-cell-derived DA neurons should be useful for cellular and molecular studies of DA neurons and for clinical application in the treatment of Parkinson's disease. © 2004 Elsevier Ireland Ltd. All rights reserved.

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Downregulation of STAT3 activation is required for presumptive rod photoreceptor cells to differentiate in the postnatal retina

Ozawa Yoko, Nakao Keiko, Shimazaki Takuya, Takeda Junji, Akira Shizuo, Ishihara Katsuhiko, Hirano Toshio, Oguchi Yoshihisa, Okano Hideyuki

Molecular and Cellular Neuroscience 26 （ 2 ） 258 - 270 2004年06月

ISSN 1044-7431

Ciliary neurotrophic factor (CNTF) has been known to inhibit the differentiation of presumptive rod photoreceptor cells; however, the underlying mechanisms have remained to be elucidated. We demonstrated that STAT3 activation, but not SHP2 activation, is responsible for the CNTF/gp130 signaling that inhibits expression of Rhodopsin and its upstream activator, crx, in the retinal explants derived from P0 mice (P0 retinal explants), utilizing STAT3-deficient retina and electroporation of dominant-negative form of STAT3 (STAT3F). We also demonstrated that STAT3 activation in presumptive rod photoreceptor cells at E18.5 is rapidly downregulated at P0, when Rhodopsin expression starts during retinal development. Persistent STAT3 activation in the P0 retinal explants prevented Rhodopsin expression and rapid upregulation of crx expression. STAT3-deficient retinas did not exhibit precocious rod photoreceptor cell differentiation as a whole, although they occasionally exhibited precocious upregulation of crx mRNA. Thus, we conclude that downregulation of STAT3 activation is required, but insufficient, for rod photoreceptor cell differentiation in the postnatal retina. © 2004 Elsevier Inc. All rights reserved.

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Implantation of Dendritic Cells in Injured Adult Spinal Cord Results in Activation of Endogenous Neural Stem/Progenitor Cells Leading to De Novo Neurogenesis and Functional Recovery

Mikami Yuji, Okano Hideyuki, Sakaguchi Masanori, Nakamura Masaya, Shimazaki Takuya, Okano Hirotaka James, Kawakami Yutaka, Toyama Yoshiaki, Toda Masahiro

Journal of Neuroscience Research 76 （ 4 ） 453 - 465 2004年05月

ISSN 0360-4012

We report a treatment for spinal cord injury involving implantation of dendritic cells (DCs), which act as antigen-presenting cells in the immune system. The novel mechanisms underlying this treatment produce functional recovery. Among the immune cells tested, DCs showed the strongest activity inducing proliferation and survival of neural stem/progenitor cells (NSPCs) in vitro. Furthermore, in DC-implanted adult mice, endogenous NSPCs in the injured spinal cord were activated for mitotic de novo neurogenesis. These DCs produced neurotrophin-3 and activated endogenous microglia in the injured spinal cord. Behavioral analysis revealed the locomotor functions of DC-implanted mice to have recovered significantly as compared to those of control mice. Our results suggest that DC-implantation exerts trophic effects, including activation of endogenous NSPCs, leading to repair of the injured adult spinal cord. © 2004 Wiley-Liss, Inc.

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RMD-1 is a novel protein with multiple coiled-coil domains that regulates microtubule-based processes in C. elegans embryos

岡野栄之

CELL STRUCTURE AND FUNCTION 29 36 - 36 2004年05月

研究論文（学術雑誌）, ISSN 0386-7196

Spatiotemporal patterns of Musashil expression during inner ear development

Sakaguchi Hirofumi, Yaoi Takeshi, Suzuki Toshihiro, Okano Hideyuki, Hisa Yasuo, Fushiki Shinji

NeuroReport 15 （ 6 ） 997 - 1001 2004年04月

ISSN 0959-4965

Musashil (Msi I) is an RNA binding protein associated with asymmetric cell divisions in neural progenitor cells.To investigate the involvement of MsiI in the inner ear development, we studied the expression of MsiI in mouse inner ears with RT-PCR and immunohistochemistry. Immunohistochemistry revealed that MsiI was expressed in all otocyst cells at embryonic day (E) 10 and 12. MsiI immunoreactivity became lost in hair cells after E14 in vestibule and after E16 in cochlea, whereas it persisted in supporting cells until adulthood. The subcellular localization of MsiI changed from "cytoplasmic predominance" to "nuclear predominance" during the first 2 weeks after birth. The present data suggested that Msi may play a role in inner ear development. © 2004 Lippincott Williams & Wilkins.

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Blockade of Interleukin-6 Receptor Suppresses Reactive Astrogliosis and Ameliorates Functional Recovery in Experimental Spinal Cord Injury

Okada S., Nakamura M., Mikami Y., Shimazaki T., Mihara M., Ohsugi Y., Iwamoto Y., Yoshizaki K., Kishimoto T., Toyama Y., Okano Hideyuki

Journal of Neuroscience Research 76 （ 2 ） 265 - 276 2004年04月

ISSN 0360-4012

Endogenous neural stem/progenitor cells (NSPCs) have recently been shown to differentiate exclusively into astrocytes, the cells that are involved in glial scar formation after spinal cord injury (SCI). The microenvironment of the spinal cord, especially the inflammatory cytokines that dramatically increase in the acute phase at the injury site, is considered to be an important cause of inhibitory mechanism of neuronal differentiation following SCI. Interleukin-6 (IL-6), which has been demonstrated to induce NSPCs to undergo astrocytic differentiation selectively through the JAK/STAT pathway in vitro, has also been demonstrated to play a critical role as a proinflammatory cytokine and to be associated with secondary tissue damage in SCI. In this study, we assessed the efficacy of rat anti-mouse IL-6 receptor monoclonal antibody (MR16-1) in the treatment of acute SCI in mice. Immediately after contusive SCI with a modified NYU impactor, mice were intraperitoneally injected with a single dose of MR16-1 (100 μg/g body weight), the lesions were assessed histologically, and the functional recovery was evaluated. MR16-1 not only suppressed the astrocytic diffentiation-promoting effect of IL-6 signaling in vitro but inhibited the development of astrogliosis after SCI in vivo. MR16-1 also decreased the number of invading inflammatory cells and the severity of connective tissue scar formation. In addition, we observed significant functional recovery in the mice treated with MR16-1 compared with control mice. These findings suggest that neutralization of IL-6 signaling in the acute phase of SCI represents an attractive option for the treatment of SCI. © 2004 Wiley-Liss, Inc.

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Sox21 is a repressor of neuronal differentiation and is antagonized by YB-1

Ohba Hiroyuki, Chiyoda Tatsuyuki, Endo Emmy, Yano Masato, Hayakawa Yoshika, Sakaguchi Masanori, Darnell Robert B., Okano Hirotaka J., Okano Hideyuki

Neuroscience Letters 358 （ 3 ） 157 - 160 2004年04月

ISSN 0304-3940

Sox21, a high-mobility group box transcription factor, is expressed throughout the immature neural stem/progenitor population in ventricular zone but not in the cortical plate in embryonic mouse brain and its expression is restricted to the subventricular zone in the adult brain. In undifferentiated PC12 cells, endogenous Sox21 expression is detected but its expression ceases during the nerve growth factor (NGF)-induced neuronal differentiation. Overexpression of Sox21 results in a substantial repression of NGF-induced neurite outgrowth in PC12 cells. Further, we biochemically identified a Sox21-associating protein, Y-box binding protein 1 which not only binds to Sox21 but also partially restores NGF-induced neurite outgrowth of PC12 cells inhibited by Sox21. These results suggest that Sox21 is a repressor of neuronal differentiation in the developing nervous system. © 2004 Elsevier Ireland Ltd. All rights reserved.

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再生医療の過去、現在、未来

岡野栄之

炎症・再生 24 （ 2 ） 82-83 2004年03月

研究論文（学術雑誌）, 単著

Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression.

'Ieda Masaki, Fukuda Keiichi, Hisaka Yasuyo, Kimura Kensuke, Kawaguchi Haruko, Fujita Jun, Shimida Kouji, Takeshita Eiko, Okano Hideyuki, Kurihara Yukiko, Kurihara Hiroki, Ishida Junji, Fukamizu Akiyoshi, Federoff J. Howard, Ogawa Satoshi'

Journal of Clinical Investigation 113 876-884 2004年03月

研究論文（学術雑誌）, 共著, 査読有り

幹細胞を用いた移植治療

'辻俊幸,　吉崎崇仁,　岡野栄之'

分子リウマチ 1 （ 1 ） 50-55 2004年02月

研究論文（学術雑誌）, 単著

Expression of Musashi1, a neural RNA-binding protein, in the cochlea of young adult mice

Murata Junko, Murayama Ayako, Horii Arata, Doi Katsumi, Harada Tamotsu, Okano Hideyuki, Kubo Takeshi

Neuroscience Letters 354 （ 3 ） 201 - 204 2004年01月

ISSN 0304-3940

Musashi1 (Msi1) is an RNA-binding protein expressed in neural stem/progenitor cells, astroglial progenitor cells and astrocytes in the vertebrate central nervous system. We hypothesized that Msi1 is expressed in only some of the supporting cells in the cochlea, which could become hair cell progenitors under special circumstances after an injury. To observe this, we investigated Msi1 expression in young adult mouse cochlea by immunohistochemistry using monoclonal antibody against Msi1. Msi1 immunostaining was found in a variety of supporting cells but not in outer hair cells in the organ of Corti. Although an immunoreactive ring was found around the inner hair cells, it also seemed to originate from the supporting cells. We suppose that this wide expression of Msi1 in supporting cells indicates that those cells might have the potential to become hair cell progenitors if injured, but that some other mechanisms strictly inhibit this ability. © 2003 Elsevier Ireland Ltd. All rights reserved.

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Unexpectedly efficient homing capacity of purified murine hematopoietic stem cell.

'Matsuzaki Yumi, Kinjo Kentaro, Mulligan C.Richard, Okano Hideyuki'

Immunity 20 87-93 2004年01月

研究論文（学術雑誌）, 共著, 査読有り

Comparison between fetal spinal-cord- and forebrain-derived neural stem/progenitor cells as a source of transplantation for spinal cord injury

Watanabe Kota, Nakamura Masaya, Iwanami Akio, Fujita Yuko, Kanemura Yonehiro, Toyama Yoshiaki, Okano Hideyuki

Developmental Neuroscience 26 （ 2-4 ） 275 - 287 2004年

ISSN 0378-5866

Recently, we have shown that the transplantation of spinal-cord-derived neural stem/progenitor cells (NSPCs) can contribute to the repair of injured spinal cords in adult rats, which may correspond to a behavioral recovery. To apply these results to clinical practice, a system for supplying human NSPCs on a large scale must be established. However, human spinal-cord-derived NSPCs are known to have a low proliferation rate, compared with forebrain-derived NSPCs. This low proliferative potency limits the feasibility of large-scale spinal cord-derived NSPC use. Thus, forebrain-derived NSPCs should be examined as an alternative to spinal-cord-derived NSPCs for the treatment of spinal cord injuries. In this study, we compared spinal-cord- and forebrain-derived NSPCs transplanted into injured spinal cords with respect to their fates in vivo as well as the animals' functional recovery. Both spinal-cord- and forebrain-derived NSPCs promoted functional recovery in rats with spinal cord injuries. While both spinal-cord- and fore-brain-derived NSPCs survived, migrated and differentiated into neurons, astrocytes and oligodendrocytes in response to the microenvironment within the injured spinal cord after transplantation, forebrain-derived NSPCs differentiated into more neurons and fewer oligodendrocytes, compared to spinal-cord-derived NSPCs. Neurons that had differentiated from the transplanted forebrain-derived NSPCs were shown to be positive for neurotransmitters like GABA, glutamate and glycine, although authentic glycinergic neurons are not normally present within the forebrain. Thus, at least a subpopulation of the transplanted forebrain-derived NSPCs differentiated into spinal-cord-type neurons. In conclusion, forebrain-derived NSPCs could be used as an alternative to spinal-cord-derived NSPCs as a potential therapeutic agent for spinal cord injuries. Copyright © 2004 S. Karger AG.

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Vascular adventitia generates neuronal progenitors in the monkey hippocampus after ischemia

Yamashima Tetsumori, Tonchev Anton B., Vachkov Ivan H., Popivanova Boryana K., Seki Tatsunori, Sawamoto Kazunobu, Okano Hideyuki

Hippocampus 14 （ 7 ） 861 - 875 2004年

ISSN 1050-9631

In the adult hippocampus, neurogenesis proceeds in the subgranular zone (SGZ) of the dentate gyrus (DG), but not in the cornu Ammonis (CA). Recently, we demonstrated in monkeys that transient brain ischemia induces an increase of the neuronal progenitor cells in the SGZ, but not in CA1, in the second week after the insult. To identify the origin of primary neuronal progenitors in vivo, we compared the postischemic monkey DG and CA1, using light and electron microscopy, focusing on specific phenotype markers, as well as the expression of neurotrophic factors. Laser confocal microscopy showed that 1-3% of 5-bromo-2′-deoxyuridine (BrdU)-positive cells in the SGZ after 2-96 h labeling were also positive for neuronal markers such as TUC4, βIII tubulin, and NeuN on days 9 and 15. In contrast, despite the presence of numerous BrdU-positive cells, CA1 showed no neurogenesis at any time points, and all the progenitors were positive for glial markers: Iba1 or S-100β on days 4, 9, and 15. Highly polysialylated neural cell adhesion molecule (PSA-NCAM)-positive cells were abundant in the SGZ, but were absent in CA1. On day 9, most of the immature neurons positive for βIII-tubulin in SGZ showed an increase in PSA-NCAM immunoreactivity. The immunoreactivity of brain-derived neurotrophic factor (BDNF) was abundant at the vascular adventitia of the SGZ, but was absent at the adventitia of CA1. BrdU-positive progenitor cells were frequently seen in the vicinity of proliferating blood vessels. Ultrastructural analysis indicated that most of the neuronal progenitor cells and microglia originated from the pericytes of capillaries and/or adventitial cells of arterioles (called vascular adventitia). The detaching adventitial cells showed mitotic figures in the perivascular space, and the resultant neuronal progenitor cells made contact with dendritic spines associated with synaptic vesicles or boutons. These data implicate the vascular adventitia as a novel potential source of neuronal progenitor cells in the postischemic primate SGZ. © 2004 Wiley-Liss, Inc.

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Correlation between quantitative imaging and behavior in unilaterally 6-OHDA-lesioned rats

Inaji Motoki, Okauchi Takashi, Ando Kiyoshi, Maeda Jun, Nagai Yuji, Yoshizaki Takahito, Okano Hideyuki, Nariai Tadashi, Ohno Kikuo, Obayashi Shigeru, Higuchi Makoto, Suhara Tetsuya

Brain Research 1064 （ 1-2 ） 136 - 145 2005年12月

ISSN 0006-8993

We evaluated correlation between neurochemical and functional alterations of the nigrostriatal dopaminergic system in rat brains lesioned with 6-hydroxydopamine (6-OHDA), that model hemi-Parkinson's disease (PD), by using three different quantitative in vivo and in vitro methods. Rats unilaterally lesioned with different doses of 6-OHDA underwent two types of in vivo experiments: (1) a rotational behavioral study with methamphetamine (MAP) or apomorphine (APO); and (2) a positron emission tomography (PET) study with [¹¹C]PE2I (radioligand for dopamine transporters) or [ ¹¹C]raclopride (radioligand for dopamine D2 receptors). An in vitro autoradiographic study with the same radioligands was also conducted. The number of rotations after the MAP or APO injection increased with increased doses of 6-OHDA. The in vitro and in vivo binding of [¹¹C]PE2I dose-dependently decreased in response to the 6-OHDA injections, while that of [¹¹C]raclopride dose-dependently increased. There was a significant negative hyperbolic correlation between the number of rotations after MAP injection and the binding of [¹¹C]PE2I. In contrast, there was a significant positive linear correlation between the number of rotations after APO injections and the binding of [¹¹C]raclopride. These results robustly reveal a molecular pharmacological basis of parkinsonian symptoms in animal models of PD, and indicate the utility and validity of in vivo PET measurements in assessing pre- and post-synaptic dopaminergic functions. © 2005 Elsevier B.V. All rights reserved.

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