Faculty Profiles - ASANUMA Masato

Papers - ASANUMA Masato

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Spatiotemporal expression pattern of dyslexia susceptibility 1 candidate 1 (DYX1C1) during rat cerebral cortex development

Kazumasa Zensho, Ikuko Miyazaki, Aika Isse, Ichika Misawa, Kaori Masai, Makio Oka, Hirokazu Tsukahara, Masato Asanuma

Pediatric Research 2025.2

Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Abstract

Background

Developmental dyslexia (DD) is a common learning disorder with significant consequences for affected individuals. Although several candidate genes, including dyslexia susceptibility 1 candidate 1 (DYX1C1), have been implicated in dyslexia, their role in brain development remains unclear. We aimed to elucidate the spatiotemporal expression patterns of DYX1C1 during cerebral cortex development in rats.

Methods

We investigated DYX1C1 expression during cerebral cortex development using rat embryos at various gestational stages (E13.5, 15.5, 17.5 and 20.5) by immunohistochemistry (n = 7 embryos/stage), quantitative real-time PCR (n = 6), and in situ hybridization (n = 11–15).

Results

The DYX1C1-positive cells were predominantly located in the outermost layers of the cortical plate, particularly at E15.5. DYX1C1 mRNA expression peaked at E15.5 and subsequently declined. DYX1C1-positive cells did not co-localize with reelin-positive Cajal-Retzius cells, but co-localized with neuronal markers expressed during development, and had shorter primary cilia than DYX1C1-negative cells.

Conclusions

Our findings highlight the dynamic expression of DYX1C1 in the developing cerebral cortex of rats, implicating its involvement in neurodevelopmental processes. Further investigation of the functional interactions of DYX1C1, particularly its relationship with reelin and its role in cerebrocortical and hippocampal development, may provide insights into the pathophysiology of dyslexia and neurodevelopmental disorders.

Impact

Our study elucidates spatiotemporal expression patterns of endogenous DYX1C1 predominantly in the primitive cortical zone (PCZ), outermost layer of the cortical plate (CP) during cerebral cortex development, particularly peaked at E15.5.

We revealed the spatial relationship between DYX1C1-positive and reelin-expressing Cajal-Retzius (CR) cells, and co-localize with neuronal markers expressed during cerebral cortex development, indicating its contribution to neuronal migration and cortical layer formation.

DYX1C1-positive cells mainly in the PCZ possess shorter primary cilia than DYX1C1-negative cells, suggesting the completion of migration.

DOI： 10.1038/s41390-025-03920-6

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Other Link： https://www.nature.com/articles/s41390-025-03920-6

Editorial: Glial crosstalk in neurological disorders Reviewed

Ikuko Miyazaki, Masato Asanuma, Francisco Javier Díaz-Corrales

Frontiers in Cell and Developmental Biology 12 1515052 2024.11

Neurogenesis impairment with glial activation in the hippocampus-connected regions of intracerebroventricular streptozotocin-injected mice Reviewed

Kaori Masai, Yuta Nakayama, Kotaro Shin, Chiaki Sugahara, Ikuko Miyazaki, Takao Yasuhara, Isao Date, Masato Asanuma

Neuroscience Letters 820 137598 - 137598 2024.1

Behavioural and neurochemical alterations following acute inflammation induced by intraperitoneal and intratracheal injection with lipopolysaccharide in mice. Reviewed

Yasuhisa Izushi, Shouki Tanaka, Teppei Ueda, Soichiro Ushio, Yuichi Tasaka, Ikuko Miyazaki, Masato Asanuma, Yoshihisa Kitamura

Naunyn-Schmiedeberg's Archives of Pharmacology 2024

Differentially Expressed Nedd4-binding Protein Ndfip1 Protects Neurons Against Methamphetamine-induced Neurotoxicity. Reviewed

Masato Asanuma, Ikuko Miyazaki, Jean Lud Cadet

Neurotoxicity Research 2024

Phosphorylated SARM1 is involved in the pathological process of rotenone-induced neurodegeneration Reviewed

Hitoshi Murata, May Tha Zin Phoo, Toshiki Ochi, Nahoko Tomonobu, Ken-ichi Yamamoto, Rie Kinoshita, Ikuko Miyazaki, Masahiro Nishibori, Masato Asanuma, Masakiyo Sakaguchi

The Journal of Biochemistry 174 ( 6 ) 533 - 548 2023.9

Language：English Publishing type：Research paper (scientific journal) Publisher：Oxford University Press (OUP)

Abstract

Sterile alpha and Toll/interleukin receptor motif-containing protein 1 (SARM1) is a NAD+ hydrolase that plays a key role in axonal degeneration and neuronal cell death. We reported that c-Jun N-terminal kinase (JNK) activates SARM1 through phosphorylation at Ser-548. The importance of SARM1 phosphorylation in the pathological process of Parkinson’s disease (PD) has not been determined. We thus conducted the present study by using rotenone (an inducer of PD-like pathology) and neurons derived from induced pluripotent stem cells (iPSCs) from healthy donors and a patient with familial PD PARK2 (FPD2). The results showed that compared to the healthy neurons, FPD2 neurons were more vulnerable to rotenone-induced stress and had higher levels of SARM1 phosphorylation. Similar cellular events were obtained when we used PARK2-knockdown neurons derived from healthy donor iPSCs. These events in both types of PD-model neurons were suppressed in neurons treated with JNK inhibitors, Ca2+-signal inhibitors, or by a SARM1-knockdown procedure. The degenerative events were enhanced in neurons overexpressing wild-type SARM1 and conversely suppressed in neurons overexpressing the SARM1-S548A mutant. We also detected elevated SARM1 phosphorylation in the midbrain of PD-model mice. The results indicate that phosphorylated SARM1 plays an important role in the pathological process of rotenone-induced neurodegeneration.

DOI： 10.1093/jb/mvad068

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Other Link： https://academic.oup.com/jb/article-pdf/174/6/533/54447957/mvad068.pdf

Multifunctional Metallothioneins as a Target for Neuroprotection in Parkinson’s Disease Reviewed

Ikuko Miyazaki, Masato Asanuma

Antioxidants 12 ( 4 ) 894 - 894 2023.4

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Parkinson’s disease (PD) is characterized by motor symptoms based on a loss of nigrostriatal dopaminergic neurons and by non-motor symptoms which precede motor symptoms. Neurodegeneration accompanied by an accumulation of α-synuclein is thought to propagate from the enteric nervous system to the central nervous system. The pathogenesis in sporadic PD remains unknown. However, many reports indicate various etiological factors, such as oxidative stress, inflammation, α-synuclein toxicity and mitochondrial impairment, drive neurodegeneration. Exposure to heavy metals contributes to these etiopathogenesis and increases the risk of developing PD. Metallothioneins (MTs) are cysteine-rich metal-binding proteins; MTs chelate metals and inhibit metal-induced oxidative stress, inflammation and mitochondrial dysfunction. In addition, MTs possess antioxidative properties by scavenging free radicals and exert anti-inflammatory effects by suppression of microglial activation. Furthermore, MTs recently received attention as a potential target for attenuating metal-induced α-synuclein aggregation. In this article, we summarize MTs expression in the central and enteric nervous system, and review protective functions of MTs against etiopathogenesis in PD. We also discuss neuroprotective strategies for the prevention of central dopaminergic and enteric neurodegeneration by targeting MTs. This review highlights multifunctional MTs as a target for the development of disease-modifying drugs for PD.

DOI： 10.3390/antiox12040894

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Central and enteric neuroprotective effects by Eucommia ulmoides extracts on neurodegeneration in rotenone-induced parkinsonian mouse. Reviewed

Fuminori Imafuku, Ikuko Miyazaki, Jin Sun, Sunao Kamimai, Takashi Shimizu, Toshiaki Toyota, Yusei Okamoto, Nami Isooka, Ryo Kikuoka, Yoshihisa Kitamura, Masato Asanuma

Acta Medica Okayama 76 ( 4 ) 373 - 383 2022.8

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Parkinson's disease (PD) is a progressive neurodegenerative disease of both the central and peripheral / enteric nervous systems. Oxidative stress and neuroinflammation are associated with the pathogenesis of PD, suggesting that anti-oxidative and anti-inflammatory compounds could be neuroprotective agents for PD. Eucommia ulmoides (EU) is a traditional herbal medicine which exerts neuroprotective effects by anti-inflammatory and anti-oxidative properties. Our previous study showed that treatment with chlorogenic acid, a component of EU, protected against neurodegeneration in the central and enteric nervous systems in a PD model. In this study, we examined the effects of EU extract (EUE) administration on dopaminergic neurodegeneration, glial response and α-synuclein expression in the substantia nigra pars compacta (SNpc), and intestinal enteric neurodegeneration in low-dose rotenone-induced PD model mice. Daily oral administration of EUE ameliorated dopaminergic neurodegeneration and α-synuclein accumulation in the SNpc. EUE treatment inhibited rotenone-induced decreases in the number of total astrocytes and in those expressing the antioxidant molecule metallothionein. EUE also prevented rotenone-induced microglial activation. Furthermore, EUE treatment exerted protective effects against intestinal neuronal loss in the PD model. These results suggest that EU exerts neuroprotective effects in the central and enteric nervous systems of rotenone-induced parkinsonism mice, in part by glial modification.

DOI： 10.18926/AMO/63889

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Neuroprotective Effects of Anti-high Mobility Group Box-1 Monoclonal Antibody Against Methamphetamine-Induced Dopaminergic Neurotoxicity Reviewed

Kaori Masai, Keita Kuroda, Nami Isooka, Ryo Kikuoka, Shinki Murakami, Sunao Kamimai, Dengli Wang, Keyue Liu, Ikuko Miyazaki, Masahiro Nishibori, Masato Asanuma

Neurotoxicity Research 39 ( 5 ) 1511 - 1523 2021.10

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

DOI： 10.1007/s12640-021-00402-5

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Other Link： https://link.springer.com/article/10.1007/s12640-021-00402-5/fulltext.html

Glial cells as possible targets of neuroprotection through neurotrophic and antioxidative molecules in the central and enteric nervous systems in Parkinson’s disease. Reviewed

Nami Isooka, Ikuko Miyazaki, Masato Asanuma

Acta Medica Okayama 75 ( 5 ) 549 - 556 2021.10

Influence of 5-HT2A receptor function on anxiety-like behavior induced by a combination treatment with doxorubicin and cyclophosphamide in rats. Reviewed International journal

Hironori Tabuchi, Yoshihisa Kitamura, Soichiro Ushio, Shiho Kan, Yudai Wada, Yusuke Sumiyoshi, Yasuhisa Izushi, Ikuko Miyazaki, Masato Asanuma, Toshiaki Sendo

Psychopharmacology 238 ( 12 ) 3607 - 3614 2021.9

Language：English Publishing type：Research paper (scientific journal)

Anxiety-like behavior induced by a combination of doxorubicin and cyclophosphamide may be mediated by serotonin (5-HT)2A receptor hyperactivity. The anxiolytic effects of fluoxetine may be inhibited by this combination. The present study examined the mechanisms underlying anxiety-like behavior induced by the combination doxorubicin and cyclophosphamide in rats. Anxiety-like behavior was induced during a light-dark test by the doxorubicin and cyclophosphamide treatment (once a week for 2 weeks). 5-HT2A receptor and 5-HT2A receptor-mediated extracellular signal-related kinase (ERK)1/2 levels were measured using Western blotting. 5-HT reuptake activity in fluoxetine-treated rats was also examined using microdialysis. ( ±)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane, a 5-HT2A receptor agonist, induced anxiety-like behavior. The fluoxetine treatment increased extracellular 5-HT concentrations in the hippocampus of vehicle- and doxorubicin and cyclophosphamide-treated rats. 5-HT transporter levels in the hippocampus were not affected by chemotherapy. The doxorubicin and cyclophosphamide treatment did not alter 5-HT2A receptor levels in the frontal cortex. However, chemotherapy increased 5-HT2A receptor-mediated ERK1/2 phosphorylation levels significantly more than the vehicle treatment. The present results suggest that anxiety-like behavior induced by the combination of doxorubicin and cyclophosphamide is mediated by 5-HT2A receptor hyperactivity without an increase in 5-HT2A receptor levels in rats.

DOI： 10.1007/s00213-021-05979-5

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Glutathione and Related Molecules in Parkinsonism Invited Reviewed

Masato Asanuma, Ikuko Miyazaki

International Journal of Molecular Sciences 22 ( 16 ) 8689 - 8689 2021.8

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Glutathione (GSH) is the most abundant intrinsic antioxidant in the central nervous system, and its substrate cysteine readily becomes the oxidized dimeric cystine. Since neurons lack a cystine transport system, neuronal GSH synthesis depends on cystine uptake via the cystine/glutamate exchange transporter (xCT), GSH synthesis, and release in/from surrounding astrocytes. Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), a detoxifying master transcription factor, is expressed mainly in astrocytes and activates the gene expression of various phase II drug-metabolizing enzymes or antioxidants including GSH-related molecules and metallothionein by binding to the antioxidant response element (ARE) of these genes. Accumulating evidence has shown the involvement of dysfunction of antioxidative molecules including GSH and its related molecules in the pathogenesis of Parkinson’s disease (PD) or parkinsonian models. Furthermore, we found several agents targeting GSH synthesis in the astrocytes that protect nigrostriatal dopaminergic neuronal loss in PD models. In this article, the neuroprotective effects of supplementation and enhancement of GSH and its related molecules in PD pathology are reviewed, along with introducing new experimental findings, especially targeting of the xCT-GSH synthetic system and Nrf2–ARE pathway in astrocytes.

DOI： 10.3390/ijms22168689

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Lactoferrin-like Immunoreactivity in Distinct Neuronal Populations in the Mouse Central Nervous System. Reviewed

Shigeyoshi Shimaoka, Hitomi Hamaoka, Junji Inoue, Masato Asanuma, Ikuo Tooyama, Yoichi Kondo

Acta Medica Okayama 75 ( 2 ) 153 - 167 2021.4

Language：English Publishing type：Research paper (scientific journal)

Lactoferrin (Lf) is an iron-binding glycoprotein mainly found in exocrine secretions and the secondary granules of neutrophils. In the central nervous system (CNS), expression of the Lf protein has been reported in the lesions of some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as in the aged brain. Lf is primarily considered an iron chelator, protecting cells from potentially toxic iron or iron-requiring microorganisms. Other biological functions of Lf include immunomodulation and transcriptional regulation. However, the roles of Lf in the CNS have yet to be fully clarified. In this study, we raised an antiserum against mouse Lf and investigated the immunohistochemical localization of Lf-like immunoreactivity (Lf-LI) throughout the CNS of adult mice. Lf-LI was found in some neuronal populations throughout the CNS. Intense labeling was found in neurons in the olfactory systems, hypothalamic nuclei, entorhinal cortex, and a variety of brainstem nuclei. This study provides detailed information on the Lf-LI distribution in the CNS, and the findings should promote further understanding of both the physiological and pathological significance of Lf in the CNS.

DOI： 10.18926/AMO/61894

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アストロサイトの亜鉛関連分子を標的としたパーキンソン病治療戦略

宮崎育子, 浅沼幹人

日本薬理学雑誌 156 ( 2 ) 76 - 80 2021.2

パーキンソン病での神経保護標的としてのアストロサイトの抗酸化分子

浅沼幹人, 宮崎育子

日本薬理学雑誌 156 ( 1 ) 14 - 20 2021.1

N-Acetylcysteine Attenuates the Anxiety-Like Behavior and Spatial Cognition Impairment Induced by Doxorubicin and Cyclophosphamide Combination Treatment in Rats Reviewed

Yoshihisa Kitamura, Soichiro Ushio, Yusuke Sumiyoshi, Yudai Wada, Ikuko Miyazaki, Masato Asanuma, Toshiaki Sendo

Pharmacology 106 ( 5-6 ) 286 - 293 2021

Language：English Publishing type：Research paper (scientific journal) Publisher：S. Karger AG

Background: Cancer patients can suffer from psychological and cognitive disorders after chemotherapy, which influence quality of life. Objective: Oxidative stress may contribute to the psychological and cognitive disorders induced in rats by chemotherapy. In the present study, we examined the effects of N-acetylcysteine, an anti-oxidant, on anxiety-like behavior and cognitive impairment in rats treated with a combination of doxorubicin and cyclophosphamide. Methods: Rats were intraperitoneally injected with doxorubicin and cyclophosphamide once a week for 2 weeks. The light-dark test and the novel location recognition test were used to assess anxiety-like behavior and spatial cognition, respectively. The rats’ hippocampal levels of glutathione (GSH) and glutathione disulfide (GSSG) were measured using a GSSG/GSH quantification kit. Results: Combined treatment with doxorubicin and cyclophosphamide produced anxiety-like behavior and cognitive impairment in rats. N-acetylcysteine reversed the anxiety-like behavior and inhibition of novel location recognition induced by the combination treatment. Furthermore, the combination of doxorubicin and cyclophosphamide significantly reduced the rats’ hippocampal GSH/GSSG ratios. N-acetylcysteine reversed the reduction in the GSH/GSSG ratio seen in the doxorubicin and cyclophosphamide-treated rats. Conclusion: These results suggest that N-acetylcysteine inhibits doxorubicin and cyclophosphamide-induced anxiety-like behavior and cognitive impairment by reducing oxidative stress in the hippocampus.

DOI： 10.1159/000512117

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Neuron-Astrocyte Interactions in Parkinson’s Disease Invited Reviewed

Ikuko Miyazaki, Masato Asanuma

Cells 9 ( 12 ) 2623 - 2623 2020.12

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Parkinson’s disease (PD) is the second most common neurodegenerative disease. PD patients exhibit motor symptoms such as akinesia/bradykinesia, tremor, rigidity, and postural instability due to a loss of nigrostriatal dopaminergic neurons. Although the pathogenesis in sporadic PD remains unknown, there is a consensus on the involvement of non-neuronal cells in the progression of PD pathology. Astrocytes are the most numerous glial cells in the central nervous system. Normally, astrocytes protect neurons by releasing neurotrophic factors, producing antioxidants, and disposing of neuronal waste products. However, in pathological situations, astrocytes are known to produce inflammatory cytokines. In addition, various studies have reported that astrocyte dysfunction also leads to neurodegeneration in PD. In this article, we summarize the interaction of astrocytes and dopaminergic neurons, review the pathogenic role of astrocytes in PD, and discuss therapeutic strategies for the prevention of dopaminergic neurodegeneration. This review highlights neuron-astrocyte interaction as a target for the development of disease-modifying drugs for PD in the future.

DOI： 10.3390/cells9122623

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Mirtazapine exerts astrocyte-mediated dopaminergic neuroprotection Reviewed

Ryo Kikuoka, Ikuko Miyazaki, Natsuki Kubota, Megumi Maeda, Daiki Kagawa, Masaaki Moriyama, Asuka Sato, Shinki Murakami, Yoshihisa Kitamura, Toshiaki Sendo, Masato Asanuma

Scientific Reports 10 ( 1 ) 20698 - 20698 2020.12

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

<title>Abstract</title>Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), is known to activate serotonin (5-HT) 1A receptor. Our recent study demonstrated that stimulation of astrocytic 5-HT1A receptors promoted astrocyte proliferation and upregulated antioxidative property in astrocytes to protect dopaminergic neurons against oxidative stress. Here, we evaluated the neuroprotective effects of mirtazapine against dopaminergic neurodegeneration in models of Parkinson’s disease (PD). Mirtazapine administration attenuated the loss of dopaminergic neurons in the substantia nigra and increased the expression of the antioxidative molecule metallothionein (MT) in the striatal astrocytes of 6-hydroxydopamine (6-OHDA)-injected parkinsonian mice via 5-HT1A receptors. Mirtazapine protected dopaminergic neurons against 6-OHDA-induced neurotoxicity in mesencephalic neuron and striatal astrocyte cocultures, but not in enriched neuronal cultures. Mirtazapine-treated neuron-conditioned medium (Mir-NCM) induced astrocyte proliferation and upregulated MT expression via 5-HT1A receptors on astrocytes. Furthermore, treatment with medium from Mir-NCM-treated astrocytes protected dopaminergic neurons against 6-OHDA neurotoxicity, and these effects were attenuated by treatment with a MT-1/2-specific antibody or 5-HT1A antagonist. Our study suggests that mirtazapine could be an effective disease-modifying drug for PD and highlights that astrocytic 5-HT1A receptors may be a novel target for the treatment of PD.

DOI： 10.1038/s41598-020-77652-4

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Other Link： http://www.nature.com/articles/s41598-020-77652-4

The Rotenone Models Reproducing Central and Peripheral Features of Parkinson’s Disease Reviewed

Ikuko Miyazaki, Masato Asanuma

NeuroSci 1 ( 1 ) 1 - 14 2020.8

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Parkinson’s disease (PD) is a complex, multi-system, neurodegenerative disorder; PD patients exhibit motor symptoms (such as akinesia/bradykinesia, tremor, rigidity, and postural instability) due to a loss of nigrostriatal dopaminergic neurons, and non-motor symptoms such as hyposmia, autonomic disturbance, depression, and REM sleep behavior disorder (RBD), which precedes motor symptoms. Pathologically, α-synuclein deposition is observed in the central and peripheral nervous system of sporadic PD patients. To clarify the mechanism of neurodegeneration in PD and to develop treatment to slow or stop PD progression, there is a great need for experimental models which reproduce neurological features of PD. Animal models exposed to rotenone, a commonly used pesticide, have received most attention since Greenamyre and his colleagues reported that chronic exposure to rotenone could reproduce the anatomical, neurochemical, behavioral, and neuropathological features of PD. In addition, recent studies demonstrated that rotenone induced neuropathological change not only in the central nervous system but also in the peripheral nervous system in animals. In this article, we review rotenone models especially focused on reproducibility of central and peripheral multiple features of PD. This review also highlights utility of rotenone models for investigation of PD pathogenesis and development of disease-modifying drugs for PD in future.

DOI： 10.3390/neurosci1010001

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The neurotoxicity of psychoactive phenethylamines “2C series” in cultured monoaminergic neuronal cell lines Reviewed

Masato Asanuma, Ikuko Miyazaki, Masahiko Funada

Forensic Toxicology 38 ( 2 ) 394 - 408 2020.7

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

DOI： 10.1007/s11419-020-00527-w

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Other Link： http://link.springer.com/article/10.1007/s11419-020-00527-w/fulltext.html

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Papers - ASANUMA Masato