Publications by authors named "Daiki Asano"

23 Publications

  • Page 1 of 1

Decline in Motor Function during the COVID-19 Pandemic Restrictions and Its Recovery in a Child with Cerebral Palsy: A Case Report.

Children (Basel) 2021 Jun 17;8(6). Epub 2021 Jun 17.

Neurorehabilitation Research Center, Kio University, Nara 635-0832, Japan.

Children with cerebral palsy (CP) experience various restrictions owing to their underdeveloped mobility. Home confinement due to the coronavirus disease 2019 pandemic may further increase these restrictions. We report the case of a 7-year-old boy with CP (Gross Motor Function Classification System level IV) whose motor function declined during the period when physical therapy was discontinued due to lockdown, approximately four months. At the end of the home confinement, the patient's ability to maintain a sitting posture and weight-bearing capacity of the lower extremities decreased. His Gross Motor Function Measure total score also decreased from 34.5% to 31.9%. After resuming physical therapy, the patient recovered the function status seen before the discontinuation of physical therapy, but this took almost twice as long as the confinement period. We reaffirm that frequent physical therapy is crucial for maintaining motor function in non-ambulatory children with CP. As a countermeasure for the future, urgent efforts are needed for the development of telerehabilitation.
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http://dx.doi.org/10.3390/children8060511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234799PMC
June 2021

Impairment of endothelium-dependent vasodilator function of retinal blood vessels in adult rats with a history of retinopathy of prematurity.

J Pharmacol Sci 2021 Aug 7;146(4):233-243. Epub 2021 May 7.

Department of Molecular Pharmacology, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. Electronic address:

Retinopathy of prematurity (ROP) is a proliferative retinal vascular disease, initiated by delayed retinal vascular growth after premature birth. In the majority of cases, ROP resolves spontaneously; however, a history of ROP may increase the risk of long-term visual problems. In this study, we evaluated the endothelial function of retinal blood vessels in adult rats with a history of ROP. ROP was induced in rats by subcutaneous injection of a vascular endothelial growth factor receptor tyrosine kinase inhibitor (KRN633) on postnatal day (P) 7 and P8. On P56, vasodilator responses to acetylcholine, GSK1016790A (an activator of transient receptor potential vanilloid 4 channels), NOR3 (a nitric oxide [NO] donor), and salbutamol (a β-adrenoceptor agonist) were assessed. Compared to age-matched controls, retinal vasodilator responses to acetylcholine and GSK1016790A were attenuated in P56 rats with a history of ROP. No attenuation of acetylcholine-induced retinal vasodilator response was observed under inhibition of NO synthase. Retinal vasodilator responses to NOR3 and salbutamol were unaffected. These results suggest that the production of and/or release of NO is impaired in retinal blood vessels in adult rats with a history of ROP. A history of ROP might increase the risk of impaired retinal circulation in adulthood.
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http://dx.doi.org/10.1016/j.jphs.2021.04.008DOI Listing
August 2021

Metformin Protects against NMDA-Induced Retinal Injury through the MEK/ERK Signaling Pathway in Rats.

Int J Mol Sci 2021 Apr 23;22(9). Epub 2021 Apr 23.

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo 108-8641, Japan.

Metformin, an anti-hyperglycemic drug of the biguanide class, exerts positive effects in several non-diabetes-related diseases. In this study, we aimed to examine the protective effects of metformin against -methyl-D-aspartic acid (NMDA)-induced excitotoxic retinal damage in rats and determine the mechanisms of its protective effects. Male Sprague-Dawley rats (7 to 9 weeks old) were used in this study. Following intravitreal injection of NMDA (200 nmol/eye), the number of neuronal cells in the ganglion cell layer and parvalbumin-positive amacrine cells decreased, whereas the number of CD45-positive leukocytes and Iba1-positive microglia increased. Metformin attenuated these NMDA-induced responses. The neuroprotective effect of metformin was abolished by compound C, an inhibitor of AMP-activated protein kinase (AMPK). The AMPK activator, AICAR, exerted a neuroprotective effect in NMDA-induced retinal injury. The MEK1/2 inhibitor, U0126, reduced the neuroprotective effect of metformin. These results suggest that metformin protects against NMDA-induced retinal neurotoxicity through activation of the AMPK and MEK/extracellular signal-regulated kinase (ERK) signaling pathways. This neuroprotective effect could be partially attributable to the inhibitory effects on inflammatory responses.
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http://dx.doi.org/10.3390/ijms22094439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123037PMC
April 2021

Self-Rated Depressive Symptoms in Children and Youth with and without Cerebral Palsy: A Pilot Study.

Behav Sci (Basel) 2020 Nov 1;10(11). Epub 2020 Nov 1.

Neurorehabilitation Research Center, Kio University, Nara 635-0832, Japan.

Children with cerebral palsy (CP) often exhibit mental health problems, such as depressive symptoms. The purpose of this study was to describe the self-rated depressive symptoms in children with and without CP and to investigate the associated predictors. Participants included 24 children with CP and 33 typically developing (TD) children. Depressive symptoms were assessed using the Birleson Depression Self-Rating Scale for Children. Parents of the participants completed the Strengths and Difficulties Questionnaire. Severity of self-rated depressive symptoms was higher in children with CP than that in TD children. Particularly, decline in activities and enjoyment was identified as a contributor to the increased severity of depressive symptoms. Hierarchical multiple regression analysis revealed that the greater severity of depressive symptoms in children with CP was mediated by hyperactivity/inattention and peer problems. Our study suggests that it is imperative to provide opportunities to participate in social activities from an early age.
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http://dx.doi.org/10.3390/bs10110167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694084PMC
November 2020

Abnormal Vascular Phenotypes Associated with the Timing of Interruption of Retinal Vascular Development in Rats.

Biol Pharm Bull 2020 ;43(5):859-863

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences.

Pathological angiogenesis is a leading cause of blindness in several retinal diseases. The key driving factor inducing pathological angiogenesis is the pronounced hypoxia leading to a marked, increased production of vascular endothelial growth factor (VEGF). The aim of this study was to determine whether the abnormal vascular growth occurs in a manner dependent on the degree of the vascular defects. Vascular defects of two different degrees were created in the retina by subcutaneously treating neonatal rats with the VEGF receptor (VEGFR) tyrosine kinase inhibitor KRN633 on postnatal day (P) 4 and P5 (P4/5) or P7 and P8 (P7/8). The structure of the retinal vasculature changes was examined immunohistochemically. Prevention of vascular growth and regression of some preformed capillaries were observed on the next day, after completion of each treatment (i.e., P6 and P9). The vascular regrowth occurred as a result of eliminating the inhibitory effect on the VEGFR signaling pathway. KRN633 (P4/5)-treated rats exhibited a retinal vasculature with aggressive intravitreal neovascularization on P21. On the other hand, the appearance of tortuous arteries is a representative vascular pathological feature in retinas of KRN633 (P7/8)-treated groups. These results suggest that an interruption of the retinal vascular development at different time points induces different vascular pathological features in the retina. Pharmacological agents targeting the VEGF signaling pathway are useful for creating an abnormal retinal vasculature with various pathological features in order to evaluate the efficacy of anti-angiogenic compounds.
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http://dx.doi.org/10.1248/bpb.b19-01065DOI Listing
January 2021

[Expression changes in microRNA in the retina of retinal degenerative diseases].

Nihon Yakurigaku Zasshi 2020 ;155(2):81-86

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences.

Because visual information accounts for 80-90% of sensory information that we get from our circumstance, loss of vision seriously diminishes our quality of life. According to a recent epidemiological study, glaucoma is the first, and retinitis pigmentosa (RP) is the second leading causes of acquired blindness in Japan. Degeneration of the retinal ganglion cells (RGC) and photoreceptor cells causes glaucoma and RP, respectively. Intraocular pressure-lowering therapy is an only effective treatment for glaucoma, and the agents that protect RGC directly against glaucomatous injury have not been available yet. In addition, there is no effective treatment for RP at present. microRNAs are a class of small, endogenous, non-coding RNAs comprised of approximately 20 nucleotides. It has been clarified that microRNAs reduces the stability of the target mRNAs and/or repress the translation of the target genes. A single microRNA can affect the transcription of multiple mRNAs, and almost 30% of human genes are thought to be regulated by microRNAs. Therefore, it has been considered that the expression changes of microRNAs are possible to cause various diseases, such as cancer and neurodegenerative diseases. Recently, the expression changes in microRNAs have been reported in the retina of experimental model animals for glaucoma and RP. The expressional changes of microRNAs are suggested to be related with development and progression of glaucoma and RP. Here, we will discuss about the relationship between the expressional changes of microRNAs and neuronal cell death in glaucoma and RP.
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http://dx.doi.org/10.1254/fpj.19121DOI Listing
March 2020

Changes in components of the neurovascular unit in the retina in a rat model of retinopathy of prematurity.

Cell Tissue Res 2020 Mar 2;379(3):473-486. Epub 2019 Dec 2.

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.

An impairment of cellular interactions between the elements of the neurovascular unit contributes to the onset and/or progression of retinal diseases. The present study aims to examine how elements of the neurovascular unit are altered in a rat model of retinopathy of prematurity (ROP). Neonatal rats were treated subcutaneously with the vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor KRN633 (10 mg/kg) on postnatal day (P) 7 and P8 to induce ROP. Morphological assessments were performed of blood vessels, astrocytes and neuronal cells in the retina. Aggressive angiogenesis, tortuous arteries and enlarged veins were observed in the retinal vasculature of KRN633-treated (ROP) rats from P14 to P28, compared to age-matched control (vehicle-treated) animals. Morphological abnormalities in the retinal vasculature showed a tendency toward spontaneous recovery from P28 to P35 in ROP rats. Immunofluorescence staining for glial fibrillary acidic protein and Pax2 (astrocyte markers) revealed that morphological changes to and a reduction in the number of astrocytes occurred in ROP rats. The developmental cell death was slightly accelerated in ROP rats; however, no visible changes in the morphology of retinal layers were observed on P35. The abnormalities in astrocytes might contribute, at least in part, to the formation of abnormal retinal blood vessels and the pathogenesis of ROP.
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http://dx.doi.org/10.1007/s00441-019-03112-9DOI Listing
March 2020

Cellular Mechanisms of Angiogenesis in Neonatal Rat Models of Retinal Neurodegeneration.

Int J Mol Sci 2019 Sep 25;20(19). Epub 2019 Sep 25.

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.

Νeuronal and glial cells play an important role in the development of vasculature in the retina. In this study, we investigated whether re-vascularization occurs in retinal neurodegenerative injury models. To induce retinal injury, -methyl-D-aspartic acid (NMDA, 200 nmol) or kainic acid (KA, 20 nmol) was injected into the vitreous chamber of the eye on postnatal day (P)7. Morphological changes in retinal neurons and vasculature were assessed on P14, P21, and P35. Prevention of vascular growth and regression of some capillaries were observed on P14 in retinas of NMDA- and KA-treated eyes. However, vascular growth and re-vascularization started on P21, and the retinal vascular network was established by P35 in retinas with neurodegenerative injuries. The re-vascularization was suppressed by a two-day treatment with KRN633, an inhibitor of VEGF receptor tyrosine kinase, on P21 and P22. Astrocytes and Müller cells expressed vascular endothelial growth factor (VEGF), and the distribution pattern of VEGF was almost the same between the control and the NMDA-induced retinal neurodegenerative injury model, except for the difference in the thickness of the inner retinal layer. During re-vascularization, angiogenic sprouts from pre-existing blood vessels were present along the network of fibronectins formed by astrocytes. These results suggest that glial cells contribute to angiogenesis in neonatal rat models of retinal neurodegeneration.
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http://dx.doi.org/10.3390/ijms20194759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801463PMC
September 2019

Attenuation of Retinal Endothelial Vasodilator Function in a Rat Model of Retinopathy of Prematurity.

Curr Eye Res 2019 12 18;44(12):1360-1368. Epub 2019 Jul 18.

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan.

: Retinopathy of prematurity (ROP) is characterized by morphological abnormalities in retinal blood vessels, but how an episode of ROP affects vascular function remains to be fully elucidated. The purpose of the present study was to assess the distribution of pericyte/smooth muscle in retinal blood vessels and retinal vasodilator responses in a rat model of ROP.: ROP was induced in rats by the subcutaneous injection of the vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor KRN633 (10 mg/kg) on postnatal day (P) 7 and P8. The distribution of pericyte/smooth muscle in retinal blood vessels was examined on P14 and P35 by immunohistochemistry. Retinal vasodilator responses were assessed on P35 by measuring the diameter of retinal arterioles in fundus images.: In retinas of KRN633-treated (ROP) rats, progressive angiogenesis, tortuous arteries, enlarged veins, and enhanced expression of α-smooth muscle actin in pericytes on capillaries and veins were observed on P14. These abnormalities in retinal vasculature showed a tendency to normalize by P35. Vasodilation of retinal arterioles induced by acetylcholine, an endothelium-dependent vasodilator, was smaller in P35 ROP rats than age-matched controls, whereas retinal vasodilator responses to the nitric oxide (NO) donor NOR3 were unaltered.: Phenotypic changes in pericytes occur in the ROP model rats and endothelium-dependent vasodilatory mechanisms in retinal blood vessels are impaired. The impaired vasodilator function may contribute to the progression and pathogenesis of ROP.
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http://dx.doi.org/10.1080/02713683.2019.1641825DOI Listing
December 2019

Role of Neuron⁻Glia Signaling in Regulation of Retinal Vascular Tone in Rats.

Int J Mol Sci 2019 Apr 20;20(8). Epub 2019 Apr 20.

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.

The interactions between neuronal, glial, and vascular cells play a key role in regulating blood flow in the retina. In the present study, we examined the role of the interactions between neuronal and glial cells in regulating the retinal vascular tone in rats upon stimulation of retinal neuronal cells by intravitreal injection of N-methyl-d-aspartic acid (NMDA). The retinal vascular response was assessed by measuring the diameter of the retinal arterioles in the in vivo fundus images. Intravitreal injection of NMDA produced retinal vasodilation that was significantly diminished following the pharmacological inhibition of nitric oxide (NO) synthase (nNOS), loss of inner retinal neurons, or intravitreal injection of glial toxins. Immunohistochemistry revealed the expression of nNOS in ganglion and calretinin-positive amacrine cells. Moreover, glial toxins significantly prevented the retinal vasodilator response induced by intravitreal injection of NOR3, an NO donor. Mechanistic analysis revealed that NO enhanced the production of vasodilatory prostanoids and epoxyeicosatrienoic acids in glial cells in a ryanodine receptor type 1-dependent manner, subsequently inducing the retinal vasodilator response. These results suggest that the NO released from stimulated neuronal cells acts as a key messenger in neuron-glia signaling, thereby causing neuronal activity-dependent and glial cell-mediated vasodilation in the retina.
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http://dx.doi.org/10.3390/ijms20081952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514555PMC
April 2019

Involvement of matrix metalloproteinases in capillary degeneration following NMDA-induced neurotoxicity in the neonatal rat retina.

Exp Eye Res 2019 05 16;182:101-108. Epub 2019 Mar 16.

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan. Electronic address:

Interactions between neuronal cells and vascular cells in the retina are critical for maintaining retinal tissue homeostasis. Impairment of cellular interactions contributes to development and progression of retinal diseases. Previous studies demonstrated that neuronal cell damage leads to capillary degeneration in an N-methyl-D-aspartic acid (NMDA)-induced retinal degeneration model. However, the mechanisms underlying this phenomenon are not fully understood. In this study, we examined the possible role of matrix metalloproteinase (MMP)-9 in neuronal cell loss and capillary degeneration in NMDA-treated retinas of neonatal rats. Intravitreal injection of NMDA (50 or 200 nmol) was performed on postnatal day (P) 7 and morphological changes in retinal neurons and vasculature were examined on P14. The MMP inhibitor CP101537 (100 nmol) or vehicle (dimethyl sulfoxide) was intravitreally injected simultaneously with, or 2 days after, NMDA injection. CP101537 protected against neurovascular degeneration in a time-dependent manner as follows: 1) simultaneous injection of CP101537 with NMDA prevented morphological changes in retinal neurons induced by NMDA (50 nmol); and 2) reduction in capillary density and number of vertical sprouts induced by NMDA (200 nmol) was prevented when CP101537 was injected 2 days after NMDA injection. Gelatin zymography and western blot analyses indicated that activity and protein levels of MMP-9 were enhanced from 4 h to 2 days after NMDA injection. Increased activity and protein levels of MMP-9 were suppressed by MMP inhibitors (CP101537 and GM6001). In situ zymography revealed that MMP activity was enhanced throughout the retinal vasculature in NMDA-treated retinas. These results indicate that MMP-9 plays an important role in neurovascular degeneration in the injured retina. Inhibition of MMP-9 may be an effective strategy for preventing and reducing neurovascular degeneration.
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http://dx.doi.org/10.1016/j.exer.2019.03.005DOI Listing
May 2019

Manual Dexterity Is a Strong Predictor of Visuo-Motor Temporal Integration in Children.

Front Psychol 2018 12;9:948. Epub 2018 Jun 12.

Graduate School of Clinical Education & The Center for the Study of Child Development, Institute for Education, Mukogawa Women's University, Hyogo, Japan.

Although visuo-motor temporal integration in children is suggested to be related to motor control and motor learning, its relevance is still unclear. On the other hand, visuo-motor temporal integration ability undergoes developmental changes with age. In the current correlational study, we measured manual dexterity and visuo-motor temporal integration ability in 132 children with typical development (age, 4-15 years) and investigated the relationship between the two functions. The Movement Assessment Battery for Children-2nd edition was used as an indicator of manual dexterity. The delay detection threshold (DDT) and steepness of the probability curve for delay detection, which was measured by the delayed visual feedback detection task for self-generated movement, were used as indices of the visuo-motor temporal integration ability. The results indicated significant correlations between manual dexterity/age and DDT/steepness of the probability curve for delay detection. In addition, hierarchical multiple regression analysis showed that both manual dexterity and age significantly contributed to visuo-motor temporal integration, indicating a better fit than when only age was employed as an independent variable. Importantly, there was no interaction effect between age and manual dexterity. These findings were the first to suggest that manual dexterity is a significant predictor of visuo-motor temporal integration ability in children, regardless of age. The present study validated the important relationship between visuo-motor temporal integration and manual dexterity in children. Considering the limitations of the current study, including the non-homogeneous sample, further studies are still warranted to validate the results.
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http://dx.doi.org/10.3389/fpsyg.2018.00948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005835PMC
June 2018

Deficits in Visuo-Motor Temporal Integration Impacts Manual Dexterity in Probable Developmental Coordination Disorder.

Front Neurol 2018 5;9:114. Epub 2018 Mar 5.

Hyogo Children's Sleep and Development Medical Research Center, Kobe, Japan.

The neurological basis of developmental coordination disorder (DCD) is thought to be deficits in the internal model and mirror-neuron system (MNS) in the parietal lobe and cerebellum. However, it is not clear if the visuo-motor temporal integration in the internal model and automatic-imitation function in the MNS differs between children with DCD and those with typical development (TD). The current study aimed to investigate these differences. Using the manual dexterity test of the Movement Assessment Battery for Children (second edition), the participants were either assigned to the probable DCD (pDCD) group or TD group. The former was comprised of 29 children with clumsy manual dexterity, while the latter consisted of 42 children with normal manual dexterity. Visuo-motor temporal integration ability and automatic-imitation function were measured using the delayed visual feedback detection task and motor interference task, respectively. Further, the current study investigated whether autism-spectrum disorder (ASD) traits, attention-deficit hyperactivity disorder (ADHD) traits, and depressive symptoms differed among the two groups, since these symptoms are frequent comorbidities of DCD. In addition, correlation and multiple regression analyses were performed to extract factors affecting clumsy manual dexterity. In the results, the delay-detection threshold (DDT) and steepness of the delay-detection probability curve, which indicated visuo-motor temporal integration ability, were significantly prolonged and decreased, respectively, in children with pDCD. The interference effect, which indicated automatic-imitation function, was also significantly reduced in this group. These results highlighted that children with clumsy manual dexterity have deficits in visuo-motor temporal integration and automatic-imitation function. There was a significant correlation between manual dexterity, and measures of visuo-motor temporal integration, and ASD traits and ADHD traits and ASD. Multiple regression analysis revealed that the DDT, which indicated visuo-motor temporal integration, was the greatest predictor of poor manual dexterity. The current results supported and provided further evidence for the internal model deficit hypothesis. Further, they suggested a neurorehabilitation technique that improved visuo-motor temporal integration could be therapeutically effective for children with DCD.
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http://dx.doi.org/10.3389/fneur.2018.00114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844924PMC
March 2018

Retinal neuronal cell loss prevents abnormal retinal vascular growth in a rat model of retinopathy of prematurity.

Exp Eye Res 2018 03 2;168:115-127. Epub 2018 Feb 2.

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. Electronic address:

A short-term blockade of the vascular endothelial growth factor (VEGF)-mediated pathway in neonatal rats results in formation of severe retinopathy of prematurity (ROP)-like retinal blood vessels. The present study aimed to examine the role of retinal neurons in the formation of abnormal retinal blood vessels. Newborn rats were treated subcutaneously with the VEGF receptor tyrosine kinase inhibitor, KRN633 (10 mg/kg), or its vehicle (0.5% methylcellulose in water) on postnatal day (P) 7 and P8. To induce excitotoxic loss of retinal neurons, N-methyl-D-aspartic acid (NMDA) was injected into the vitreous chamber of the eye on P9. Changes in retinal morphology, blood vessels, and proliferative status of vascular cells were evaluated on P11 and P14. The number of cells in the ganglion cell layer and the thickness of the inner plexiform layer and inner nuclear layer were significantly decreased 2 days (P11) after NMDA treatment. The pattern and degree of NMDA-induced changes in retinal morphology were similar between vehicle-treated (control) and KRN633-treated (ROP) rats. In ROP rats, increases in the density of capillaries, the tortuosity index of arteries, and the proliferating vascular cells were observed on P14. The expansion of the endothelial cell network was prevented, and the capillary density and the number of proliferating cells were reduced in NMDA-treated retinas of both control and ROP rats. Following NMDA-induced neuronal cell loss, no ROP-like blood vessels were observed in the retinas. These results suggest that retinal neurons play an important role in the formation of normal and ROP-like retinal blood vessels.
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http://dx.doi.org/10.1016/j.exer.2017.12.007DOI Listing
March 2018

Role of Glial Cells in μ-Opioid Receptor-Mediated Vasodilation in the Rat Retina.

Curr Eye Res 2018 03 27;43(3):350-356. Epub 2017 Nov 27.

a Department of Molecular Pharmacology , Kitasato University School of Pharmaceutical Sciences , Tokyo Japan.

Purpose: Our recent study demonstrated that herkinorin, a non-opioid μ-receptor agonist derived from salvinorin A, dilates retinal arterioles through stimulation of μ-opioid receptors in rats. Activation of neuronal nitric oxide (NO) synthase and the presence of ganglion cells in the retina appear to be crucial for inducing μ-opioid receptor-mediated retinal vasodilation. In the present study, we examined the role of the interaction between neurons and glia in the retinal vasodilator mechanism involving μ-opioid receptors in rats.

Materials And Methods: The localization of μ-opioid receptors and neuronal NO synthase (nNOS) in the rat retina was examined using immunohistochemistry. The retinal vascular responses were evaluated by measuring the diameter of retinal arterioles in in vivo fundus images. Both systemic blood pressure and heart rate were continuously recorded.

Results: Immunoreactivity of μ-opioid receptors was found in ganglion cells and astrocytes, while that of nNOS was detected in ganglion cells and amacrine cells. Herkinorin increased retinal arteriolar diameter without significantly changing mean blood pressure and heart rate. The retinal vasodilator response to herkinorin was significantly attenuated by treatment with glial toxins (fluorocitrate and disialoganglioside-GD1b). The glial toxins markedly prevented vasodilation induced by intravitreal injection, but not by intravenous infusion, of NOR3, an NO donor.

Conclusion: These results suggest that retinal glial cells play an important role in the μ-opioid receptor-mediated retinal vasodilation in rats. Stimulation of μ-opioid receptors on retinal ganglion cells may affect the activity of glial cells, thereby changing retinal vascular tone.
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http://dx.doi.org/10.1080/02713683.2017.1403631DOI Listing
March 2018

Transcranial Direct Current Stimulation of the Temporoparietal Junction and Inferior Frontal Cortex Improves Imitation-Inhibition and Perspective-Taking with no Effect on the Autism-Spectrum Quotient Score.

Front Behav Neurosci 2017 9;11:84. Epub 2017 May 9.

Neurorehabilitation Research Center, Kio UniversityNara, Japan.

Lesions to brain regions such as the temporoparietal junction (TPJ) and inferior frontal cortex (IFC) are thought to cause autism-spectrum disorder (ASD). Previous studies indicated that transcranial direct current stimulation (tDCS) of the right TPJ improves social cognitive functions such as imitation-inhibition and perspective-taking. Although previous work shows that tDCS of the right IFC improves imitation-inhibition, its effects on perspective-taking have yet to be determined. In addition, the role of the TPJ and IFC in determining the Autism-Spectrum Quotient (AQ), which is a measure of autism spectrum traits, is still unclear. Thus, the current study performed tDCS on the right TPJ and the right IFC of healthy adults, and examined its effects on imitation-inhibition, perspective-taking and AQ scores. Based on previous studies, we hypothesized that anodal tDCS of the right IFC and right TPJ would improve imitation-inhibition, perspective-taking and the AQ score. Anodal tDCS of the right TPJ or IFC significantly decreased the interference effect in an imitation-inhibition task and the cost of perspective-taking in a perspective-taking task, in comparison to the sham stimulation control. These findings indicated that both the TPJ and the IFC play a role in imitation-inhibition and perspective-taking, i.e., control of self and other representations. However, anodal stimulation of the right TPJ and the right IFC did not alter participants' AQ. This finding conflicts with results from previous brain imaging studies, which could be attributed to methodological differences such as variation in sex, age and ASD. Therefore, further research is necessary to determine the relationship between the TPJ and IFC, and the AQ.
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http://dx.doi.org/10.3389/fnbeh.2017.00084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5422472PMC
May 2017

Associations between tactile localization and motor function in children with motor deficits.

Int J Dev Disabil 2017 Jan 12;64(2):113-119. Epub 2017 Jan 12.

Department of Neurorehabilitation, Graduate School of Health Science, Kio University, Nara, Japan.

Children with developmental disorders often have poor motor performance. This study aimed to address the association between tactile localization ability, an indicator of body image, and motor function in children with motor deficits. Eighteen children with motor deficits participated, and their upper and lower limbs were assessed. To assess the level to which the patient's body image was developed, a tactile localization task (TLT) was used. In the TLT, experimenters touched a child's fingers, toes, or lower extremities (L/E), and the participants were asked to identify the location of the touch on a body part illustration. We compared TLT ability between high and low motor function groups, and investigated the correlation between TLT and the measures of motor function, age, and non-verbal intelligence. The high motor function group had significantly higher L/E TLT scores than the low motor function group, except in the tests involving the fingers and toes. Furthermore, the L/E TLT correlated only with motor function measures (Gross Motor Function Measure score, measured using one-leg standing time and one-leg hopping ability). The results suggest that children with motor deficits experience developmental delay in terms of their body image.
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http://dx.doi.org/10.1080/20473869.2016.1278316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115462PMC
January 2017

Protective effects of PF-4708671 against N-methyl-d-aspartic acid-induced retinal damage in rats.

Fundam Clin Pharmacol 2016 Dec 10;30(6):529-536. Epub 2016 Aug 10.

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.

We previously demonstrated that rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), protects against N-methyl-d-aspartic acid (NMDA)-induced retinal damage in rats. Rapamycin inhibits mTOR activity, thereby preventing the phosphorylation of ribosomal protein S6, which is a downstream target of S6 kinase. Therefore, we aimed to determine whether PF-4708671, an inhibitor of S6 kinase, protects against NMDA-induced retinal injury. Intravitreal injection of NMDA (200 nmol/eye) caused cell loss in the ganglion cell layer and neuroinflammatory responses, such as an increase in the number of CD45-positive leukocytes and Iba1-positive microglia. Surprisingly, simultaneous injection of PF-4708671 (50 nmol/eye) with NMDA significantly attenuated these responses without affecting phosphorylated S6 levels. These results suggest that PF-4708671 and rapamycin likely protect against NMDA-induced retinal damage via distinct pathways. The neuroprotective effect of PF-4708671 is unlikely to be associated with inhibition of the S6 kinase, even though PF-4708671 is reported to be a S6 kinase inhibitor.
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http://dx.doi.org/10.1111/fcp.12216DOI Listing
December 2016

Protective Effects of Everolimus against N-Methyl-D-aspartic Acid-Induced Retinal Damage in Rats.

Biol Pharm Bull 2015 ;38(11):1765-71

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences.

We previously demonstrated that rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), protects against N-methyl-D-aspartic acid (NMDA)-induced retinal neurotoxicity, but the mechanism underlying this protection is not fully understood. The present study aimed to examine the effects of everolimus, another inhibitor of mTOR, on neuronal cell loss and inflammation in a rat model of NMDA-induced retinal neurotoxicity, and to determine whether the extracellular signal-regulated kinase (ERK) pathway contributes to the protective effect of everolimus. Intravitreal injection of NMDA (200 nmol) resulted in (1) cell loss in the ganglion cell layer, (2) increase in the numbers of CD45-positive leukocytes and Iba1-positive microglia, and (3) phosphorylation of ribosomal protein S6 (pS6), a downstream indicator of mTOR activity. Simultaneous injection of everolimus with NMDA significantly attenuated these NMDA-induced responses. The neuroprotective effect of everolimus was almost completely prevented by the mitogen-activated protein kinase/ERK kinase inhibitor U0126 (1 nmol). NMDA increased the level of phosphorylated ERK (pERK) in Müller cells, and increase in pERK levels was also observed after co-injection of NMDA and everolimus. These results suggest that everolimus has a neuroprotective effect against NMDA-induced retinal neurotoxicity, an effect that seems to be mediated partly by activation of the ERK pathway in Müller cells.
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http://dx.doi.org/10.1248/bpb.b15-00464DOI Listing
August 2016

Preventive effects of rapamycin on inflammation and capillary degeneration in a rat model of NMDA-induced retinal injury.

Biol Pharm Bull 2015 ;38(2):321-4

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences.

Inhibitors of the mammalian target of rapamycin (mTOR) have been shown to protect against neuronal injury, but the mechanisms underlying this effect are not fully understood. The present study aimed to examine the effects of rapamycin, an inhibitor of the mTOR pathway, on inflammation and capillary degeneration in a rat model of N-methyl-D-aspartate (NMDA)-induced retinal neurotoxicity. Inflammation and capillary degeneration were evaluated by counting the numbers of CD45-positive leukocytes and Iba1-positive microglia, and by measuring the length of empty basement membrane sleeves, respectively. Marked increases in the numbers of leukocytes and microglia were observed 1 d after intravitreal injection of NMDA (200 nmol), and significant capillary degeneration was observed after 7 d. These NMDA-induced changes were significantly reduced by the simultaneous injection of rapamycin (20 nmol) with NMDA. These results suggest that rapamycin has preventive effects on inflammation and capillary degeneration during retinal injury.
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http://dx.doi.org/10.1248/bpb.b14-00631DOI Listing
December 2015

Regression of retinal capillaries following N-methyl-D-aspartate-induced neurotoxicity in the neonatal rat retina.

J Neurosci Res 2015 Feb 3;93(2):380-90. Epub 2014 Oct 3.

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan.

Degeneration of retinal capillaries occurs following N-methyl-D-aspartate (NMDA)-induced retinal neurotoxicity, and the degree of capillary degeneration decreases in an age-dependent manner. To determine the role of vascular endothelial growth factor (VEGF) in the high susceptibility of capillaries to neuronal damage during the early postnatal stage, this study compares the vascular regression patterns between NMDA-treated retinas and retinas treated with N-[2-chloro-4-{(6,7-dimethoxy-4-quinazolinyl)oxy}phenyl]-N'-propylurea (KRN633), a VEGF receptor tyrosine kinase inhibitor, in neonatal rats. Two days after a single intravitreal injection of NMDA (200 nmol/eye) on postnatal day (P) 7, substantial retinal neuron loss and delayed expansion of the retinal vascular bed were observed. The reduction in the capillary density in the central retina reached statistical significance 4 days after NMDA treatment. In retinas of rats injected subcutaneously with KRN633 (10 mg/kg) on P7 and P8, simplified vasculature attributable to capillary regression and prevention of endothelial cell growth were seen on P9, whereas no visible changes in the morphology of the retinal layers were observed. The degree of capillary degeneration in NMDA-treated retinas was less than that in KRN633-treated retinas. No apparent changes in immunoreactivities for VEGF were found 2 days after NMDA treatment. These results indicate that neuronal cell loss in the retina precedes retinal capillary degeneration following NMDA treatment, and VEGF-dependent immature capillaries might be more susceptible to NMDA-induced neuronal damage.
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http://dx.doi.org/10.1002/jnr.23492DOI Listing
February 2015

Age-dependent changes in the severity of capillary degeneration in rat retina following N-methyl-D-aspartate-induced neurotoxicity.

Curr Eye Res 2015 May 30;40(5):549-53. Epub 2014 Jun 30.

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences , Tokyo , Japan , and.

Purpose: Previous studies have shown that injury to the retinal vasculature, including capillary degeneration, occurs following N-methyl-d-aspartate (NMDA)-induced neuronal cell loss, but it is unclear whether there are age-dependent differences in the severity of vascular damage. The purpose of the present study was to determine age-related changes in retinal capillary degeneration in NMDA-induced retinal damage rat model.

Materials And Methods: A single intravitreal injection of NMDA (200 nmol/eye) was performed in 1-, 2-, 3-, 7- and 15-week-old male Sprague-Dawley rats. Seven days after NMDA injection, damage to retinal neurons and blood vessels were assessed by measuring the number of cells in the ganglion cell layer and the length of empty basement membrane sleeves, left behind by regressing endothelial cells, respectively.

Results: At all ages examined, the NMDA-induced neurotoxicity exhibited similar levels of ganglion cell death. However, the degeneration of capillaries in NMDA-treated retina was severe during the early stages of retinal vascular development, and the degree of capillary degeneration decreased with age.

Conclusion: The degree of retinal capillary degeneration in NMDA-induced retinal damage rat model decreases in an age-dependent manner. Retinal capillaries may be resistant to retinal neuronal damage in young adults.
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http://dx.doi.org/10.3109/02713683.2014.933851DOI Listing
May 2015