The Experts below are selected from a list of 276 Experts worldwide ranked by ideXlab platform
Hitoshi Takagi - One of the best experts on this subject based on the ideXlab platform.
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Axonal Protection by Nicotinamide Riboside via SIRT1-Autophagy Pathway in TNF-Induced Optic Nerve Degeneration.
Molecular neurobiology, 2020Co-Authors: Yasushi Kitaoka, Kana Sase, Chihiro Tsukahara, Naoki Fujita, Ibuki Arizono, Hitoshi TakagiAbstract:Nicotinamide adenine dinucleotide (NAD+) synthesis pathway has been involved in many biological functions. Nicotinamide riboside (NR) is widely used as an NAD+ precursor and known to increase NAD+ level in several tissues. The present study aimed to examine the effect of NR on tumor necrosis factor (TNF)-induced optic Nerve Degeneration and to investigate whether it alters SIRT1 expression and autophagic status in optic Nerve. We also examined the localization of nicotinamide riboside kinase 1 (NRK1), which is a downstream enzyme for NR biosynthesis pathway in retina and optic Nerve. Intravitreal injection of TNF or TNF plus NR was performed on rats. The p62 and LC3-II protein levels were examined to evaluate autophagic flux in optic Nerve. Immunohistochemical analysis was performed to localize NRK1 expression. Morphometric analysis showed substantial axonal protection by NR against TNF-induced axon loss. TNF-induced increment of p62 protein level was significantly inhibited by NR administration. NR administration alone significantly increased the LC3-II levels and reduced p62 levels compared with the basal levels, and upregulated SIRT1 levels in optic Nerve. Immunohistochemical analysis showed that NRK1 exists in retinal ganglion cells (RGCs) and Nerve fibers in retina and optic Nerve. NR administration apparently upregulated NRK1 levels in the TNF-treated eyes as well as the control eyes. Pre-injection of an SIRT1 inhibitor resulted in a significant increase of p62 levels in the NR plus TNF treatment group, implicating that SIRT1 regulates autophagy status. In conclusion, NRK1 exists in RGCs and optic Nerve axons. NR exerted protection against axon loss induced by TNF with possible involvement of upregulated NRK1 and SIRT1-autophagy pathway.
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Axonal protection by a small molecule SIRT1 activator, SRT2104, with alteration of autophagy in TNF-induced optic Nerve Degeneration
Japanese Journal of Ophthalmology, 2020Co-Authors: Yasushi Kitaoka, Kana Sase, Chihiro Tsukahara, Naoki Fujita, Naoto Tokuda, Jiro Kogo, Hitoshi TakagiAbstract:Purpose To examine the effects of SRT2104, an SIRT1 activator, in optic Nerve Degeneration induced by TNF and to investigate whether it affects the autophagic status after induction of axonal Degeneration. Study design Experimental. Methods Adult male Wistar rats received intravitreal injection of TNF alone, concomitant injection of SRT2104 and TNF, or injection of SRT2104 alone. The autophagic status in the optic Nerve was evaluated to examine p62 and LC3-II expression by immunoblot analysis. The effect of SRT2104 on TNF-induced axon loss was determined by counting the number of axons. Results Intravitreal injection of SRT2104 showed a modest protective tendency in the 2-pmol-treated groups against TNF-induced axon loss, although the tendency was not significant on quantitative analysis. However, significant protective effects were found in the 20- or 200-pmol-treated groups. Injection of SRT2104 alone significantly decreased the p62 levels and increased the LC3-II levels as compared with the basal levels. Similarly, concomitant injection of SRT2104 and TNF significantly decreased the p62 levels and increased the LC3-II levels as compared with the TNF-treated group. Upregulation of SIRT1 expression was observed in the optic Nerve after SRT2104 treatment. Conclusion The SIRT1 activator SRT2104 exerts axonal protection in TNF-induced optic Nerve Degeneration. This effect may be associated with upregulated autophagic status in the optic Nerve.
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Axonal protection by a small molecule SIRT1 activator, SRT2104, with alteration of autophagy in TNF-induced optic Nerve Degeneration.
Japanese journal of ophthalmology, 2020Co-Authors: Yasushi Kitaoka, Kana Sase, Chihiro Tsukahara, Naoki Fujita, Naoto Tokuda, Jiro Kogo, Hitoshi TakagiAbstract:To examine the effects of SRT2104, an SIRT1 activator, in optic Nerve Degeneration induced by TNF and to investigate whether it affects the autophagic status after induction of axonal Degeneration. Experimental. Adult male Wistar rats received intravitreal injection of TNF alone, concomitant injection of SRT2104 and TNF, or injection of SRT2104 alone. The autophagic status in the optic Nerve was evaluated to examine p62 and LC3-II expression by immunoblot analysis. The effect of SRT2104 on TNF-induced axon loss was determined by counting the number of axons. Intravitreal injection of SRT2104 showed a modest protective tendency in the 2-pmol-treated groups against TNF-induced axon loss, although the tendency was not significant on quantitative analysis. However, significant protective effects were found in the 20- or 200-pmol-treated groups. Injection of SRT2104 alone significantly decreased the p62 levels and increased the LC3-II levels as compared with the basal levels. Similarly, concomitant injection of SRT2104 and TNF significantly decreased the p62 levels and increased the LC3-II levels as compared with the TNF-treated group. Upregulation of SIRT1 expression was observed in the optic Nerve after SRT2104 treatment. The SIRT1 activator SRT2104 exerts axonal protection in TNF-induced optic Nerve Degeneration. This effect may be associated with upregulated autophagic status in the optic Nerve.
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Axonal protection by tacrolimus with inhibition of NFATc1 in TNF-induced optic Nerve Degeneration
Neurochemical research, 2019Co-Authors: Chihiro Tsukahara, Kana Sase, Naoki Fujita, Hitoshi Takagi, Yasushi KitaokaAbstract:Tacrolimus, a calcineurin (CaN) inhibitor, has been used for treatment of refractory allergic ocular disease, although its role in optic Nerve Degeneration remains to be elucidated. In this study, we investigated whether tacrolimus modulates tumor necrosis factor (TNF)-mediated axonal Degeneration and whether it alters nuclear factor of activated T cells (NFATc), a downstream effector of CaN signaling. Immunoblot analysis showed no significant difference in CaNAα protein levels in optic Nerve on day 3, 7, or 14 after TNF injection compared with PBS injection. However, a significant increase in NFATc1 protein level was observed in optic Nerve 7 days after TNF injection. This increase was negated by simultaneous administration of tacrolimus. Administration of tacrolimus alone did not change the NFATc1 protein level in comparison to that observed after PBS injection. A significant increase in TNF protein level was observed in optic Nerve 14 days after TNF injection and this increase was prevented by tacrolimus. Immunohistochemical analysis showed the immunoreactivity of NFATc1 to be increased in optic Nerve after TNF injection. This increased immunoreactivity was colocalized with glial fibrillary acidic protein and was suppressed by tacrolimus. Treatment of tacrolimus significantly ameliorated the TNF-mediated axonal loss. These results suggest that tacrolimus is neuroprotective against axon loss in TNF-induced optic neuropathy and that the effect arises from suppression of the CaN/NFATc1 pathway.
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Axonal Protection by Ripasudil, a Rho Kinase Inhibitor, via Modulating Autophagy in TNF-Induced Optic Nerve Degeneration.
Investigative ophthalmology & visual science, 2017Co-Authors: Yasushi Kitaoka, Kana Sase, Chihiro Tsukahara, Kaori Kojima, Naoto Tokuda, Jiro Kogo, Akira Shiono, Hitoshi TakagiAbstract:Purpose The Rho kinase inhibitor ripasudil decreases intraocular pressure, although its role in optic Nerve axonal damage should be clarified. We therefore investigated whether ripasudil modulates TNF-induced axonal loss and affects autophagy machinery after the induction of optic Nerve Degeneration. Methods Rats were given intravitreal injection of TNF, concomitant injection of ripasudil hydrochloride hydrate and TNF, or ripasudil alone. Axon numbers were counted to evaluate the effects of ripasudil against axon loss. Immunoblot analysis was performed to examine p62 as well as LC3-II expression in optic Nerves. Electron microscopy was used to determine autophagosome numbers in axons and glia. Immunogold labeling was performed to evaluate autophagosomes in axons. Results Ripasudil injected intravitreally resulted in significant neuroprotection against TNF-induced axon loss. Intravitreal TNF injection upregulated p62 in the optic Nerve, but ripasudil completely inhibited this increment. The ripasudil alone injection diminished p62 and enhanced LC3-II protein levels significantly compared with baseline. Ripasudil-induced upregulation of LC3-II was seen after TNF injection, and immunohistochemical analysis revealed that LC3 colocalized in Nerve fibers. Electron microscopic analysis revealed that autophagosomes were present in axons and glia, although autophagosome numbers increased significantly after ripasudil injection only in axons. Conclusions These results suggest that ripasudil-enhanced intra-axonal autophagy is at least partly involved in axonal protection.
Yasushi Kitaoka - One of the best experts on this subject based on the ideXlab platform.
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Axonal Protection by Nicotinamide Riboside via SIRT1-Autophagy Pathway in TNF-Induced Optic Nerve Degeneration.
Molecular neurobiology, 2020Co-Authors: Yasushi Kitaoka, Kana Sase, Chihiro Tsukahara, Naoki Fujita, Ibuki Arizono, Hitoshi TakagiAbstract:Nicotinamide adenine dinucleotide (NAD+) synthesis pathway has been involved in many biological functions. Nicotinamide riboside (NR) is widely used as an NAD+ precursor and known to increase NAD+ level in several tissues. The present study aimed to examine the effect of NR on tumor necrosis factor (TNF)-induced optic Nerve Degeneration and to investigate whether it alters SIRT1 expression and autophagic status in optic Nerve. We also examined the localization of nicotinamide riboside kinase 1 (NRK1), which is a downstream enzyme for NR biosynthesis pathway in retina and optic Nerve. Intravitreal injection of TNF or TNF plus NR was performed on rats. The p62 and LC3-II protein levels were examined to evaluate autophagic flux in optic Nerve. Immunohistochemical analysis was performed to localize NRK1 expression. Morphometric analysis showed substantial axonal protection by NR against TNF-induced axon loss. TNF-induced increment of p62 protein level was significantly inhibited by NR administration. NR administration alone significantly increased the LC3-II levels and reduced p62 levels compared with the basal levels, and upregulated SIRT1 levels in optic Nerve. Immunohistochemical analysis showed that NRK1 exists in retinal ganglion cells (RGCs) and Nerve fibers in retina and optic Nerve. NR administration apparently upregulated NRK1 levels in the TNF-treated eyes as well as the control eyes. Pre-injection of an SIRT1 inhibitor resulted in a significant increase of p62 levels in the NR plus TNF treatment group, implicating that SIRT1 regulates autophagy status. In conclusion, NRK1 exists in RGCs and optic Nerve axons. NR exerted protection against axon loss induced by TNF with possible involvement of upregulated NRK1 and SIRT1-autophagy pathway.
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Axonal protection by a small molecule SIRT1 activator, SRT2104, with alteration of autophagy in TNF-induced optic Nerve Degeneration
Japanese Journal of Ophthalmology, 2020Co-Authors: Yasushi Kitaoka, Kana Sase, Chihiro Tsukahara, Naoki Fujita, Naoto Tokuda, Jiro Kogo, Hitoshi TakagiAbstract:Purpose To examine the effects of SRT2104, an SIRT1 activator, in optic Nerve Degeneration induced by TNF and to investigate whether it affects the autophagic status after induction of axonal Degeneration. Study design Experimental. Methods Adult male Wistar rats received intravitreal injection of TNF alone, concomitant injection of SRT2104 and TNF, or injection of SRT2104 alone. The autophagic status in the optic Nerve was evaluated to examine p62 and LC3-II expression by immunoblot analysis. The effect of SRT2104 on TNF-induced axon loss was determined by counting the number of axons. Results Intravitreal injection of SRT2104 showed a modest protective tendency in the 2-pmol-treated groups against TNF-induced axon loss, although the tendency was not significant on quantitative analysis. However, significant protective effects were found in the 20- or 200-pmol-treated groups. Injection of SRT2104 alone significantly decreased the p62 levels and increased the LC3-II levels as compared with the basal levels. Similarly, concomitant injection of SRT2104 and TNF significantly decreased the p62 levels and increased the LC3-II levels as compared with the TNF-treated group. Upregulation of SIRT1 expression was observed in the optic Nerve after SRT2104 treatment. Conclusion The SIRT1 activator SRT2104 exerts axonal protection in TNF-induced optic Nerve Degeneration. This effect may be associated with upregulated autophagic status in the optic Nerve.
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Axonal protection by a small molecule SIRT1 activator, SRT2104, with alteration of autophagy in TNF-induced optic Nerve Degeneration.
Japanese journal of ophthalmology, 2020Co-Authors: Yasushi Kitaoka, Kana Sase, Chihiro Tsukahara, Naoki Fujita, Naoto Tokuda, Jiro Kogo, Hitoshi TakagiAbstract:To examine the effects of SRT2104, an SIRT1 activator, in optic Nerve Degeneration induced by TNF and to investigate whether it affects the autophagic status after induction of axonal Degeneration. Experimental. Adult male Wistar rats received intravitreal injection of TNF alone, concomitant injection of SRT2104 and TNF, or injection of SRT2104 alone. The autophagic status in the optic Nerve was evaluated to examine p62 and LC3-II expression by immunoblot analysis. The effect of SRT2104 on TNF-induced axon loss was determined by counting the number of axons. Intravitreal injection of SRT2104 showed a modest protective tendency in the 2-pmol-treated groups against TNF-induced axon loss, although the tendency was not significant on quantitative analysis. However, significant protective effects were found in the 20- or 200-pmol-treated groups. Injection of SRT2104 alone significantly decreased the p62 levels and increased the LC3-II levels as compared with the basal levels. Similarly, concomitant injection of SRT2104 and TNF significantly decreased the p62 levels and increased the LC3-II levels as compared with the TNF-treated group. Upregulation of SIRT1 expression was observed in the optic Nerve after SRT2104 treatment. The SIRT1 activator SRT2104 exerts axonal protection in TNF-induced optic Nerve Degeneration. This effect may be associated with upregulated autophagic status in the optic Nerve.
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Axonal protection by tacrolimus with inhibition of NFATc1 in TNF-induced optic Nerve Degeneration
Neurochemical research, 2019Co-Authors: Chihiro Tsukahara, Kana Sase, Naoki Fujita, Hitoshi Takagi, Yasushi KitaokaAbstract:Tacrolimus, a calcineurin (CaN) inhibitor, has been used for treatment of refractory allergic ocular disease, although its role in optic Nerve Degeneration remains to be elucidated. In this study, we investigated whether tacrolimus modulates tumor necrosis factor (TNF)-mediated axonal Degeneration and whether it alters nuclear factor of activated T cells (NFATc), a downstream effector of CaN signaling. Immunoblot analysis showed no significant difference in CaNAα protein levels in optic Nerve on day 3, 7, or 14 after TNF injection compared with PBS injection. However, a significant increase in NFATc1 protein level was observed in optic Nerve 7 days after TNF injection. This increase was negated by simultaneous administration of tacrolimus. Administration of tacrolimus alone did not change the NFATc1 protein level in comparison to that observed after PBS injection. A significant increase in TNF protein level was observed in optic Nerve 14 days after TNF injection and this increase was prevented by tacrolimus. Immunohistochemical analysis showed the immunoreactivity of NFATc1 to be increased in optic Nerve after TNF injection. This increased immunoreactivity was colocalized with glial fibrillary acidic protein and was suppressed by tacrolimus. Treatment of tacrolimus significantly ameliorated the TNF-mediated axonal loss. These results suggest that tacrolimus is neuroprotective against axon loss in TNF-induced optic neuropathy and that the effect arises from suppression of the CaN/NFATc1 pathway.
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Axonal Protection by Ripasudil, a Rho Kinase Inhibitor, via Modulating Autophagy in TNF-Induced Optic Nerve Degeneration.
Investigative ophthalmology & visual science, 2017Co-Authors: Yasushi Kitaoka, Kana Sase, Chihiro Tsukahara, Kaori Kojima, Naoto Tokuda, Jiro Kogo, Akira Shiono, Hitoshi TakagiAbstract:Purpose The Rho kinase inhibitor ripasudil decreases intraocular pressure, although its role in optic Nerve axonal damage should be clarified. We therefore investigated whether ripasudil modulates TNF-induced axonal loss and affects autophagy machinery after the induction of optic Nerve Degeneration. Methods Rats were given intravitreal injection of TNF, concomitant injection of ripasudil hydrochloride hydrate and TNF, or ripasudil alone. Axon numbers were counted to evaluate the effects of ripasudil against axon loss. Immunoblot analysis was performed to examine p62 as well as LC3-II expression in optic Nerves. Electron microscopy was used to determine autophagosome numbers in axons and glia. Immunogold labeling was performed to evaluate autophagosomes in axons. Results Ripasudil injected intravitreally resulted in significant neuroprotection against TNF-induced axon loss. Intravitreal TNF injection upregulated p62 in the optic Nerve, but ripasudil completely inhibited this increment. The ripasudil alone injection diminished p62 and enhanced LC3-II protein levels significantly compared with baseline. Ripasudil-induced upregulation of LC3-II was seen after TNF injection, and immunohistochemical analysis revealed that LC3 colocalized in Nerve fibers. Electron microscopic analysis revealed that autophagosomes were present in axons and glia, although autophagosome numbers increased significantly after ripasudil injection only in axons. Conclusions These results suggest that ripasudil-enhanced intra-axonal autophagy is at least partly involved in axonal protection.
Kana Sase - One of the best experts on this subject based on the ideXlab platform.
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Axonal Protection by Nicotinamide Riboside via SIRT1-Autophagy Pathway in TNF-Induced Optic Nerve Degeneration.
Molecular neurobiology, 2020Co-Authors: Yasushi Kitaoka, Kana Sase, Chihiro Tsukahara, Naoki Fujita, Ibuki Arizono, Hitoshi TakagiAbstract:Nicotinamide adenine dinucleotide (NAD+) synthesis pathway has been involved in many biological functions. Nicotinamide riboside (NR) is widely used as an NAD+ precursor and known to increase NAD+ level in several tissues. The present study aimed to examine the effect of NR on tumor necrosis factor (TNF)-induced optic Nerve Degeneration and to investigate whether it alters SIRT1 expression and autophagic status in optic Nerve. We also examined the localization of nicotinamide riboside kinase 1 (NRK1), which is a downstream enzyme for NR biosynthesis pathway in retina and optic Nerve. Intravitreal injection of TNF or TNF plus NR was performed on rats. The p62 and LC3-II protein levels were examined to evaluate autophagic flux in optic Nerve. Immunohistochemical analysis was performed to localize NRK1 expression. Morphometric analysis showed substantial axonal protection by NR against TNF-induced axon loss. TNF-induced increment of p62 protein level was significantly inhibited by NR administration. NR administration alone significantly increased the LC3-II levels and reduced p62 levels compared with the basal levels, and upregulated SIRT1 levels in optic Nerve. Immunohistochemical analysis showed that NRK1 exists in retinal ganglion cells (RGCs) and Nerve fibers in retina and optic Nerve. NR administration apparently upregulated NRK1 levels in the TNF-treated eyes as well as the control eyes. Pre-injection of an SIRT1 inhibitor resulted in a significant increase of p62 levels in the NR plus TNF treatment group, implicating that SIRT1 regulates autophagy status. In conclusion, NRK1 exists in RGCs and optic Nerve axons. NR exerted protection against axon loss induced by TNF with possible involvement of upregulated NRK1 and SIRT1-autophagy pathway.
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Axonal protection by a small molecule SIRT1 activator, SRT2104, with alteration of autophagy in TNF-induced optic Nerve Degeneration
Japanese Journal of Ophthalmology, 2020Co-Authors: Yasushi Kitaoka, Kana Sase, Chihiro Tsukahara, Naoki Fujita, Naoto Tokuda, Jiro Kogo, Hitoshi TakagiAbstract:Purpose To examine the effects of SRT2104, an SIRT1 activator, in optic Nerve Degeneration induced by TNF and to investigate whether it affects the autophagic status after induction of axonal Degeneration. Study design Experimental. Methods Adult male Wistar rats received intravitreal injection of TNF alone, concomitant injection of SRT2104 and TNF, or injection of SRT2104 alone. The autophagic status in the optic Nerve was evaluated to examine p62 and LC3-II expression by immunoblot analysis. The effect of SRT2104 on TNF-induced axon loss was determined by counting the number of axons. Results Intravitreal injection of SRT2104 showed a modest protective tendency in the 2-pmol-treated groups against TNF-induced axon loss, although the tendency was not significant on quantitative analysis. However, significant protective effects were found in the 20- or 200-pmol-treated groups. Injection of SRT2104 alone significantly decreased the p62 levels and increased the LC3-II levels as compared with the basal levels. Similarly, concomitant injection of SRT2104 and TNF significantly decreased the p62 levels and increased the LC3-II levels as compared with the TNF-treated group. Upregulation of SIRT1 expression was observed in the optic Nerve after SRT2104 treatment. Conclusion The SIRT1 activator SRT2104 exerts axonal protection in TNF-induced optic Nerve Degeneration. This effect may be associated with upregulated autophagic status in the optic Nerve.
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Axonal protection by a small molecule SIRT1 activator, SRT2104, with alteration of autophagy in TNF-induced optic Nerve Degeneration.
Japanese journal of ophthalmology, 2020Co-Authors: Yasushi Kitaoka, Kana Sase, Chihiro Tsukahara, Naoki Fujita, Naoto Tokuda, Jiro Kogo, Hitoshi TakagiAbstract:To examine the effects of SRT2104, an SIRT1 activator, in optic Nerve Degeneration induced by TNF and to investigate whether it affects the autophagic status after induction of axonal Degeneration. Experimental. Adult male Wistar rats received intravitreal injection of TNF alone, concomitant injection of SRT2104 and TNF, or injection of SRT2104 alone. The autophagic status in the optic Nerve was evaluated to examine p62 and LC3-II expression by immunoblot analysis. The effect of SRT2104 on TNF-induced axon loss was determined by counting the number of axons. Intravitreal injection of SRT2104 showed a modest protective tendency in the 2-pmol-treated groups against TNF-induced axon loss, although the tendency was not significant on quantitative analysis. However, significant protective effects were found in the 20- or 200-pmol-treated groups. Injection of SRT2104 alone significantly decreased the p62 levels and increased the LC3-II levels as compared with the basal levels. Similarly, concomitant injection of SRT2104 and TNF significantly decreased the p62 levels and increased the LC3-II levels as compared with the TNF-treated group. Upregulation of SIRT1 expression was observed in the optic Nerve after SRT2104 treatment. The SIRT1 activator SRT2104 exerts axonal protection in TNF-induced optic Nerve Degeneration. This effect may be associated with upregulated autophagic status in the optic Nerve.
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Axonal protection by tacrolimus with inhibition of NFATc1 in TNF-induced optic Nerve Degeneration
Neurochemical research, 2019Co-Authors: Chihiro Tsukahara, Kana Sase, Naoki Fujita, Hitoshi Takagi, Yasushi KitaokaAbstract:Tacrolimus, a calcineurin (CaN) inhibitor, has been used for treatment of refractory allergic ocular disease, although its role in optic Nerve Degeneration remains to be elucidated. In this study, we investigated whether tacrolimus modulates tumor necrosis factor (TNF)-mediated axonal Degeneration and whether it alters nuclear factor of activated T cells (NFATc), a downstream effector of CaN signaling. Immunoblot analysis showed no significant difference in CaNAα protein levels in optic Nerve on day 3, 7, or 14 after TNF injection compared with PBS injection. However, a significant increase in NFATc1 protein level was observed in optic Nerve 7 days after TNF injection. This increase was negated by simultaneous administration of tacrolimus. Administration of tacrolimus alone did not change the NFATc1 protein level in comparison to that observed after PBS injection. A significant increase in TNF protein level was observed in optic Nerve 14 days after TNF injection and this increase was prevented by tacrolimus. Immunohistochemical analysis showed the immunoreactivity of NFATc1 to be increased in optic Nerve after TNF injection. This increased immunoreactivity was colocalized with glial fibrillary acidic protein and was suppressed by tacrolimus. Treatment of tacrolimus significantly ameliorated the TNF-mediated axonal loss. These results suggest that tacrolimus is neuroprotective against axon loss in TNF-induced optic neuropathy and that the effect arises from suppression of the CaN/NFATc1 pathway.
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Axonal Protection by Ripasudil, a Rho Kinase Inhibitor, via Modulating Autophagy in TNF-Induced Optic Nerve Degeneration.
Investigative ophthalmology & visual science, 2017Co-Authors: Yasushi Kitaoka, Kana Sase, Chihiro Tsukahara, Kaori Kojima, Naoto Tokuda, Jiro Kogo, Akira Shiono, Hitoshi TakagiAbstract:Purpose The Rho kinase inhibitor ripasudil decreases intraocular pressure, although its role in optic Nerve axonal damage should be clarified. We therefore investigated whether ripasudil modulates TNF-induced axonal loss and affects autophagy machinery after the induction of optic Nerve Degeneration. Methods Rats were given intravitreal injection of TNF, concomitant injection of ripasudil hydrochloride hydrate and TNF, or ripasudil alone. Axon numbers were counted to evaluate the effects of ripasudil against axon loss. Immunoblot analysis was performed to examine p62 as well as LC3-II expression in optic Nerves. Electron microscopy was used to determine autophagosome numbers in axons and glia. Immunogold labeling was performed to evaluate autophagosomes in axons. Results Ripasudil injected intravitreally resulted in significant neuroprotection against TNF-induced axon loss. Intravitreal TNF injection upregulated p62 in the optic Nerve, but ripasudil completely inhibited this increment. The ripasudil alone injection diminished p62 and enhanced LC3-II protein levels significantly compared with baseline. Ripasudil-induced upregulation of LC3-II was seen after TNF injection, and immunohistochemical analysis revealed that LC3 colocalized in Nerve fibers. Electron microscopic analysis revealed that autophagosomes were present in axons and glia, although autophagosome numbers increased significantly after ripasudil injection only in axons. Conclusions These results suggest that ripasudil-enhanced intra-axonal autophagy is at least partly involved in axonal protection.
Sung-tsang Hsieh - One of the best experts on this subject based on the ideXlab platform.
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brain imaging signature of neuropathic pain phenotypes in small fiber neuropathy altered thalamic connectome and its associations with skin Nerve Degeneration
Pain, 2020Co-Authors: Chichao Chao, Yeahuey Lin, Sung-tsang Hsieh, Mingtsung Tseng, Paulchen Hsieh, Chienho Janice Lin, Shinleh Huang, Mingchang ChiangAbstract:Small-fiber neuropathy (SFN) has been traditionally considered as a pure disorder of peripheral nervous system, characterized by neuropathic pain and Degeneration of small-diameter Nerve fibers in the skin. Previous functional MRI studies revealed abnormal activations of pain networks, but the structural basis underlying such maladaptive functional alterations remains elusive. We applied diffusion tensor imaging (DTI) to explore the influences of SFN on brain microstructures. Forty-one pathology-proven SFN patients with reduced skin innervation were recruited. White matter connectivity with the thalamus as the seed was assessed using probabilistic tractography of DTI. SFN patients had reduced thalamic connectivity with the insular cortex and the sensorimotor areas including the postcentral and precentral gyri. Furthermore, the degree of skin Nerve Degeneration, measured by intraepidermal Nerve fiber density (IENFd), was associated with the reduction of connectivity between the thalamus and pain-related areas according to different neuropathic pain phenotypes, specifically, the frontal, cingulate, motor, and limbic areas for burning, electrical shocks, tingling, mechanical allodynia, and numbness. Despite altered white matter connectivity, there was no change in white matter integrity assessed with fractional anisotropy. Our findings indicate that alterations in structural connectivity may serve as a biomarker of maladaptive brain plasticity that contributes to neuropathic pain after peripheral Nerve Degeneration.
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Brain imaging signature of neuropathic pain phenotypes in small-fiber neuropathy: altered thalamic connectome and its associations with skin Nerve Degeneration.
Pain, 2020Co-Authors: Chichao Chao, Yeahuey Lin, Sung-tsang Hsieh, Mingtsung Tseng, Paulchen Hsieh, Chienho Janice Lin, Shinleh Huang, Mingchang ChiangAbstract:ABSTRACT Small-fiber neuropathy (SFN) has been traditionally considered as a pure disorder of the peripheral nervous system, characterized by neuropathic pain and Degeneration of small-diameter Nerve fibers in the skin. Previous functional magnetic resonance imaging studies revealed abnormal activations of pain networks, but the structural basis underlying such maladaptive functional alterations remains elusive. We applied diffusion tensor imaging to explore the influences of SFN on brain microstructures. Forty-one patients with pathology-proven SFN with reduced skin innervation were recruited. White matter connectivity with the thalamus as the seed was assessed using probabilistic tractography of diffusion tensor imaging. Patients with SFN had reduced thalamic connectivity with the insular cortex and the sensorimotor areas, including the postcentral and precentral gyri. Furthermore, the degree of skin Nerve Degeneration, measured by intraepidermal Nerve fiber density, was associated with the reduction of connectivity between the thalamus and pain-related areas according to different neuropathic pain phenotypes, specifically, the frontal, cingulate, motor, and limbic areas for burning, electrical shocks, tingling, mechanical allodynia, and numbness. Despite altered white matter connectivity, there was no change in white matter integrity assessed with fractional anisotropy. Our findings indicate that alterations in structural connectivity may serve as a biomarker of maladaptive brain plasticity that contributes to neuropathic pain after peripheral Nerve Degeneration.
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Sensory Nerve Degeneration in a mouse model mimicking early manifestations of familial amyloid polyneuropathy due to transthyretin Ala97Ser
Neuropathology and applied neurobiology, 2018Co-Authors: Hung-wei Kan, Hao Chiang, Whei-min Lin, Shu-wha Lin, Sung-tsang HsiehAbstract:Aims Sensory Nerve Degeneration and consequent abnormal sensations are the earliest and most prevalent manifestations of familial amyloid polyneuropathy (FAP) due to amyloidogenic transthyretin (TTR). FAP is a relentlessly progressive degenerative disease of the peripheral nervous system. However, there is a lack of mouse models to replicate the early neuropathic manifestations of FAP. Methods We established human TTR knock-in mice by replacing one allele of the mouse Ttr locus with human wild-type TTR (hTTRwt ) or human TTR with the A97S mutation (hTTRA97S ). Given the late onset of neuropathic manifestations in A97S-FAP, we investigated Nerve pathology, physiology, and behavioural tests in these mice at two age points: the adult group (8 - 56 weeks) and the ageing group (> 104 weeks). Results In the adult group, Nerve profiles, neurophysiology and behaviour were similar between hTTRwt and hTTRA97S mice. By contrast, ageing hTTRA97S mice showed small fibre neuropathy with decreased intraepidermal Nerve fibre density and behavioural signs of mechanical allodynia. Furthermore, significant reductions in sural Nerve myelinated Nerve fibre density and sensory Nerve action potential amplitudes in these mice indicated Degeneration of large sensory fibres. The unaffected motor Nerve physiology replicated the early symptoms of FAP patients, that is, sensory Nerves were more vulnerable to mutant TTR than motor Nerves. Conclusions These results demonstrate that the hTTRA97S mouse model develops sensory Nerve pathology and corresponding physiology mimicking A97S-FAP and provides a platform to develop new therapies for the early stage of A97S-FAP.
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Physiological and pathological characterization of capsaicin‐induced reversible Nerve Degeneration and hyperalgesia
European journal of pain (London England), 2018Co-Authors: Hao Chiang, Chichao Chao, Yeahuey Lin, Mingtsung Tseng, Kai-fong Chang, Hung-wei Kan, Hsueh-wen Hsueh, Sung-tsang HsiehAbstract:BACKGROUND The study aimed to investigate the physiology, psychophysics, pathology and their relationship in reversible nociceptive Nerve Degeneration, and the physiology of acute hyperalgesia. METHODS We enrolled 15 normal subjects to investigate intraepidermal Nerve fibre (IENF) density, contact heat-evoked potential (CHEP) and thermal thresholds during the capsaicin-induced skin Nerve Degeneration-regeneration; and CHEP and thermal thresholds at capsaicin-induced acute hyperalgesia. RESULTS After 2-week capsaicin treatment, IENF density of skin was markedly reduced with reduced amplitude and prolonged latency of CHEP, and increased warm and heat pain thresholds. The time courses of skin Nerve regeneration and reversal of physiology and psychophysics were different: IENF density was still lower at 10 weeks after capsaicin treatment than that at baseline, whereas CHEP amplitude and warm threshold became normalized within 3 weeks after capsaicin treatment. Although CHEP amplitude and IENF density were best correlated in a multiple linear regression model, a one-phase exponential association model showed better fit than a simple linear one, that is in the regeneration phase, the slope of the regression line between CHEP amplitude and IENF density was steeper in the subgroup with lower IENF densities than in the one with higher IENF densities. During capsaicin-induced hyperalgesia, recordable rate of CHEP to 43 °C heat stimulation was higher with enhanced CHEP amplitude and pain perception compared to baseline. CONCLUSIONS There were differential restoration of IENF density, CHEP and thermal thresholds, and changed CHEP-IENF relationships during skin reinnervation. CHEP can be a physiological signature of acute hyperalgesia. SIGNIFICANCE These observations suggested the relationship between nociceptive Nerve terminals and brain responses to thermal stimuli changed during different degree of skin denervation, and CHEP to low-intensity heat stimulus can reflect the physiology of hyperalgesia.
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imaging signatures of altered brain responses in small fiber neuropathy reduced functional connectivity of the limbic system after peripheral Nerve Degeneration
Pain, 2015Co-Authors: Paulchen Hsieh, Chichao Chao, Yeahuey Lin, Mingtsung Tseng, Mingchang Chiang, Wenyih Isaac Tseng, Kuanhong Liu, Sung-tsang HsiehAbstract:Small-fiber neuropathy (SFN) is hallmarked by Degeneration of small unmyelinated peripheral Nerve fibers in the skin. Traditionally, it has been considered as a pure disorder of the peripheral nervous system. Nevertheless, previous work found that dysfunction of skin Nerves led to abnormal recruitment of pain-related regions, suggesting that the brain may be affected in SFN. This report combined structural and functional magnetic resonance imaging to identify structural and functional changes in the brain of 19 patients with SFN compared with 17 healthy controls. We applied tensor-based morphometry to detect brain structural alterations in SFN. Greater volume reduction in pain-processing regions, particularly the bilateral anterior cingulate cortices (ACCs), was associated with greater depletion of intraepidermal Nerve fibers, a pathological biomarker of skin Nerve Degeneration. Based on the hypothesis that structural alterations in the pain-processing regions might impair their functional connectivity, we further applied psychophysiological interaction analysis to assess functional connectivity of the ACCs during noxious heat stimulation. There was significant reduction in functional connectivity from the ACCs to the limbic areas (the parahippocampal gyrus and the posterior cingulate cortex), pain-processing area (the insula), and visuospatial areas (the cuneus). Moreover, the degree of reduction in functional connectivity for the ACC to the amygdala and the precuneus was linearly correlated with the severity of intraepidermal Nerve fiber depletion. Our findings suggest that SFN is not a pure peripheral nervous system disorder. The pain-related brain networks tend to break into functionally independent components, with severity linked to the degree of skin Nerve Degeneration.
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Silicone oil-associated optic Nerve Degeneration
American Journal of Ophthalmology, 2001Co-Authors: Maike Budde, Leonard M. Holbach, Claus Cursiefen, Gottfried O. H. NaumannAbstract:PURPOSE: To report the frequency and extent of silicone oil migration into the optic Nerve during silicone oil endotamponade. METHODS: Histopathologic analysis of 74 eyes enucleated after silicone oil endotamponade. RESULTS: In 14 of 74 enucleated eyes (24%), optically empty vacuoles regarded as silicone oil vacuoles were observed in the retrolaminar optic Nerve. In three eyes, silicone oil in the optic Nerve was surrounded by a granulomatous inflammatory reaction. In serial cross sections, the vacuoles extended up to the line of surgical transsection (up to 9 mm) of the optic Nerve and constituted up to 40% of the total cross-sectional area. CONCLUSIONS: After silicone oil endotamponade, silicone oil may replace a considerable amount of tissue of the retrolaminar optic Nerve. A granulomatous inflammatory reaction surrounding silicone oil may add to optic Nerve damage.
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Silicone oil-associated optic Nerve Degeneration
American Journal of Ophthalmology, 2001Co-Authors: Maike Budde, Leonard M. Holbach, Claus Cursiefen, Gottfried O. H. NaumannAbstract:PURPOSE: To report the frequency and extent of silicone oil migration into the optic Nerve during silicone oil endotamponade. METHODS: Histopathologic analysis of 74 eyes enucleated after silicone oil endotamponade. RESULTS: In 14 of 74 enucleated eyes (24%), optically empty vacuoles regarded as silicone oil vacuoles were observed in the retrolaminar optic Nerve. In three eyes, silicone oil in the optic Nerve was surrounded by a granulomatous inflammatory reaction. In serial cross sections, the vacuoles extended up to the line of surgical transsection (up to 9 mm) of the optic Nerve and constituted up to 40% of the total cross-sectional area. CONCLUSIONS: After silicone oil endotamponade, silicone oil may replace a considerable amount of tissue of the retrolaminar optic Nerve. A granulomatous inflammatory reaction surrounding silicone oil may add to optic Nerve damage.