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Akinori Akaike - One of the best experts on this subject based on the ideXlab platform.
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potential protective effect of highly bioavailable curcumin on an oxidative stress model induced by microinjection of sodium nitroprusside in mice brain
Food & Function, 2014Co-Authors: Qand Agha Nazari, Yuki Takadatakatori, Yasuhiko Izumi, Akinori Akaike, Tadashi Hashimoto, Atsushi Imaizumi, Toshiaki KumeAbstract:Curcumin, a polyphenolic compound has several pharmacological activities, such as anticancer, anti-inflammatory and antioxidant effects. However, curcumin shows poor oral bioavailability. The purpose of this study was to investigate the protective effects of highly bioavailable curcumin, Theracurmin®, and curcumin, against sodium nitroprusside (SNP)-induced oxidative damage in mice brain. Intrastriatal microinjection of Theracurmin® or curcumin with SNP significantly protected against SNP-induced brain damage and Motor Dysfunction. Oral administration of Theracurmin® (1 and 3 g kg−1, containing 100 and 300 mg kg−1 curcumin, respectively) significantly protected against SNP-induced brain damage and Motor Dysfunction. However, oral administration of 300 mg kg−1 curcumin did not protect against Motor Dysfunction induced by SNP. These results suggest that curcumin and Theracurmin® have protective effects against SNP-induced oxidative damage. Moreover, oral administration of Theracurmin®, had more potency in protecting against brain damage, suggesting a higher bioavailability of Theracurmin® following oral administration.
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protective effect of luteolin on an oxidative stress model induced by microinjection of sodium nitroprusside in mice
Journal of Pharmacological Sciences, 2013Co-Authors: Qand Agha Nazari, Toshiaki Kume, Yuki Takadatakatori, Yasuhiko Izumi, Akinori AkaikeAbstract:Accumulating lines of evidence showed that luteolin, a polyphenolic compound, has potent neuroprotective effects. The purpose of this study was to examine whether luteolin can protect against sodium nitroprusside (SNP)-induced oxidative damage in mouse brain. Intrastriatal co-injection of luteolin (3 - 30 nmol) with SNP (10 nmol) dose-dependently protected against brain damage and Motor Dysfunction. Oral administrations of luteolin (600 - 1200 mg/kg) dose-dependently protected against brain damage and Motor Dysfunction induced by striatal injection of SNP. Furthermore, luteolin (30 - 100 μM) concentration dependently protected against Fe(2+)-induced lipid peroxidation in mouse brain homogenate. Luteolin (1 - 100 μg/ml) showed potent DPPH radical scavenging ability, when compared with ascorbic acid and glutathione. Finally, a ferrozine assay showed that luteolin (30 - 100 μg/ml) has Fe(2+)-chelating ability, but this was weaker than that of ethylenediaminetetraacetic acid. These results suggest that intrastriatal or oral administration of luteolin protected mice brain from SNP-induced oxidative damage by scavenging and chelating effects.
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in vivo brain oxidative stress model induced by microinjection of sodium nitroprusside in mice
Journal of Pharmacological Sciences, 2012Co-Authors: Qand Agha Nazari, Keita Mizuno, Toshiaki Kume, Yuki Takadatakatori, Yasuhiko Izumi, Akinori AkaikeAbstract:Sodium nitroprusside (SNP) is widely used as a potent vasodilator and a nitric oxide (NO) donor, whereas the cytotoxicity of SNP has been well documented. SNP releases several potentially toxic products such as cyanide anion, NO, and iron. We investigated the mechanisms of cell death and Motor Dysfunction induced by microinjection of SNP in mice to establish a brain oxidative stress model and then examined the anti-oxidant activity of glutathione. Intrastriatal microinjection of SNP (1 - 10 nmol) induced brain damage and Motor Dysfunction in a dose-dependent manner when the effects were evaluated with behavioral tests and TTC staining. NOC-18 (10 nmol), another NO donor, and KCN (10 nmol) did not cause Motor Dysfunction. However, FeCl(2) (10 nmol) caused Motor Dysfunction. In addition, simultaneous injection of SNP and deferoxamine (10 nmol), an iron-chelating agent, prevented SNP-induced brain damage and Motor Dysfunction, suggesting a role of iron-related radicals in SNP-toxicity. Moreover, reduced glutathione (1 - 10 nmol), a natural anti-oxidant substance, dose-dependently prevented Motor Dysfunction induced by SNP-toxicity. Finally, deferoxamine and glutathione (10 nmol) significantly protected against brain damage and Motor Dysfunction induced by FeCl(2) toxicity. These results suggest that cell death induced by injection of SNP is caused by iron-related radical reactions, but not by NO and cyanide anion.
Kazuhisa Takahashi - One of the best experts on this subject based on the ideXlab platform.
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reduced field of view diffusion tensor imaging of the spinal cord shows Motor Dysfunction of the lower extremities in patients with cervical compression myelopathy
Spine, 2018Co-Authors: Satoshi Maki, Kazuhisa Takahashi, Masao Koda, Mitsutoshi Ota, Yoshihiro Oikawa, Koshiro Kamiya, Taigo Inada, Takeo Furuya, Yoshitada Masuda, Koji MatsumotoAbstract:STUDY DESIGN A cross-sectional study. OBJECTIVE The aim of this study was to quantify spinal cord Dysfunction at the tract level in patients with cervical compressive myelopathy (CCM) using reduced field-of-view (rFOV) diffusion tensor imaging (DTI). SUMMARY OF BACKGROUND DATA Although magnetic resonance imaging (MRI) is the standard used for radiological evaluation of CCM, information acquired by MRI does not necessarily reflect the severity of spinal cord disorder. There is a growing interest in developing imaging methods to quantify spinal cord Dysfunction. To acquire high-resolution DTI, a new scheme using rFOV has been proposed. METHODS We enrolled 10 healthy volunteers and 20 patients with CCM in this study. The participants were studied using a 3.0-T MRI system. For DTI acquisitions, diffusion-weighted spin-echo rFOV single-shot echo-planar imaging was used. Regions-of-interest (ROI) for the lateral column (LC) and posterior column (PC) tracts were determined on the basis of a map of fractional anisotropy (FA) of the spinal cord and FA values were measured. The FA of patients with CCM was compared with that of healthy controls and correlated with Japanese Orthopaedic Association (JOA) score. RESULTS In LC and PC tracts, FA values in patients with CCM were significantly lower than in healthy volunteers. Total JOA scores correlated moderately with FA in LC and PC tracts. JOA subscores for Motor Dysfunction of the lower extremities correlated strongly with FA in LC and PC tracts. CONCLUSION It is feasible to evaluate the cervical spinal cord at the tract level using rFOV DTI. Although FA values at the maximum compression level were not well correlated with total JOA scores, they were strongly correlated with JOA subscores for Motor Dysfunction of the lower extremities. Our findings suggest that FA reflects white matter Dysfunction below the maximum compression level and FA can be used as an imaging biomarker of spinal cord Dysfunction. LEVEL OF EVIDENCE 4.
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Rho kinase inhibitor improves Motor Dysfunction and hypoalgesia in a rat model of lumbar spinal canal stenosis.
Spine, 2007Co-Authors: Toshinori Ito, Seiji Ohtori, Katsuhiko Hata, Inoue, Hideshige Moriya, Kazuhisa Takahashi, Toshihide YamashitaAbstract:Study Design. Immunohistochemical and behavioral study using a rat cauda equina compression model. Objective. To investigate, after cauda equina compression by spinal canal stenosis (SCS), Rho activation in the spinal cord and cauda equina, and the effect of intrathecal administration of a Rho kinase inhibitor on hypoalgesia and Motor Dysfunction. Summary of Background Data. Compression of the cauda equina caused by SCS is a common clinical disorder associated with sensory disturbance and intermittent claudication. Cauda equina compression is thought to reduce blood flow and result in nerve degeneration caused by various cytokines. Rho, a member of the small GTPases, is a signal transmitter. It promotes Wallerian degeneration, decreases blood flow in the spinal cord and brain, and increases expression of several cytokines. Currently, Rho kinase inhibitor is used clinically to treat progressive nerve damage due to cerebrovascular disorders. However, its effect for SCS has not been evaluated. Methods. Forty-two 6-week-old male Sprague-Dawley rats (200–250 g) were used. For the SCS model (n = 27), a small piece of silicon was placed under the lamina of the fourth lumbar vertebra. In the sham-operated group, laminectomies were performed at L5 only (n = 15). We examined mechanical sensitivity and Motor function using von Frey hairs and a treadmill, and immunohistochemically localized Rho in the spinal ventral neurons, axons, and Schwann cells in the cauda equina. We also examined the effects of intrathecally administered Rho kinase inhibitor for hypoalgesia or Motor Dysfunction caused by SCS. Results. We observed Motor Dysfunction and hypoalgesia and activated Rho-immunoreactive cells in spinal ventral neuroreported to induce neurite and axonal outgrowth in the spinal cord and brain after nervous system injury.10,11 In addition, 1 report showed that Rho kinase was involved in Wallerian degeneration that was rescued by Rho kinase inhibitor.16 Furthermore, it is thought that Rho is involved in TNF-α and interleukin (IL) production in the central nervous system, and the production was inhibited by administering Rho kinase inhibitor in the central nervous system.17 Regardns, axons, and Schwann cells in the cauda equina. Intrathecal administration of Rho kinase inhibitor improved mechanical hypoalgesia and Motor Dysfunction caused by SCS. Conclusion. Activated Rho may play an important role in nerve damage in the cauda equina in SCS. Rho kinase inhibitor may be a useful tool in determining the pathomechanism of cauda equina syndrome caused by SCS.
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glial phosphorylated p38 map kinase mediates pain in a rat model of lumbar disc herniation and induces Motor Dysfunction in a rat model of lumbar spinal canal stenosis
Spine, 2007Co-Authors: Toshinori Ito, Seiji Ohtori, Hideshige Moriya, Gen Inoue, Takana Koshi, Hideo Doya, Tomoyuki Ozawa, Tomoko Saito, Kazuhisa TakahashiAbstract:STUDY DESIGN Immunohistochemical and behavioral study using rat models of lumbar disc herniation and cauda equina syndrome. OBJECTIVE To investigate the expression of activated p38 mitogen-activated protein kinases (p38 MAP kinase; p38) in the spinal cord and to determine the effect of intrathecal administration of a specific p38 inhibitor on pain in a lumbar disc herniation model and on Motor function and hypoalgesia in a spinal canal stenosis (SCS) model. SUMMARY OF BACKGROUND DATA In pathologic lumbar disc herniation-induced neuropathic pain and compression of cauda equina-induced Motor Dysfunction and hypoalgesia caused by SCS, glia are activated and produce certain cytokines, including tumor necrosis factor-alpha (TNF-alpha) and interleukins, which play a crucial role in the pathogenesis of nerve degeneration. p38 is phosphorylated by these cytokines, suggesting that it may play an important role in pain transmission and nerve degeneration. Here we have examined the role of p38 in rat models of lumbar disc herniation and SCS. METHODS Six-week-old male Sprague-Dawley rats were used. For the disc herniation model, autologous nucleus pulposus was applied to L5 nerve roots, which were then crushed. For the SCS model, a piece of silicon was placed under the lamina of the fourth lumbar vertebra. We assessed mechanical allodynia, hypoalgesia, and Motor function using von Frey hairs, treadmill tests, and immunohistochemical localization of phosphorylated p38 (P-p38) in the cauda equina, dorsal root ganglion (DRG), and spinal cord, which were also double-stained with NeuN (neuronal marker), GFAP (astrocyte/Schwann cell marker), or isolectin B4 (IB4; microglia marker). We also examined the effects of intrathecal administration of a specific p38 inhibitor, FR167653, on nucleus pulposus-induced pain, hypoalgesia, and Motor Dysfunction following SCS. RESULTS We demonstrated that activated P-p38-immunoreactive cells in the spinal cord and cauda equina were not observed before nerve injury but appeared in the cauda equina, DRG, and spinal dorsal horn in the disc herniation and SCS models. Double-labeling revealed that most P-p38-immunoreactive cells were isolectin B4-labeled microglia and GFAP-immunoreactive Schwann cells. Intrathecal administration of the p38 inhibitor FR167653 decreased mechanical allodynia in the disc herniation model and improved hypoalgesia and intermittent Motor Dysfunction in the SCS model. CONCLUSIONS Our findings suggest that activated p38 may play an important role in the involvement of microglia in the pathophysiology of pain following lumbar disc herniation and mechanical hypoalgesia, and Motor nerve Dysfunction of cauda equina following SCS.
Qand Agha Nazari - One of the best experts on this subject based on the ideXlab platform.
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potential protective effect of highly bioavailable curcumin on an oxidative stress model induced by microinjection of sodium nitroprusside in mice brain
Food & Function, 2014Co-Authors: Qand Agha Nazari, Yuki Takadatakatori, Yasuhiko Izumi, Akinori Akaike, Tadashi Hashimoto, Atsushi Imaizumi, Toshiaki KumeAbstract:Curcumin, a polyphenolic compound has several pharmacological activities, such as anticancer, anti-inflammatory and antioxidant effects. However, curcumin shows poor oral bioavailability. The purpose of this study was to investigate the protective effects of highly bioavailable curcumin, Theracurmin®, and curcumin, against sodium nitroprusside (SNP)-induced oxidative damage in mice brain. Intrastriatal microinjection of Theracurmin® or curcumin with SNP significantly protected against SNP-induced brain damage and Motor Dysfunction. Oral administration of Theracurmin® (1 and 3 g kg−1, containing 100 and 300 mg kg−1 curcumin, respectively) significantly protected against SNP-induced brain damage and Motor Dysfunction. However, oral administration of 300 mg kg−1 curcumin did not protect against Motor Dysfunction induced by SNP. These results suggest that curcumin and Theracurmin® have protective effects against SNP-induced oxidative damage. Moreover, oral administration of Theracurmin®, had more potency in protecting against brain damage, suggesting a higher bioavailability of Theracurmin® following oral administration.
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protective effect of luteolin on an oxidative stress model induced by microinjection of sodium nitroprusside in mice
Journal of Pharmacological Sciences, 2013Co-Authors: Qand Agha Nazari, Toshiaki Kume, Yuki Takadatakatori, Yasuhiko Izumi, Akinori AkaikeAbstract:Accumulating lines of evidence showed that luteolin, a polyphenolic compound, has potent neuroprotective effects. The purpose of this study was to examine whether luteolin can protect against sodium nitroprusside (SNP)-induced oxidative damage in mouse brain. Intrastriatal co-injection of luteolin (3 - 30 nmol) with SNP (10 nmol) dose-dependently protected against brain damage and Motor Dysfunction. Oral administrations of luteolin (600 - 1200 mg/kg) dose-dependently protected against brain damage and Motor Dysfunction induced by striatal injection of SNP. Furthermore, luteolin (30 - 100 μM) concentration dependently protected against Fe(2+)-induced lipid peroxidation in mouse brain homogenate. Luteolin (1 - 100 μg/ml) showed potent DPPH radical scavenging ability, when compared with ascorbic acid and glutathione. Finally, a ferrozine assay showed that luteolin (30 - 100 μg/ml) has Fe(2+)-chelating ability, but this was weaker than that of ethylenediaminetetraacetic acid. These results suggest that intrastriatal or oral administration of luteolin protected mice brain from SNP-induced oxidative damage by scavenging and chelating effects.
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in vivo brain oxidative stress model induced by microinjection of sodium nitroprusside in mice
Journal of Pharmacological Sciences, 2012Co-Authors: Qand Agha Nazari, Keita Mizuno, Toshiaki Kume, Yuki Takadatakatori, Yasuhiko Izumi, Akinori AkaikeAbstract:Sodium nitroprusside (SNP) is widely used as a potent vasodilator and a nitric oxide (NO) donor, whereas the cytotoxicity of SNP has been well documented. SNP releases several potentially toxic products such as cyanide anion, NO, and iron. We investigated the mechanisms of cell death and Motor Dysfunction induced by microinjection of SNP in mice to establish a brain oxidative stress model and then examined the anti-oxidant activity of glutathione. Intrastriatal microinjection of SNP (1 - 10 nmol) induced brain damage and Motor Dysfunction in a dose-dependent manner when the effects were evaluated with behavioral tests and TTC staining. NOC-18 (10 nmol), another NO donor, and KCN (10 nmol) did not cause Motor Dysfunction. However, FeCl(2) (10 nmol) caused Motor Dysfunction. In addition, simultaneous injection of SNP and deferoxamine (10 nmol), an iron-chelating agent, prevented SNP-induced brain damage and Motor Dysfunction, suggesting a role of iron-related radicals in SNP-toxicity. Moreover, reduced glutathione (1 - 10 nmol), a natural anti-oxidant substance, dose-dependently prevented Motor Dysfunction induced by SNP-toxicity. Finally, deferoxamine and glutathione (10 nmol) significantly protected against brain damage and Motor Dysfunction induced by FeCl(2) toxicity. These results suggest that cell death induced by injection of SNP is caused by iron-related radical reactions, but not by NO and cyanide anion.
Toshiaki Kume - One of the best experts on this subject based on the ideXlab platform.
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potential protective effect of highly bioavailable curcumin on an oxidative stress model induced by microinjection of sodium nitroprusside in mice brain
Food & Function, 2014Co-Authors: Qand Agha Nazari, Yuki Takadatakatori, Yasuhiko Izumi, Akinori Akaike, Tadashi Hashimoto, Atsushi Imaizumi, Toshiaki KumeAbstract:Curcumin, a polyphenolic compound has several pharmacological activities, such as anticancer, anti-inflammatory and antioxidant effects. However, curcumin shows poor oral bioavailability. The purpose of this study was to investigate the protective effects of highly bioavailable curcumin, Theracurmin®, and curcumin, against sodium nitroprusside (SNP)-induced oxidative damage in mice brain. Intrastriatal microinjection of Theracurmin® or curcumin with SNP significantly protected against SNP-induced brain damage and Motor Dysfunction. Oral administration of Theracurmin® (1 and 3 g kg−1, containing 100 and 300 mg kg−1 curcumin, respectively) significantly protected against SNP-induced brain damage and Motor Dysfunction. However, oral administration of 300 mg kg−1 curcumin did not protect against Motor Dysfunction induced by SNP. These results suggest that curcumin and Theracurmin® have protective effects against SNP-induced oxidative damage. Moreover, oral administration of Theracurmin®, had more potency in protecting against brain damage, suggesting a higher bioavailability of Theracurmin® following oral administration.
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protective effect of luteolin on an oxidative stress model induced by microinjection of sodium nitroprusside in mice
Journal of Pharmacological Sciences, 2013Co-Authors: Qand Agha Nazari, Toshiaki Kume, Yuki Takadatakatori, Yasuhiko Izumi, Akinori AkaikeAbstract:Accumulating lines of evidence showed that luteolin, a polyphenolic compound, has potent neuroprotective effects. The purpose of this study was to examine whether luteolin can protect against sodium nitroprusside (SNP)-induced oxidative damage in mouse brain. Intrastriatal co-injection of luteolin (3 - 30 nmol) with SNP (10 nmol) dose-dependently protected against brain damage and Motor Dysfunction. Oral administrations of luteolin (600 - 1200 mg/kg) dose-dependently protected against brain damage and Motor Dysfunction induced by striatal injection of SNP. Furthermore, luteolin (30 - 100 μM) concentration dependently protected against Fe(2+)-induced lipid peroxidation in mouse brain homogenate. Luteolin (1 - 100 μg/ml) showed potent DPPH radical scavenging ability, when compared with ascorbic acid and glutathione. Finally, a ferrozine assay showed that luteolin (30 - 100 μg/ml) has Fe(2+)-chelating ability, but this was weaker than that of ethylenediaminetetraacetic acid. These results suggest that intrastriatal or oral administration of luteolin protected mice brain from SNP-induced oxidative damage by scavenging and chelating effects.
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in vivo brain oxidative stress model induced by microinjection of sodium nitroprusside in mice
Journal of Pharmacological Sciences, 2012Co-Authors: Qand Agha Nazari, Keita Mizuno, Toshiaki Kume, Yuki Takadatakatori, Yasuhiko Izumi, Akinori AkaikeAbstract:Sodium nitroprusside (SNP) is widely used as a potent vasodilator and a nitric oxide (NO) donor, whereas the cytotoxicity of SNP has been well documented. SNP releases several potentially toxic products such as cyanide anion, NO, and iron. We investigated the mechanisms of cell death and Motor Dysfunction induced by microinjection of SNP in mice to establish a brain oxidative stress model and then examined the anti-oxidant activity of glutathione. Intrastriatal microinjection of SNP (1 - 10 nmol) induced brain damage and Motor Dysfunction in a dose-dependent manner when the effects were evaluated with behavioral tests and TTC staining. NOC-18 (10 nmol), another NO donor, and KCN (10 nmol) did not cause Motor Dysfunction. However, FeCl(2) (10 nmol) caused Motor Dysfunction. In addition, simultaneous injection of SNP and deferoxamine (10 nmol), an iron-chelating agent, prevented SNP-induced brain damage and Motor Dysfunction, suggesting a role of iron-related radicals in SNP-toxicity. Moreover, reduced glutathione (1 - 10 nmol), a natural anti-oxidant substance, dose-dependently prevented Motor Dysfunction induced by SNP-toxicity. Finally, deferoxamine and glutathione (10 nmol) significantly protected against brain damage and Motor Dysfunction induced by FeCl(2) toxicity. These results suggest that cell death induced by injection of SNP is caused by iron-related radical reactions, but not by NO and cyanide anion.
Toshinori Ito - One of the best experts on this subject based on the ideXlab platform.
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Rho kinase inhibitor improves Motor Dysfunction and hypoalgesia in a rat model of lumbar spinal canal stenosis.
Spine, 2007Co-Authors: Toshinori Ito, Seiji Ohtori, Katsuhiko Hata, Inoue, Hideshige Moriya, Kazuhisa Takahashi, Toshihide YamashitaAbstract:Study Design. Immunohistochemical and behavioral study using a rat cauda equina compression model. Objective. To investigate, after cauda equina compression by spinal canal stenosis (SCS), Rho activation in the spinal cord and cauda equina, and the effect of intrathecal administration of a Rho kinase inhibitor on hypoalgesia and Motor Dysfunction. Summary of Background Data. Compression of the cauda equina caused by SCS is a common clinical disorder associated with sensory disturbance and intermittent claudication. Cauda equina compression is thought to reduce blood flow and result in nerve degeneration caused by various cytokines. Rho, a member of the small GTPases, is a signal transmitter. It promotes Wallerian degeneration, decreases blood flow in the spinal cord and brain, and increases expression of several cytokines. Currently, Rho kinase inhibitor is used clinically to treat progressive nerve damage due to cerebrovascular disorders. However, its effect for SCS has not been evaluated. Methods. Forty-two 6-week-old male Sprague-Dawley rats (200–250 g) were used. For the SCS model (n = 27), a small piece of silicon was placed under the lamina of the fourth lumbar vertebra. In the sham-operated group, laminectomies were performed at L5 only (n = 15). We examined mechanical sensitivity and Motor function using von Frey hairs and a treadmill, and immunohistochemically localized Rho in the spinal ventral neurons, axons, and Schwann cells in the cauda equina. We also examined the effects of intrathecally administered Rho kinase inhibitor for hypoalgesia or Motor Dysfunction caused by SCS. Results. We observed Motor Dysfunction and hypoalgesia and activated Rho-immunoreactive cells in spinal ventral neuroreported to induce neurite and axonal outgrowth in the spinal cord and brain after nervous system injury.10,11 In addition, 1 report showed that Rho kinase was involved in Wallerian degeneration that was rescued by Rho kinase inhibitor.16 Furthermore, it is thought that Rho is involved in TNF-α and interleukin (IL) production in the central nervous system, and the production was inhibited by administering Rho kinase inhibitor in the central nervous system.17 Regardns, axons, and Schwann cells in the cauda equina. Intrathecal administration of Rho kinase inhibitor improved mechanical hypoalgesia and Motor Dysfunction caused by SCS. Conclusion. Activated Rho may play an important role in nerve damage in the cauda equina in SCS. Rho kinase inhibitor may be a useful tool in determining the pathomechanism of cauda equina syndrome caused by SCS.
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glial phosphorylated p38 map kinase mediates pain in a rat model of lumbar disc herniation and induces Motor Dysfunction in a rat model of lumbar spinal canal stenosis
Spine, 2007Co-Authors: Toshinori Ito, Seiji Ohtori, Hideshige Moriya, Gen Inoue, Takana Koshi, Hideo Doya, Tomoyuki Ozawa, Tomoko Saito, Kazuhisa TakahashiAbstract:STUDY DESIGN Immunohistochemical and behavioral study using rat models of lumbar disc herniation and cauda equina syndrome. OBJECTIVE To investigate the expression of activated p38 mitogen-activated protein kinases (p38 MAP kinase; p38) in the spinal cord and to determine the effect of intrathecal administration of a specific p38 inhibitor on pain in a lumbar disc herniation model and on Motor function and hypoalgesia in a spinal canal stenosis (SCS) model. SUMMARY OF BACKGROUND DATA In pathologic lumbar disc herniation-induced neuropathic pain and compression of cauda equina-induced Motor Dysfunction and hypoalgesia caused by SCS, glia are activated and produce certain cytokines, including tumor necrosis factor-alpha (TNF-alpha) and interleukins, which play a crucial role in the pathogenesis of nerve degeneration. p38 is phosphorylated by these cytokines, suggesting that it may play an important role in pain transmission and nerve degeneration. Here we have examined the role of p38 in rat models of lumbar disc herniation and SCS. METHODS Six-week-old male Sprague-Dawley rats were used. For the disc herniation model, autologous nucleus pulposus was applied to L5 nerve roots, which were then crushed. For the SCS model, a piece of silicon was placed under the lamina of the fourth lumbar vertebra. We assessed mechanical allodynia, hypoalgesia, and Motor function using von Frey hairs, treadmill tests, and immunohistochemical localization of phosphorylated p38 (P-p38) in the cauda equina, dorsal root ganglion (DRG), and spinal cord, which were also double-stained with NeuN (neuronal marker), GFAP (astrocyte/Schwann cell marker), or isolectin B4 (IB4; microglia marker). We also examined the effects of intrathecal administration of a specific p38 inhibitor, FR167653, on nucleus pulposus-induced pain, hypoalgesia, and Motor Dysfunction following SCS. RESULTS We demonstrated that activated P-p38-immunoreactive cells in the spinal cord and cauda equina were not observed before nerve injury but appeared in the cauda equina, DRG, and spinal dorsal horn in the disc herniation and SCS models. Double-labeling revealed that most P-p38-immunoreactive cells were isolectin B4-labeled microglia and GFAP-immunoreactive Schwann cells. Intrathecal administration of the p38 inhibitor FR167653 decreased mechanical allodynia in the disc herniation model and improved hypoalgesia and intermittent Motor Dysfunction in the SCS model. CONCLUSIONS Our findings suggest that activated p38 may play an important role in the involvement of microglia in the pathophysiology of pain following lumbar disc herniation and mechanical hypoalgesia, and Motor nerve Dysfunction of cauda equina following SCS.
