The Experts below are selected from a list of 1842 Experts worldwide ranked by ideXlab platform
Hiroaki Shimokawa - One of the best experts on this subject based on the ideXlab platform.
-
preventive and therapeutic effects of the selective rho kinase inhibitor Fasudil on experimental autoimmune neuritis
Journal of the Neurological Sciences, 2011Co-Authors: Arnold Angelo M Pineda, Hiroaki Shimokawa, Motozumi Minohara, Nobutoshi Kawamura, Takuya Matsushita, Ryo Yamasaki, Hua Piao, Junichi KiraAbstract:Abstract We studied the effects of Fasudil, a selective Rho-kinase inhibitor, on experimental autoimmune neuritis (EAN). Continuous parenteral administration of Fasudil prevented the development of EAN induced by P0 peptide 180–199 in Lewis rats while it also reduced EAN severity when administered after disease onset. Immunohistochemical examination disclosed a marked decrease in the amount of inflammatory cell infiltration and attenuation of demyelination and axonal degeneration. Specific proliferation of lymphocytes from Fasudil-treated rats in response to P0 peptide was significantly reduced as compared with those from phosphate-buffered saline (PBS)-treated rats. Fasudil treatment was associated with a significant reduction in secretion of IFN-γ; by contrast, secretion of IL-4 was almost the same in the Fasudil- and PBS-treated groups. As a result, the IFN-γ/IL-4 ratio in the supernatant was significantly deceased in Fasudil-treated rats compared with PBS-treated ones. Therefore, our results indicate a beneficial effect of selective blockade of Rho-kinase in animals with autoimmune inflammation of the peripheral nerves, and may provide a rationale for the selective blockade of Rho-kinase as a new therapy for Guillain-Barre syndrome.
-
involvement of rho kinase in cold ischemia reperfusion injury after liver transplantation in rats
Transplantation, 2004Co-Authors: Satoko Shiotani, Hiroaki Shimokawa, Mitsuo Shimada, Taketoshi Suehiro, Yuji Soejima, Tomoharu Yosizumi, Yoshihiko MaeharaAbstract:BACKGROUND Reperfusion of ischemic tissues is known to cause the generation of reactive oxygen species (ROS) with resultant tissue damage. However, the sources of ROS in reperfused tissues are not fully characterized. We hypothesized that the small GTPase Rho and its target effector Rho-kinase/ROK/ROCK are involved in the oxidative burst in reperfused tissue with resultant reperfusion injury. METHODS In an in vivo rat model of liver transplantation using cold ischemia for 12 hr followed by reperfusion, a specific Rho-kinase inhibitor, Fasudil (30 mg/kg), was administered orally 1 hr before the transplantation. RESULTS Fasudil suppressed the ischemia-reperfusion (I/R)-induced generation of ROS after reperfusion (P<0.01) and also suppressed the release of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta) 3 hr after reperfusion, resulting in a significant reduction of I/R-induced hepatocellular injury (P<0.05), necrosis, apoptosis (P<0.01), and neutrophil infiltration (P<0.0001) 12 hr after reperfusion. All animals receiving a graft without Fasudil died within 3 days, whereas 40% of those receiving Fasudil survived (P<0.001). CONCLUSIONS The present study demonstrates that Rho-kinase-mediated production of ROS and inflammatory cytokines are substantially involved in the pathogenesis of hepatocellular necrosis and apoptosis induced by cold I/R in vivo and that Rho-kinase may be regarded as a novel therapeutic target for the disorder.
-
long term inhibition of rho kinase suppresses angiotensin ii induced cardiovascular hypertrophy in rats in vivo effect on endothelial nad p h oxidase system
Circulation Research, 2003Co-Authors: Midoriko Higashi, Hiroaki Shimokawa, Tsuyoshi Hattori, Junko Hiroki, Yasushi Mukai, Keiko Morikawa, Toshihiro Ichiki, Shosuke Takahashi, Akira TakeshitaAbstract:Intracellular signaling pathway mediated by small GTPase Rho and its effector Rho-kinase plays an important role in regulation of vascular smooth muscle contraction and other cellular functions. We have recently demonstrated that Rho-kinase is substantially involved in angiotensin II-induced gene expressions and various cellular responses in vitro. However, it remains to be examined whether Rho-kinase is involved in the angiotensin II-induced cardiovascular hypertrophy in vivo and, if so, what mechanisms are involved. Long-term infusion of angiotensin II for 4 weeks caused hypertrophic changes of vascular smooth muscle and cardiomyocytes in rats. Both changes were significantly suppressed by concomitant oral treatment with Fasudil, which is metabolized to a specific Rho-kinase inhibitor, hydroxyFasudil, after oral administration. Angiotensin II caused a perivascular accumulation of macrophages and Rho-kinase activation, both of which were also significantly suppressed by Fasudil. Vascular NAD(P)H oxidase expression (nox1, nox4, gp91phox, and p22phox) and endothelial production of superoxide anions were markedly increased by angiotensin II, both of which were also significantly suppressed by Fasudil. Thus, Fasudil ameliorated the impaired endothelium-dependent relaxations caused by angiotensin II without affecting vasodilator function of vascular smooth muscle. These results provide evidence that Rho-kinase is substantially involved in the angiotensin II-induced cardiovascular hypertrophy in rats in vivo. The suppression of endothelial NAD(P)H oxidase upregulation and resultant superoxide production and the amelioration of endothelial vasodilator function may be involved in this process. (Circ Res. 2003;93:767-775.)
-
rho kinase inhibition with intracoronary Fasudil prevents myocardial ischemia in patients with coronary microvascular spasm
Journal of the American College of Cardiology, 2003Co-Authors: Masahiro Mohri, Hiroaki Shimokawa, Akihiro Masumoto, Yoji Hirakawa, Akira TakeshitaAbstract:OBJECTIVES We sought to determine whether a potent Rho-kinase inhibitor Fasudil prevents the occurrence of myocardial ischemia in patients with microvascular angina attributable to coronary microvascular spasm. BACKGROUND Effective treatment of patients with angina who have normal coronary arteriograms (microvascular angina) has not yet been established. Rho-kinase-mediated calcium sensitization of the myosin light chain in smooth muscle cells has been implicated as substantially contributing to vascular hyperconstriction. METHODS We studied consecutive 18 patients with angina and normal epicardial coronaries in whom intracoronary acetylcholine (ACh) induced myocardial ischemia (ischemic electrocardiographic changes, myocardial lactate production, or both) without angiographically demonstrable epicardial coronary vasospasm. All patients underwent a second ACh challenge test after pretreatment with either saline (n = 5) or Fasudil (4.5 mg intracoronarily, n = 13). RESULTS Myocardial ischemia was reproducibly induced by ACh in the saline group. In contrast, 11 of the 13 patients pretreated with Fasudil had no evidence of myocardial ischemia during the second infusion of ACh (p < 0.01). The lactate extraction ratio (median value [interquartile range]) during ACh infusion was improved by Fasudil pretreatment, from -0.16 (-0.25 to 0.04) to 0.09 (0.05 to 0.18) (p = 0.0125). CONCLUSIONS Fasudil ameliorated myocardial ischemia in patients who were most likely having coronary microvascular spasm. The inhibition of Rho-kinase may be a novel therapeutic strategy for this group of patients with microvascular angina.
-
suppression of coronary artery spasm by the rho kinase inhibitor Fasudil in patients with vasospastic angina
Circulation, 2002Co-Authors: Akihiro Masumoto, Hiroaki Shimokawa, Masahiro Mohri, Lemmy Urakami, Makoto Usui, Akira TakeshitaAbstract:Background— Increased activity of Rho-kinase causes hypercontraction of vascular smooth muscle and has been implicated as playing a pathogenetic role in divergent cardiovascular diseases such as coronary artery spasm. We examined whether an intracoronary infusion of Fasudil, a selective Rho-kinase inhibitor, would attenuate coronary vasoconstrictor responses to acetylcholine (ACh) in patients with vasospastic angina. Methods and Results— We studied 20 consecutive patients in whom coronary artery spasm was provoked by intracoronary ACh. The patients underwent a second ACh challenge after pretreatment with intracoronary saline (n=5) or Fasudil (n=15; 300 μg/min for 15 minutes). Angina and coronary vasospasm were reproducibly induced by the second testing in patients who received saline. In contrast, Fasudil markedly attenuated the coronary constriction induced by ACh (P<0.001) and prevented the occurrence of chest pain and ischemic ECG changes in all treated patients (both P<0.01 versus saline). Fasudil, at...
Akira Takeshita - One of the best experts on this subject based on the ideXlab platform.
-
long term inhibition of rho kinase suppresses angiotensin ii induced cardiovascular hypertrophy in rats in vivo effect on endothelial nad p h oxidase system
Circulation Research, 2003Co-Authors: Midoriko Higashi, Hiroaki Shimokawa, Tsuyoshi Hattori, Junko Hiroki, Yasushi Mukai, Keiko Morikawa, Toshihiro Ichiki, Shosuke Takahashi, Akira TakeshitaAbstract:Intracellular signaling pathway mediated by small GTPase Rho and its effector Rho-kinase plays an important role in regulation of vascular smooth muscle contraction and other cellular functions. We have recently demonstrated that Rho-kinase is substantially involved in angiotensin II-induced gene expressions and various cellular responses in vitro. However, it remains to be examined whether Rho-kinase is involved in the angiotensin II-induced cardiovascular hypertrophy in vivo and, if so, what mechanisms are involved. Long-term infusion of angiotensin II for 4 weeks caused hypertrophic changes of vascular smooth muscle and cardiomyocytes in rats. Both changes were significantly suppressed by concomitant oral treatment with Fasudil, which is metabolized to a specific Rho-kinase inhibitor, hydroxyFasudil, after oral administration. Angiotensin II caused a perivascular accumulation of macrophages and Rho-kinase activation, both of which were also significantly suppressed by Fasudil. Vascular NAD(P)H oxidase expression (nox1, nox4, gp91phox, and p22phox) and endothelial production of superoxide anions were markedly increased by angiotensin II, both of which were also significantly suppressed by Fasudil. Thus, Fasudil ameliorated the impaired endothelium-dependent relaxations caused by angiotensin II without affecting vasodilator function of vascular smooth muscle. These results provide evidence that Rho-kinase is substantially involved in the angiotensin II-induced cardiovascular hypertrophy in rats in vivo. The suppression of endothelial NAD(P)H oxidase upregulation and resultant superoxide production and the amelioration of endothelial vasodilator function may be involved in this process. (Circ Res. 2003;93:767-775.)
-
rho kinase inhibition with intracoronary Fasudil prevents myocardial ischemia in patients with coronary microvascular spasm
Journal of the American College of Cardiology, 2003Co-Authors: Masahiro Mohri, Hiroaki Shimokawa, Akihiro Masumoto, Yoji Hirakawa, Akira TakeshitaAbstract:OBJECTIVES We sought to determine whether a potent Rho-kinase inhibitor Fasudil prevents the occurrence of myocardial ischemia in patients with microvascular angina attributable to coronary microvascular spasm. BACKGROUND Effective treatment of patients with angina who have normal coronary arteriograms (microvascular angina) has not yet been established. Rho-kinase-mediated calcium sensitization of the myosin light chain in smooth muscle cells has been implicated as substantially contributing to vascular hyperconstriction. METHODS We studied consecutive 18 patients with angina and normal epicardial coronaries in whom intracoronary acetylcholine (ACh) induced myocardial ischemia (ischemic electrocardiographic changes, myocardial lactate production, or both) without angiographically demonstrable epicardial coronary vasospasm. All patients underwent a second ACh challenge test after pretreatment with either saline (n = 5) or Fasudil (4.5 mg intracoronarily, n = 13). RESULTS Myocardial ischemia was reproducibly induced by ACh in the saline group. In contrast, 11 of the 13 patients pretreated with Fasudil had no evidence of myocardial ischemia during the second infusion of ACh (p < 0.01). The lactate extraction ratio (median value [interquartile range]) during ACh infusion was improved by Fasudil pretreatment, from -0.16 (-0.25 to 0.04) to 0.09 (0.05 to 0.18) (p = 0.0125). CONCLUSIONS Fasudil ameliorated myocardial ischemia in patients who were most likely having coronary microvascular spasm. The inhibition of Rho-kinase may be a novel therapeutic strategy for this group of patients with microvascular angina.
-
suppression of coronary artery spasm by the rho kinase inhibitor Fasudil in patients with vasospastic angina
Circulation, 2002Co-Authors: Akihiro Masumoto, Hiroaki Shimokawa, Masahiro Mohri, Lemmy Urakami, Makoto Usui, Akira TakeshitaAbstract:Background— Increased activity of Rho-kinase causes hypercontraction of vascular smooth muscle and has been implicated as playing a pathogenetic role in divergent cardiovascular diseases such as coronary artery spasm. We examined whether an intracoronary infusion of Fasudil, a selective Rho-kinase inhibitor, would attenuate coronary vasoconstrictor responses to acetylcholine (ACh) in patients with vasospastic angina. Methods and Results— We studied 20 consecutive patients in whom coronary artery spasm was provoked by intracoronary ACh. The patients underwent a second ACh challenge after pretreatment with intracoronary saline (n=5) or Fasudil (n=15; 300 μg/min for 15 minutes). Angina and coronary vasospasm were reproducibly induced by the second testing in patients who received saline. In contrast, Fasudil markedly attenuated the coronary constriction induced by ACh (P<0.001) and prevented the occurrence of chest pain and ischemic ECG changes in all treated patients (both P<0.01 versus saline). Fasudil, at...
Yoshihiro Fukumoto - One of the best experts on this subject based on the ideXlab platform.
-
acute vasodilator effects of inhaled Fasudil a specific rho kinase inhibitor in patients with pulmonary arterial hypertension
Heart and Vessels, 2010Co-Authors: Hiroshi Fujita, Yoshihiro Fukumoto, Kenya Saji, Koichiro Sugimura, Jun Demachi, Jun NawataAbstract:We have previously demonstrated that long-term inhibition of Rho-kinase ameliorates pulmonary arterial hypertension (PAH) in animal models. In the present study, we examined acute vasodilator effects of inhaled Fasudil, a specific Rho-kinase inhibitor, as a more feasible option to locally deliver the drug for PAH. We examined 15 patients with PAH (13 women and 2 men, 45 ± 4 years old), including idiopathic PAH (n = 5), PAH associated with connective tissue disease (n = 6), PAH with congenital heart disease (n = 3), and portal PAH (n = 1). In those patients, we performed right heart catheterization with a Swan-Ganz catheter in the two protocols with inhalation of nitric oxide (NO) (40 ppm, 10 min) and Fasudil (30 mg, 10 min) with a sufficient interval (>30 min). Both NO and Fasudil inhalation significantly reduced mean pulmonary arterial pressure (PAP) (NO: P < 0.01, Fasudil: P < 0.05) and tended to decrease pulmonary vascular resistance (NO: P = 0.07, Fasudil: P = 0.1), but did not affect cardiac index. The ratio of pulmonary to systemic vascular resistance was significantly reduced both in NO and Fasudil inhalation (NO: P < 0.01, Fasudil: P < 0.05), indicating that both NO and Fasudil inhalation selectively affect lung tissues. Interestingly, there was no correlation in the vasodilator effects between NO and Fasudil, and a positive correlation with serum levels of high-sensitivity C-reactive protein was noted for Fasudil but not for NO. These results suggest that inhalation of Fasudil is as effective as NO in patients with PAH, possibly through different mechanisms.
-
acute vasodilator effect of Fasudil a rho kinase inhibitor in monocrotaline induced pulmonary hypertension in rats
Journal of Cardiovascular Pharmacology, 2007Co-Authors: Bao Hua Jiang, Shunsuke Tawara, Kohtaro Abe, Aya Takaki, Yoshihiro FukumotoAbstract:Pulmonary arterial hypertension is a progressive and fatal disease for which Rho-kinase may be substantially involved. In this study, we examined the acute vasodilator effects of Fasudil, a Rho-kinase inhibitor, in monocrotaline (MCT)-induced pulmonary hypertension (PH) in rats. Three weeks after a single subcutaneous injection of MCT (60 mg/kg), hemodynamic variables were measured under conscious and free-moving conditions before and after oral administration of Fasudil. MCT caused a significant elevation of mean pulmonary arterial pressure (mPAP). Although a low dose of Fasudil (3 mg/kg) had no effect on mPAP, a middle dose (10 mg/kg) caused a significant reduction in mPAP without change in mean systemic arterial pressure (mSAP), and a high dose (30 mg/kg) significantly reduced both mPAP and mSAP. Rho-kinase activity was significantly increased by MCT injection in pulmonary arteries but not in the aorta. Fasudil (10 mg/kg) inhibited only the Rho-kinase activity in pulmonary arteries without any effect in the aorta. Plasma concentration of hydroxyFasudil, a metabolite of Fasudil, was within its clinical range in humans. These results demonstrate that Fasudil exerts effective and selective vasodilatation of pulmonary arteries in rats with MCT-induced PH at a given dose, suggesting its usefulness for the treatment of the fatal disorder.
-
usefulness of Fasudil a rho kinase inhibitor to treat intractable severe coronary spasm after coronary artery bypass surgery
Journal of Cardiovascular Pharmacology, 2004Co-Authors: Kousuke Inokuchi, Yoshihiro Fukumoto, Akira Ito, Tetsuya Matoba, Akira Shiose, Takahiro Nishida, Munetaka Masuda, Shigeki MoritaAbstract:We have recently demonstrated that Fasudil, a Rho-kinase inhibitor, is effective in suppressing coronary artery spasm in patients with vasospastic angina. Thus, blockade of Rho-kinase may provide a novel therapeutic strategy to treat ischemic coronary syndrome caused by the spasm. Severe coronary artery spasm still remains a life-threatening serious complication of coronary artery bypass grafting (CABG). In this study, we examined the inhibitory effect of Fasudil in patients with intractable severe coronary spasm after CABG. Three patients who underwent CABG showed severe myocardial ischemia resistant to intensive therapy with intravenous conventional vasodilators, including isosorbide dinitrate (ISDN), diltiazem, and nicorandil. Coronary angiography revealed severe coronary spasm in native coronary arteries and/or bypass arterial grafts in all patients. Since intracoronary and/or intragraft administration of ISDN was ineffective to resolve the spasm, we then administered Fasudil (1.5 mg/min for 15 minutes) into the spastic arteries. Fasudil successfully resolved the spasm and improved myocardial ischemia in all patients without any systemic adverse effects. In conclusion, the treatment with Fasudil may be useful to treat intractable and otherwise fatal coronary spasm resistant to intensive conventional vasodilator therapy after CABG.
Fakhrul Ahsan - One of the best experts on this subject based on the ideXlab platform.
-
car a homing peptide prolongs pulmonary preferential vasodilation by increasing pulmonary retention and reducing systemic absorption of liposomal Fasudil
Molecular Pharmaceutics, 2019Co-Authors: Ali Keshavarz, Ivan F Mcmurtry, Eva Nozikgrayck, Ahmed Alobaida, Kurt R Stenmark, Fakhrul AhsanAbstract:Here, we sought to elucidate the role of CAR (a cyclic peptide) in the accumulation and distribution of Fasudil, a drug for pulmonary arterial hypertension (PAH), in rat lungs and in producing pulmonary specific vasodilation in PAH rats. As such, we prepared liposomes of Fasudil and CAR-conjugated liposomal Fasudil and assessed the liposomes for CAR conjugation, physical properties, entrapment efficiencies, in vitro release profiles, and stabilities upon incubation in cell culture media, storage, and aerosolization. We also studied the cellular uptake of Fasudil in different formulations, quantified heparan sulfate (HS) in pulmonary arterial smooth muscle cells (PASMCs), and investigated the distribution of the liposomes in the lungs of PAH rats. We assessed the drug accumulation in a close and recirculating isolated perfused rat lung model and studied the pharmacokinetics and pharmacological efficacy of the drug and formulations in Sugen/hypoxia-induced PAH rats. The entrapment efficiency of the liposoma...
-
liposomal Fasudil a rho kinase inhibitor for prolonged pulmonary preferential vasodilation in pulmonary arterial hypertension
Journal of Controlled Release, 2013Co-Authors: Vivek Gupta, Nilesh Gupta, Imam H Shaik, Reza Mehvar, Ivan F Mcmurtry, Masahiko Oka, Eva Nozikgrayck, Masanobu Komatsu, Fakhrul AhsanAbstract:Current pharmacological interventions for pulmonary arterial hypertension (PAH) require continuous infusions, multiple inhalations, or oral administration of drugs that act on various pathways involved in the pathogenesis of PAH. However, invasive methods of administration, short duration of action, and lack of pulmonary selectivity result in noncompliance and poor patient outcomes. In this study, we tested the hypothesis that encapsulation of an investigational anti-PAH molecule Fasudil (HA-1077), a Rho-kinase inhibitor, into liposomal vesicles results in prolonged vasodilation in distal pulmonary arterioles. Liposomes were prepared by hydration and extrusion method and Fasudil was loaded by ammonium sulfate-induced transmembrane electrochemical gradient. Liposomes were then characterized for various physicochemical properties. Optimized formulations were tested for pulmonary absorption and their pharmacological efficacy in a monocrotaline (MCT) induced rat model of PAH. The entrapment efficiency of optimized liposomal Fasudil formulations was between 68.1±0.8% and 73.6±2.3%, and the cumulative release at 37°C was 98-99% over a period of 5 days. Compared to intravenous (IV) Fasudil, a ~10 fold increase in the terminal plasma half-life was observed when liposomal Fasudil was administered as aerosols. The t1/2 of IV Fasudil was 0.39±0.12 h. and when given as liposomes via pulmonary route, the t1/2 extended to 4.71±0.72 h. One h after intratracheal instillation of liposomal Fasudil, mean pulmonary arterial pressure (MPAP) was reduced by 37.6±5.7% and continued to decrease for about 3 h, suggesting that liposomal formulations produced pulmonary preferential vasodilation in MCT induced PAH rats. Overall, this study established the proof-of-principle that aerosolized liposomal Fasudil is a feasible option for a non-invasive, controlled release and pulmonary preferential treatment of PAH.
Baoguo Xiao - One of the best experts on this subject based on the ideXlab platform.
-
targeting the shift from m1 to m2 macrophages in experimental autoimmune encephalomyelitis mice treated with Fasudil
PLOS ONE, 2013Co-Authors: Chunyun Liu, Haifei Zhang, M F Guo, Jian Meng, Yong Xie, Ling Feng, Shaowei Hou, Yueting Liu, Baoguo XiaoAbstract:We observed the therapeutic effect of Fasudil and explored its mechanisms in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Fasudil, a selective Rho kinase (ROCK) inhibitor, was injected intraperitoneally at 40 mg/kg/d in early and late stages of EAE induction. Fasudil ameliorated the clinical severity of EAE at different stages, and decreased the expression of ROCK-II in spleen, accompanied by an improvement in demyelination and inhibition of inflammatory cells. Fasudil mainly inhibited CD4+IL-17+ T cells in early treatment, but also elevated CD4+IL-10+ regulatory T cells and IL-10 production in late treatment. The treatment of Fasudil shifted inflammatory M1 to anti-inflammatory M2 macrophages in both early and late treatment, being shown by inhibiting CD16/32, iNOS, IL-12, TLR4 and CD40 and increasing CD206, Arg-1, IL-10 and CD14 in spleen. By using Western blot and immunohistochemistry, iNOS and Arg-1, as two most specific markers for M1 and M2, was inhibited or induced in splenic macrophages and spinal cords of EAE mice treated with Fasudil. In vitro experiments also indicate that Fasudil shifts M1 to M2 phenotype, which does not require the participation or auxiliary of other cells. The polarization of M2 macrophages was associated with the decrease of inflammatory cytokine IL-1β, TNF-α and MCP-1. These results demonstrate that Fasudil has therapeutic potential in EAE possibly through inducing the polarization of M2 macrophages and inhibiting inflammatory responses.
-
rho kinase inhibitor Fasudil regulates microglia polarization and function
Neuroimmunomodulation, 2013Co-Authors: Haifei Zhang, M F Guo, Jian Meng, Chunyun Liu, Yong Xie, Ling Feng, Baoguo XiaoAbstract:Macrophages/microglia exhibit phenotypic and functional heterogeneity under physiological and pathological conditions. Owing to this heterogeneity, the polarization of macrophages/microglia is capable of effecting both detrimental and beneficial outcomes in various disease processes. In this study, murine microglial cell line BV-2 and primary microglia were used as cell models to elucidate the polarization of microglia. Using flow cytometry, Western blot, chemical/enzymatic determination, and immunohistochemistry, treatment with LPS primed microglia into the M1 phenotype in both BV-2 cells and primary microglia, while Fasudil skewed LPS-stimulated M1 toward M2 microglia, which showed lower NF-κB activity and inflammatory cytokines IL-1β, IL-6, and TNF-α, and increased anti-inflammatory cytokine IL-10. To examine whether the regulatory role of LPS and Fasudil on microglia can occur in vivo, mice were administered LPS (25 μg/10 μl) via nasal instillation every other day for 1 month. The results demonstrated that LPS also triggered iNOS(+)/CD11b(+) M1 microglia in the brain, while Fasudil increased Arg-1(+)/CD11b(+) M2 microglia, although the difference did not reach statistical significance. Fasudil-conditioned microglia medium promoted a neuroprotective effect against PC12 neurons, suggesting that Fasudil-induced M2 microglia contribute to the survival of neurons. These results indicate a new treatment option whereby Fasudil inhibits the inflammatory response by controlling a helpful polarization in microglia/macrophages.
-
Fasudil a rho kinase inhibitor drives mobilization of adult neural stem cells after hypoxia reoxygenation injury in mice
Molecular and Cellular Neuroscience, 2010Co-Authors: Jing Ding, Xin Wang, Changhai Sun, Baoguo XiaoAbstract:Rho kinase (ROCK) is important in fundamental processes of cell proliferation and survival. Blockade of ROCK promotes stem cell survival in vitro and axonal regeneration in vivo, exhibiting therapeutic potential such as spinal cord injuries and stroke. Here, we used the model of hypoxia/reoxygenation (H/R) injury to explore the possibility whether Fasudil, a ROCK inhibitor in clinical application for subarachnoid hemorrhage and stroke, mobilizes adult neural stem cells in vivo. Most interestingly, Fasudil triggers neurogenesis especially in the subventricular zone after H/R. The increase of Brdu+ cholinergic neurons was observed in striatum and forebrain cortex of Fasudil-treated mice after 30 days. Further observation demonstrates that both levels of granulocyte colony-stimulating factor (G-CSF) and astrocytes expressing G-CSF were elevated in mice treated with Fasudil, as compared to mice injected with saline. In vitro H/R model of cultured astrocytes, Fasudil promoted astrocytes to produce G-CSF in a dose-dependent manner. In addition, antibody neutralization and receptor blocking of the G-CSF pathway clearly demonstrate that Fasudil-induced neurogenesis was mediated partially through astrocyte-derived G-CSF. Our results indicate that Fasudil might represent a promising therapeutic perspective by mobilizating endogenous adult neural stem cells in the CNS.