Ibudilast suppresses TNFα production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS
Identifieur interne : 000353 ( Istex/Corpus ); précédent : 000352; suivant : 000354Ibudilast suppresses TNFα production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS
Auteurs : Akio Suzumura ; Atsushi Ito ; Minka Yoshikawa ; Makoto SawadaSource :
- Brain Research [ 0006-8993 ] ; 1999.
English descriptors
- KwdEn :
- Teeft :
- Antigen expression, Antisense, Assay, Astrocyte, Brain research, Cell death, Cyclic, Cytokine, Cytokine production, Demyelination, Dipyridamole, Glial, Glial cells, Higher concentrations, Ibudilast, Immunol, Inflammatory demyelination, Inhibitor, Inhibitory activity, Inhibitory effects, Microglia, Mrna, Multiple sclerosis, Neuronal degeneration, Oligodendrocyte, Pentoxifylline, Phosphodiesterase, Rolipram, Suzumura, Tnfa, Tnfa production, Transgenic mice, Tumor necrosis, Tumor necrosis factor.
Abstract
Abstract: Tumor necrosis factor α (TNFα) is considered to play a critical role in the development of various pathological processes in the central nervous system (CNS), such as neuronal degeneration, demyelination and HIV-related pathology. In order to search for the agents which suppress TNFα production in the CNS for future treatment of these pathological conditions, we examined the effects of ibudilast on TNFα production by murine microglia and astrocytes. Some actions of ibudilast are reportedly mediated by inhibition of type IV phosphodiesterase (PDE). Type IV PDE inhibitor has been shown to be the most effective for experimental autoimmune inflammatory demyelination. Therefore, we also determined the subtype of PDE inhibited by ibudilast. Ibudilast significantly and selectively suppressed TNFα production by microglia in a dose-dependent manner, without affecting their viability. The inhibition assay indicated that ibudilast is a rather selective inhibitor for type III PDE purified from brain, heart and kidney with moderate inhibitory activity against types I, II and IV PDEs from various tissues. Although it required 10 μM or higher concentrations to effectively suppress TNFα production in vitro, the combination of ibudilast with other subtypes of PDE inhibitors synergistically suppressed TNFα and nitric oxide production by microglia at 1 μM, a similar concentration that could be obtained in vivo at usual therapeutic dose. Thus, ibudilast, when used in a combination with other PDE inhibitors, will be useful for future strategies to treat intractable neurological diseases in which TNFα may play a causative role.
Url:
DOI: 10.1016/S0006-8993(99)01666-2
Links to Exploration step
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<front><div type="abstract" xml:lang="en">Abstract: Tumor necrosis factor α (TNFα) is considered to play a critical role in the development of various pathological processes in the central nervous system (CNS), such as neuronal degeneration, demyelination and HIV-related pathology. In order to search for the agents which suppress TNFα production in the CNS for future treatment of these pathological conditions, we examined the effects of ibudilast on TNFα production by murine microglia and astrocytes. Some actions of ibudilast are reportedly mediated by inhibition of type IV phosphodiesterase (PDE). Type IV PDE inhibitor has been shown to be the most effective for experimental autoimmune inflammatory demyelination. Therefore, we also determined the subtype of PDE inhibited by ibudilast. Ibudilast significantly and selectively suppressed TNFα production by microglia in a dose-dependent manner, without affecting their viability. The inhibition assay indicated that ibudilast is a rather selective inhibitor for type III PDE purified from brain, heart and kidney with moderate inhibitory activity against types I, II and IV PDEs from various tissues. Although it required 10 μM or higher concentrations to effectively suppress TNFα production in vitro, the combination of ibudilast with other subtypes of PDE inhibitors synergistically suppressed TNFα and nitric oxide production by microglia at 1 μM, a similar concentration that could be obtained in vivo at usual therapeutic dose. Thus, ibudilast, when used in a combination with other PDE inhibitors, will be useful for future strategies to treat intractable neurological diseases in which TNFα may play a causative role.</div>
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<note type="content">Fig. 1: Inhibition of cAMP phosphodiesterase (PDE) extracted from rat brain by type specific inhibitors. Ibudilast (Ib), like other type-specific PDE inhibitors, dose-dependently inhibited rat brain-derived PDE at the indicated doses (μM). PDE inhibitors used were, non-specific (NS); theofylline, type I-specific (I); vinpocetin, type II-specific (II); quazinone, type III-specific (III); pentoxifylline, type IV-specific (IV); rolipram, and type V-specific (V); dipyridamole. Each column indicates mean value of % inhibition of the decrease of intracellular cAMP (S.D.'s were less than 10% of the mean).</note>
<note type="content">Fig. 2: Inhibition of PDE derived from brain, heart and kidney. Ibudilast (100 μM) inhibited PDE from all three tissues. PDE inhibitors used were, non-specific (NS); theofylline at 30 μM, type I-specific (I); vinpocetin at 50 μM, type II-specific (II); quazinone at 50 μM, type III-specific (III); pentoxifylline at 100 μM, type IV-specific (IV); rolipram at 100 μM, and type V-specific (V); dipyridamole at 100 μM. Each column indicates mean value of % inhibition of decrease of intracellular cAMP (S.D.'s were less than 10% of the mean).</note>
<note type="content">Fig. 3: Additive effects of type specific-PDE on PDE inhibitor activity by ibudilast. Types I and III PDE inhibitors had no additive inhibiting effects on ibudilast against PDE from brain indicating that it acted as types I and III PDE inhibitors in the CNS. Similarly, ibudilast acts as types I, II, III and IV PDE inhibitor against kidney-derived PDE, and as types II, III and IV PDE inhibitors against heart-derived PDE. It did not act as type V PDE inhibitor at all. Each column indicates mean value of the changes of % inhibition (“% inhibition by type-specific inhibitor and ibudilast — that by ibudilast”). The concentrations of PDE inhibitors were the same as in Fig. 2.</note>
<note type="content">Fig. 4: Effects of ibudilast on viability and proliferation (MTT assay) of microglia. Each column indicates mean OD value read at 620 nm (S.D.'s were less than 10% of the mean).</note>
<note type="content">Fig. 5: Suppression of TNFα and NO production by microglia and astrocytes by ibudilast. Microglia and astrocytes were treated with 1–100 μM of ibudilast in the presence of 1 μg/ml of LPS for 24 h. Each column indicates mean value of % suppression of NO production and TNFα activity obtained from six samples (S.D.'s were less than 10% of the mean).</note>
<note type="content">Fig. 6: The expression of cytokines and iNOS mRNA. RT-PCR analyses for expression of mRNA encoding TNFα, IL-1β, IL-6, IL-10, iNOS and β-actin in none-stimulated microglia (1), microglia treated with 1 μg/ml LPS (2), with 100 μM (3), 10 μM (4) and 1 μM (5) of ibudilast. Microglia treated with 0.1% dimethylsulfoxide alone (6) was used as a control.</note>
<note type="content">Fig. 7: Effects of combination of three different PDE inhibitors at 1 μM on LPS-induced NO, superoxide and TNFα production by microglia. Each column indicates means of % suppression with three PDE inhibitors obtained from six samples (SD were less than 10% of the mean). Vin: vinpocetine (type I), Px: pentoxifylline (type III), Ci: cilostazol (type III), Th: theofylline (nonspecific) and Ib: ibudilast.</note>
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<abstract xml:lang="en"><p>Abstract: Tumor necrosis factor α (TNFα) is considered to play a critical role in the development of various pathological processes in the central nervous system (CNS), such as neuronal degeneration, demyelination and HIV-related pathology. In order to search for the agents which suppress TNFα production in the CNS for future treatment of these pathological conditions, we examined the effects of ibudilast on TNFα production by murine microglia and astrocytes. Some actions of ibudilast are reportedly mediated by inhibition of type IV phosphodiesterase (PDE). Type IV PDE inhibitor has been shown to be the most effective for experimental autoimmune inflammatory demyelination. Therefore, we also determined the subtype of PDE inhibited by ibudilast. Ibudilast significantly and selectively suppressed TNFα production by microglia in a dose-dependent manner, without affecting their viability. The inhibition assay indicated that ibudilast is a rather selective inhibitor for type III PDE purified from brain, heart and kidney with moderate inhibitory activity against types I, II and IV PDEs from various tissues. Although it required 10 μM or higher concentrations to effectively suppress TNFα production in vitro, the combination of ibudilast with other subtypes of PDE inhibitors synergistically suppressed TNFα and nitric oxide production by microglia at 1 μM, a similar concentration that could be obtained in vivo at usual therapeutic dose. Thus, ibudilast, when used in a combination with other PDE inhibitors, will be useful for future strategies to treat intractable neurological diseases in which TNFα may play a causative role.</p>
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<item><term>Multiple sclerosis</term>
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<ce:title>Ibudilast suppresses TNFα production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS</ce:title>
<ce:author-group><ce:author><ce:given-name>Akio</ce:given-name>
<ce:surname>Suzumura</ce:surname>
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<ce:author><ce:given-name>Atsushi</ce:given-name>
<ce:surname>Ito</ce:surname>
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<ce:author><ce:given-name>Minka</ce:given-name>
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<ce:textfn>Department of Neurology, Nara Medical University, Shijo-cho, Kashihara, Nara 634-0813, Japan</ce:textfn>
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<ce:affiliation id="AFF2"><ce:label>b</ce:label>
<ce:textfn>Joint Research Division for Therapies against Intractable Disease, Institute for Comprehensive Medical Sciences, Fujita Health University, Toyoake, Aichi 470-1192, Japan</ce:textfn>
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<ce:text>Corresponding author. Fax: +81-744-24-6065; E-mail: asuzumur@naramed-u.ac.jp</ce:text>
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<ce:abstract-sec><ce:simple-para view="all" id="simple-para.0045">Tumor necrosis factor α (TNFα) is considered to play a critical role in the development of various pathological processes in the central nervous system (CNS), such as neuronal degeneration, demyelination and HIV-related pathology. In order to search for the agents which suppress TNFα production in the CNS for future treatment of these pathological conditions, we examined the effects of ibudilast on TNFα production by murine microglia and astrocytes. Some actions of ibudilast are reportedly mediated by inhibition of type IV phosphodiesterase (PDE). Type IV PDE inhibitor has been shown to be the most effective for experimental autoimmune inflammatory demyelination. Therefore, we also determined the subtype of PDE inhibited by ibudilast. Ibudilast significantly and selectively suppressed TNFα production by microglia in a dose-dependent manner, without affecting their viability. The inhibition assay indicated that ibudilast is a rather selective inhibitor for type III PDE purified from brain, heart and kidney with moderate inhibitory activity against types I, II and IV PDEs from various tissues. Although it required 10 μM or higher concentrations to effectively suppress TNFα production in vitro, the combination of ibudilast with other subtypes of PDE inhibitors synergistically suppressed TNFα and nitric oxide production by microglia at 1 μM, a similar concentration that could be obtained in vivo at usual therapeutic dose. Thus, ibudilast, when used in a combination with other PDE inhibitors, will be useful for future strategies to treat intractable neurological diseases in which TNFα may play a causative role.</ce:simple-para>
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<ce:keyword><ce:text>Microglia</ce:text>
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<ce:keyword><ce:text>Cytokine</ce:text>
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<ce:keyword><ce:text>Phosphodiesterase inhibitor</ce:text>
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<abstract lang="en">Abstract: Tumor necrosis factor α (TNFα) is considered to play a critical role in the development of various pathological processes in the central nervous system (CNS), such as neuronal degeneration, demyelination and HIV-related pathology. In order to search for the agents which suppress TNFα production in the CNS for future treatment of these pathological conditions, we examined the effects of ibudilast on TNFα production by murine microglia and astrocytes. Some actions of ibudilast are reportedly mediated by inhibition of type IV phosphodiesterase (PDE). Type IV PDE inhibitor has been shown to be the most effective for experimental autoimmune inflammatory demyelination. Therefore, we also determined the subtype of PDE inhibited by ibudilast. Ibudilast significantly and selectively suppressed TNFα production by microglia in a dose-dependent manner, without affecting their viability. The inhibition assay indicated that ibudilast is a rather selective inhibitor for type III PDE purified from brain, heart and kidney with moderate inhibitory activity against types I, II and IV PDEs from various tissues. Although it required 10 μM or higher concentrations to effectively suppress TNFα production in vitro, the combination of ibudilast with other subtypes of PDE inhibitors synergistically suppressed TNFα and nitric oxide production by microglia at 1 μM, a similar concentration that could be obtained in vivo at usual therapeutic dose. Thus, ibudilast, when used in a combination with other PDE inhibitors, will be useful for future strategies to treat intractable neurological diseases in which TNFα may play a causative role.</abstract>
<note type="content">Section title: Research report</note>
<note type="content">Fig. 1: Inhibition of cAMP phosphodiesterase (PDE) extracted from rat brain by type specific inhibitors. Ibudilast (Ib), like other type-specific PDE inhibitors, dose-dependently inhibited rat brain-derived PDE at the indicated doses (μM). PDE inhibitors used were, non-specific (NS); theofylline, type I-specific (I); vinpocetin, type II-specific (II); quazinone, type III-specific (III); pentoxifylline, type IV-specific (IV); rolipram, and type V-specific (V); dipyridamole. Each column indicates mean value of % inhibition of the decrease of intracellular cAMP (S.D.'s were less than 10% of the mean).</note>
<note type="content">Fig. 2: Inhibition of PDE derived from brain, heart and kidney. Ibudilast (100 μM) inhibited PDE from all three tissues. PDE inhibitors used were, non-specific (NS); theofylline at 30 μM, type I-specific (I); vinpocetin at 50 μM, type II-specific (II); quazinone at 50 μM, type III-specific (III); pentoxifylline at 100 μM, type IV-specific (IV); rolipram at 100 μM, and type V-specific (V); dipyridamole at 100 μM. Each column indicates mean value of % inhibition of decrease of intracellular cAMP (S.D.'s were less than 10% of the mean).</note>
<note type="content">Fig. 3: Additive effects of type specific-PDE on PDE inhibitor activity by ibudilast. Types I and III PDE inhibitors had no additive inhibiting effects on ibudilast against PDE from brain indicating that it acted as types I and III PDE inhibitors in the CNS. Similarly, ibudilast acts as types I, II, III and IV PDE inhibitor against kidney-derived PDE, and as types II, III and IV PDE inhibitors against heart-derived PDE. It did not act as type V PDE inhibitor at all. Each column indicates mean value of the changes of % inhibition (“% inhibition by type-specific inhibitor and ibudilast — that by ibudilast”). The concentrations of PDE inhibitors were the same as in Fig. 2.</note>
<note type="content">Fig. 4: Effects of ibudilast on viability and proliferation (MTT assay) of microglia. Each column indicates mean OD value read at 620 nm (S.D.'s were less than 10% of the mean).</note>
<note type="content">Fig. 5: Suppression of TNFα and NO production by microglia and astrocytes by ibudilast. Microglia and astrocytes were treated with 1–100 μM of ibudilast in the presence of 1 μg/ml of LPS for 24 h. Each column indicates mean value of % suppression of NO production and TNFα activity obtained from six samples (S.D.'s were less than 10% of the mean).</note>
<note type="content">Fig. 6: The expression of cytokines and iNOS mRNA. RT-PCR analyses for expression of mRNA encoding TNFα, IL-1β, IL-6, IL-10, iNOS and β-actin in none-stimulated microglia (1), microglia treated with 1 μg/ml LPS (2), with 100 μM (3), 10 μM (4) and 1 μM (5) of ibudilast. Microglia treated with 0.1% dimethylsulfoxide alone (6) was used as a control.</note>
<note type="content">Fig. 7: Effects of combination of three different PDE inhibitors at 1 μM on LPS-induced NO, superoxide and TNFα production by microglia. Each column indicates means of % suppression with three PDE inhibitors obtained from six samples (SD were less than 10% of the mean). Vin: vinpocetine (type I), Px: pentoxifylline (type III), Ci: cilostazol (type III), Th: theofylline (nonspecific) and Ib: ibudilast.</note>
<subject lang="en"><genre>Keywords</genre>
<topic>Microglia</topic>
<topic>Cytokine</topic>
<topic>Phosphodiesterase inhibitor</topic>
<topic>Multiple sclerosis</topic>
<topic>Astrocyte</topic>
<topic>TNF</topic>
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