The Experts below are selected from a list of 186 Experts worldwide ranked by ideXlab platform
Joyce A Deleo - One of the best experts on this subject based on the ideXlab platform.
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reprint of efficacy of propentofylline a glial modulating agent on existing mechanical allodynia following peripheral nerve injury brain behav immun 21 2007 238 246
Brain Behavior and Immunity, 2007Co-Authors: Vivianne L Tawfik, Joyce A Deleo, Michael L Lacroixfralish, Nancy NutilemcmenemyAbstract:Abstract Increasing evidence points to a role for spinal neuroimmune dysregulation (glial cell activation and cytokine expression) in the pathogenesis of chronic pain. Suppression of astrocytic and microglial activation with the Methylxanthine Derivative, propentofylline, pre-emptively attenuates the development of nerve injury-induced allodynia. Currently, we investigated the ability of systemic propentofylline to reverse existing, long-term allodynia after nerve injury—a clinically relevant paradigm. Rats received L5 spinal nerve transection or sham surgery and the development of mechanical allodynia was assessed daily for 2 weeks, at which time injured rats exhibited robust responses to non-noxious von Frey filaments. On days 14–27, rats received either saline or 101 mg/kg propentofylline by intraperitoneal (i.p.) injection. On day 28 or 42 (after a 14-day drug washout period), lumbar spinal cord sections were processed for assessment of astrocytic glial fibrillary acidic protein (GFAP) and microglial OX-42 (antibody against CR3/CD11b). Propentofylline treatment to nerve injured rats resulted in significant reversal of allodynia that lasted throughout the 14-day washout period. Spinal microglial activation was observed at days 28 and 42 post-injury at the protein level, in the absence of mRNA level changes. Less robust increases in GFAP immunoreactivity were observed at days 28 and 42 post-transection. Interestingly, propentofylline treatment suppressed microglial activation at both time points in this paradigm. Taken together, our results highlight the clinical potential of the glial modulating agent, propentofylline, for the treatment of neuropathic pain as well as a role for microglia in the long-term maintenance of allodynia.
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efficacy of propentofylline a glial modulating agent on existing mechanical allodynia following peripheral nerve injury
Brain Behavior and Immunity, 2007Co-Authors: Vivianne L Tawfik, Joyce A Deleo, Michael L Lacroixfralish, Nancy NutilemcmenemyAbstract:Abstract Increasing evidence points to a role for spinal neuroimmune dysregulation (glial cell activation and cytokine expression) in the pathogenesis of chronic pain. Suppression of astrocytic and microglial activation with the Methylxanthine Derivative, propentofylline, pre-emptively attenuates the development of nerve injury-induced allodynia. Currently, we investigated the ability of systemic propentofylline to reverse existing, long-term allodynia after nerve injury—a clinically relevant paradigm. Rats received L5 spinal nerve transection or sham surgery and the development of mechanical allodynia was assessed daily for 2 weeks, at which time injured rats exhibited robust responses to non-noxious von Frey filaments. On days 14–27, rats received either saline or 101 mg/kg propentofylline by intraperitoneal (i.p.) injection. On day 28 or 42 (after a 14-day drug washout period), lumbar spinal cord sections were processed for assessment of astrocytic glial fibrillary acidic protein (GFAP) and microglial OX-42 (antibody against CR3/CD11b). Propentofylline treatment to nerve injured rats resulted in significant reversal of allodynia that lasted throughout the 14-day washout period. Spinal microglial activation was observed at days 28 and 42 post-injury at the protein level, in the absence of mRNA level changes. Less robust increases in GFAP immunoreactivity were observed at days 28 and 42 post-transection. Interestingly, propentofylline treatment suppressed microglial activation at both time points in this paradigm. Taken together, our results highlight the clinical potential of the glial modulating agent, propentofylline, for the treatment of neuropathic pain as well as a role for microglia in the long-term maintenance of allodynia.
Mark Waer - One of the best experts on this subject based on the ideXlab platform.
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use of the Methylxanthine Derivative a802715 in transplantation immunology ii in vivo experiments
Transplantation, 1997Co-Authors: Yuan Lin, Constant Segers, D Mikhalsky, Tikma Budya Tjandramaga, M Schonharting, Mark WaerAbstract:BACKGROUND We have previously demonstrated in vitro that the Methylxanthine Derivative A802715 suppresses the cyclosporine (CsA)-resistant "signal two"-dependent pathway of T cell activation and hence acts synergistically with CsA. Here, this synergism was further investigated in vivo in rats. METHODS Primary cardiac allografts were placed in the neck, and secondary grafts were transplanted intra-abdominally. A802715 was given orally for 30 days or by continuous intravenous infusion via a mini-osmotic pump for 2 weeks. CsA was given orally for up to 30 days. T cell responses were examined in vitro using mixed lymphocyte reaction, concanavalin A whole blood, and cell-mediated lympholysis assays. RESULTS In a major histocompatibility complex incompatible WKAH-->PVG combination, neither oral CsA (7.5 mg/kg/day) nor oral A802715 (100 mg/kg/day) was able to prolong graft survival. However, a combination of both drugs, given at the same dose, sustained graft survival during treatment. A similar synergism was not obtained with pentoxifylline, another Methylxanthine Derivative. The synergism between A802715 and CsA could be further increased by using a continuous intravenous infusion of A802715, since (1) lower doses of A802715 (20 mg/kg/day) and CsA (5 mg/kg/day) could be used, and (2) six of seven grafts survived permanently. In a major histocompatibility complex compatible Wag/Rij-->R/A combination, similar synergistic effects and permanent graft survival could also be obtained by oral A802715 (100 mg/kg/day) in combination with a low dose of CsA (2.5 mg/kg/day). In both strain combinations, long-term survivors accepted donor-type but rejected third-party second grafts in the absence of immunosuppression. This specific tolerance was not related to clonal deletion nor anergy, as recipient lymphocytes proliferated normally in the anti-donor mixed lymphocyte reaction. Instead, a defect in generating specific cytotoxic T lymphocytes was involved. CONCLUSIONS A802715 synergizes with CsA in vivo to induce specific transplantation tolerance and hence should be considered as a promising new immunosuppressant.
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use of the Methylxanthine Derivative a802715 in transplantation immunology i strong in vitro inhibitory effects on cd28 costimulated t cell activities
Transplantation, 1997Co-Authors: Yuan Lin, M Schonharting, Jozef Goebels, Omer Rutgeerts, Ahmad Kasran, S Van Gool, Jan Ceuppens, Mark WaerAbstract:BACKGROUND Recently, Methylxanthines such as pentoxifylline (PTX) were shown to be immunosuppressive in vitro. Unfortunately, when used in transplant patients, PTX was poorly active as an immunosuppressant. Here we report that the new Methylxanthine Derivative A802715 not only is more active than PTX, it also suppresses the cyclosporine (CsA)-resistant "signal two"-dependent pathway of T cell proliferation, making it an interesting drug to associate with CsA. METHODS "Signal one"- and "signal two"-dependent T cell activation was investigated with purified human T cells stimulated with immobilized anti-CD3 or anti-CD28 monoclonal antibody (mAb) plus phorbol myristate acetate (PMA) or with a 3T6 mouse fibroblast cell line presenting anti-CD3 mAb on transfected human Fcgamma receptors II (FcgammaRII) in the presence or absence of transfected B7-1 (CD80) molecules. RESULTS A802715 was more immunosuppressive in the mixed lymphocyte reaction (MLR) than PTX. A802715 dose-dependently suppressed polyclonal signal one-dependent T cell activation induced by anti-CD3 mAb/PMA. In addition, A802715 also suppressed signal two-dependent T cell proliferation induced by anti-CD28 mAb/PMA. The expression of the interleukin-2 receptor on T cells stimulated by anti-CD3 mAb presented on 3T6/FcgammaRII cells was equally well suppressed by A802715 and PTX. In contrast, interleukin-2 receptor or CD40L (gp39) expression by T cells after stimulation with the same anti-CD3 mAb- 3T6/FcgammaRII cells, but coexpressing transfected B7-1, was only suppressed by A802715. The anticipated synergism between A802715 and CsA was confirmed in MLR assays. Moreover, generation of cytotoxic T lymphocytes during MLR with Epstein-Barr virus-transformed B cells, which strongly express B7-1 and B7-2, was also inhibited by A802715. CONCLUSIONS These in vitro data indicate that the A802715 (1) is a stronger immunosuppressant for T cells than PTX, (2) suppresses T cell activation pathways that are resistant to PTX or CsA, and (3) acts synergistically with CsA.
Nancy Nutilemcmenemy - One of the best experts on this subject based on the ideXlab platform.
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reprint of efficacy of propentofylline a glial modulating agent on existing mechanical allodynia following peripheral nerve injury brain behav immun 21 2007 238 246
Brain Behavior and Immunity, 2007Co-Authors: Vivianne L Tawfik, Joyce A Deleo, Michael L Lacroixfralish, Nancy NutilemcmenemyAbstract:Abstract Increasing evidence points to a role for spinal neuroimmune dysregulation (glial cell activation and cytokine expression) in the pathogenesis of chronic pain. Suppression of astrocytic and microglial activation with the Methylxanthine Derivative, propentofylline, pre-emptively attenuates the development of nerve injury-induced allodynia. Currently, we investigated the ability of systemic propentofylline to reverse existing, long-term allodynia after nerve injury—a clinically relevant paradigm. Rats received L5 spinal nerve transection or sham surgery and the development of mechanical allodynia was assessed daily for 2 weeks, at which time injured rats exhibited robust responses to non-noxious von Frey filaments. On days 14–27, rats received either saline or 101 mg/kg propentofylline by intraperitoneal (i.p.) injection. On day 28 or 42 (after a 14-day drug washout period), lumbar spinal cord sections were processed for assessment of astrocytic glial fibrillary acidic protein (GFAP) and microglial OX-42 (antibody against CR3/CD11b). Propentofylline treatment to nerve injured rats resulted in significant reversal of allodynia that lasted throughout the 14-day washout period. Spinal microglial activation was observed at days 28 and 42 post-injury at the protein level, in the absence of mRNA level changes. Less robust increases in GFAP immunoreactivity were observed at days 28 and 42 post-transection. Interestingly, propentofylline treatment suppressed microglial activation at both time points in this paradigm. Taken together, our results highlight the clinical potential of the glial modulating agent, propentofylline, for the treatment of neuropathic pain as well as a role for microglia in the long-term maintenance of allodynia.
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efficacy of propentofylline a glial modulating agent on existing mechanical allodynia following peripheral nerve injury
Brain Behavior and Immunity, 2007Co-Authors: Vivianne L Tawfik, Joyce A Deleo, Michael L Lacroixfralish, Nancy NutilemcmenemyAbstract:Abstract Increasing evidence points to a role for spinal neuroimmune dysregulation (glial cell activation and cytokine expression) in the pathogenesis of chronic pain. Suppression of astrocytic and microglial activation with the Methylxanthine Derivative, propentofylline, pre-emptively attenuates the development of nerve injury-induced allodynia. Currently, we investigated the ability of systemic propentofylline to reverse existing, long-term allodynia after nerve injury—a clinically relevant paradigm. Rats received L5 spinal nerve transection or sham surgery and the development of mechanical allodynia was assessed daily for 2 weeks, at which time injured rats exhibited robust responses to non-noxious von Frey filaments. On days 14–27, rats received either saline or 101 mg/kg propentofylline by intraperitoneal (i.p.) injection. On day 28 or 42 (after a 14-day drug washout period), lumbar spinal cord sections were processed for assessment of astrocytic glial fibrillary acidic protein (GFAP) and microglial OX-42 (antibody against CR3/CD11b). Propentofylline treatment to nerve injured rats resulted in significant reversal of allodynia that lasted throughout the 14-day washout period. Spinal microglial activation was observed at days 28 and 42 post-injury at the protein level, in the absence of mRNA level changes. Less robust increases in GFAP immunoreactivity were observed at days 28 and 42 post-transection. Interestingly, propentofylline treatment suppressed microglial activation at both time points in this paradigm. Taken together, our results highlight the clinical potential of the glial modulating agent, propentofylline, for the treatment of neuropathic pain as well as a role for microglia in the long-term maintenance of allodynia.
Vivianne L Tawfik - One of the best experts on this subject based on the ideXlab platform.
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reprint of efficacy of propentofylline a glial modulating agent on existing mechanical allodynia following peripheral nerve injury brain behav immun 21 2007 238 246
Brain Behavior and Immunity, 2007Co-Authors: Vivianne L Tawfik, Joyce A Deleo, Michael L Lacroixfralish, Nancy NutilemcmenemyAbstract:Abstract Increasing evidence points to a role for spinal neuroimmune dysregulation (glial cell activation and cytokine expression) in the pathogenesis of chronic pain. Suppression of astrocytic and microglial activation with the Methylxanthine Derivative, propentofylline, pre-emptively attenuates the development of nerve injury-induced allodynia. Currently, we investigated the ability of systemic propentofylline to reverse existing, long-term allodynia after nerve injury—a clinically relevant paradigm. Rats received L5 spinal nerve transection or sham surgery and the development of mechanical allodynia was assessed daily for 2 weeks, at which time injured rats exhibited robust responses to non-noxious von Frey filaments. On days 14–27, rats received either saline or 101 mg/kg propentofylline by intraperitoneal (i.p.) injection. On day 28 or 42 (after a 14-day drug washout period), lumbar spinal cord sections were processed for assessment of astrocytic glial fibrillary acidic protein (GFAP) and microglial OX-42 (antibody against CR3/CD11b). Propentofylline treatment to nerve injured rats resulted in significant reversal of allodynia that lasted throughout the 14-day washout period. Spinal microglial activation was observed at days 28 and 42 post-injury at the protein level, in the absence of mRNA level changes. Less robust increases in GFAP immunoreactivity were observed at days 28 and 42 post-transection. Interestingly, propentofylline treatment suppressed microglial activation at both time points in this paradigm. Taken together, our results highlight the clinical potential of the glial modulating agent, propentofylline, for the treatment of neuropathic pain as well as a role for microglia in the long-term maintenance of allodynia.
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efficacy of propentofylline a glial modulating agent on existing mechanical allodynia following peripheral nerve injury
Brain Behavior and Immunity, 2007Co-Authors: Vivianne L Tawfik, Joyce A Deleo, Michael L Lacroixfralish, Nancy NutilemcmenemyAbstract:Abstract Increasing evidence points to a role for spinal neuroimmune dysregulation (glial cell activation and cytokine expression) in the pathogenesis of chronic pain. Suppression of astrocytic and microglial activation with the Methylxanthine Derivative, propentofylline, pre-emptively attenuates the development of nerve injury-induced allodynia. Currently, we investigated the ability of systemic propentofylline to reverse existing, long-term allodynia after nerve injury—a clinically relevant paradigm. Rats received L5 spinal nerve transection or sham surgery and the development of mechanical allodynia was assessed daily for 2 weeks, at which time injured rats exhibited robust responses to non-noxious von Frey filaments. On days 14–27, rats received either saline or 101 mg/kg propentofylline by intraperitoneal (i.p.) injection. On day 28 or 42 (after a 14-day drug washout period), lumbar spinal cord sections were processed for assessment of astrocytic glial fibrillary acidic protein (GFAP) and microglial OX-42 (antibody against CR3/CD11b). Propentofylline treatment to nerve injured rats resulted in significant reversal of allodynia that lasted throughout the 14-day washout period. Spinal microglial activation was observed at days 28 and 42 post-injury at the protein level, in the absence of mRNA level changes. Less robust increases in GFAP immunoreactivity were observed at days 28 and 42 post-transection. Interestingly, propentofylline treatment suppressed microglial activation at both time points in this paradigm. Taken together, our results highlight the clinical potential of the glial modulating agent, propentofylline, for the treatment of neuropathic pain as well as a role for microglia in the long-term maintenance of allodynia.
Tunjun Tsai - One of the best experts on this subject based on the ideXlab platform.
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pentoxifylline suppresses renal tumour necrosis factor α and ameliorates experimental crescentic glomerulonephritis in rats
Nephrology Dialysis Transplantation, 2004Co-Authors: Yungming Chen, Shueiliong Lin, Wenchih Chiang, Hui Y Lan, Tunjun TsaiAbstract:BACKGROUND Crescentic glomerulonephritis is a rapidly progressive form of glomerulonephritis, but treatment remains non-specific. The Methylxanthine Derivative pentoxifylline (PTX) is a clinically available phosphodiesterase inhibitor with anti-inflammatory and immunoregulatory activities. This study examined whether PTX has beneficial effects in a rat model of anti-glomerular basement membrane (GBM) crescentic glomerulonephritis. METHODS Experimental crescentic glomerulonephritis was induced in Wistar rats by intravenous injection of rabbit anti-rat GBM serum and treated with either vehicle (phosphate-buffered saline) or PTX (0.1 g/kg/day) intravenously on a daily basis. Groups of six animals were euthanized at days 3, 7, 14 or 28 after induction of disease. Effects of PTX on renal function, histology and expression of cytokines, chemokines and adhesion molecules were determined. RESULTS Compared with the vehicle-treated nephritic rats, PTX treatment beginning at the start of the nephritis significantly suppressed mRNA expression of tumour necrosis factor (TNF)-alpha, but not interleukin-1 beta, throughout the course of nephritis. Moreover, PTX decreased renal mRNAs for intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T-cell expressed and secreted (RANTES) and osteopontin (OPN) at all time points examined. These effects were associated with a significant inhibition of macrophage and T-cell infiltration, a reduction of 24-h urinary protein excretion (50-75%, P<0.05), an improvement of histological damage including glomerular crescent formation (60-70%, P<0.01) and a decrease of cortical mRNAs for type I (alpha 1) collagen and fibronectin. The efficacy of PTX could also be seen, though to a lesser extent, in rats with established nephritis. CONCLUSIONS PTX is an effective anti-inflammatory and immunomodulatory agent capable of suppressing rat crescentic glomerulonephritis. Inhibition of renal TNF-alpha, ICAM-1, RANTES, MCP-1 and OPN expression may be a mechanism whereby PTX suppresses progressive renal injury in rat crescentic glomerulonephritis.