The Experts below are selected from a list of 120 Experts worldwide ranked by ideXlab platform
Bruce G. Gold - One of the best experts on this subject based on the ideXlab platform.
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Neuroimmunophilin ligands improve functional recovery and increase axonal growth after spinal cord hemisection in rats
Journal of Neurotrauma, 2005Co-Authors: Jan Voda, Takayuki Yamaji, Bruce G. GoldAbstract:We have previously shown that FK506 accelerates the rate of nerve regeneration in the peripheral nervous system (PNS) and increases regeneration of central nervous system (CNS) axons into a peripheral nerve graft. In the present study, we examined whether FK506 and a nonimmunosuppressive derivative (FK1706) improve functional recovery and long distance regeneration following a hemisection lesion of spinal cord at T10/T11. Rats were given daily subcutaneous injections of either FK506 (2 mg/kg/day), FK1706 (2 mg/kg/day), an equivalent volume of saline or 30% DMSO as vehicle, respectively. Functional recovery was assessed using a modified Tarlov/Klinger scale, walking along progressively narrower wooden beams (7.7–1.7 cm widths), and analysis of footprints obtained during walking. Compared to both control groups, FK506 and FK1706-treated animals demonstrated significant functional recovery 4 days (beam walking), 2 weeks (footprints), and 4 weeks (Tarlov/Klinger scale). By 11 weeks, FK506-treated and FK1706-t...
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Neuroimmunophilin ligands improve functional recovery and increase axonal growth after spinal cord hemisection in rats
Journal of Neurotrauma, 2005Co-Authors: Jan Voda, Takayuki Yamaji, Bruce G. GoldAbstract:We have previously shown that FK506 accelerates the rate of nerve regeneration in the peripheral nervous system (PNS) and increases regeneration of central nervous system (CNS) axons into a peripheral nerve graft. In the present study, we examined whether FK506 and a nonimmunosuppressive derivative (FK1706) improve functional recovery and long distance regeneration following a hemisection lesion of spinal cord at T10/T11. Rats were given daily subcutaneous injections of either FK506 (2 mg/kg/day), FK1706 (2 mg/kg/day), an equivalent volume of saline or 30% DMSO as vehicle, respectively. Functional recovery was assessed using a modified Tarlov/Klinger scale, walking along progressively narrower wooden beams (7.7-1.7 cm widths), and analysis of footprints obtained during walking. Compared to both control groups, FK506 and FK1706-treated animals demonstrated significant functional recovery 4 days (beam walking), 2 weeks (footprints), and 4 weeks (Tarlov/Klinger scale). By 11 weeks, FK506-treated and FK1706-treated animals were able to walk, albeit poorly, along even the narrowest (1.7 cm) beam. At 11 weeks, the spinal cords were re-exposed and a small piece of gel foam-soaked Fluoro-Gold was placed on the injured side 2-cm caudal to the first injury. Five days later, the animals were perfused and tissues prepared for fluorescence microscopy. FK506-treated and FK1706-treated rats demonstrate a significantly greater number of retrogradely labeled neurons in the red nucleus. The results implicate a nonimmunosuppressant mechanism in FK506's action and suggest that FK506 or a nonimmunosuppressant derivative may be useful for treatment of spinal cord injuries.
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non fk506 binding protein 12 Neuroimmunophilin ligands increase neurite elongation and accelerate nerve regeneration
Journal of Neuroscience Research, 2005Co-Authors: Bruce G. Gold, David M Armistead, Minsheng WangAbstract:Neurotrophic activity of Neuroimmunophilin ligands (FK506 and its nonimmunosuppressant derivatives) has been assumed to be mediated by the FK506-binding protein-12 (FKBP-12). We recently showed that activity is retained in hippocampal neurons from FKBP-12 knockout mice, indicating that binding to FKBP-12 is not necessary. Here we show that three nonimmunosuppressant FK506 derivatives (V-13,450, V-13,629, and V-13,670) that do not bind FKBP-12 (>12.5 mM affinity) are equipotent to FKBP-12 ligands (FK506, V-10,367, and V-13,449) for increasing neurite elongation in SH-SY5Y cells. One non-FKBP-12 ligand (V-13,670) is also shown to accelerate functional recovery and nerve regeneration in the rat sciatic nerve crush model. Surprisingly, it exhibited an unusual dose-response effect upon oral administration, showing a novel bimodal dose-response for behavioral functional recovery and myelination, but not for axonal size, suggesting both Schwann cell and neuronal targets. Orally active non-FKBP-12 Neuroimmunophilin ligands may be useful for the treatment of human neurological disorders without any potential side effects resulting from FKBP-12 binding.
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fk506 and a nonimmunosuppressant derivative reduce axonal and myelin damage in experimental autoimmune encephalomyelitis Neuroimmunophilin ligand mediated neuroprotection in a model of multiple sclerosis
Journal of Neuroscience Research, 2004Co-Authors: Bruce G. Gold, Dennis Bourdette, Jan Voda, Gabriel P MckeonAbstract:Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) in which demyelination and axonal loss result in permanent neurologic disability. We examined the neuroprotective property of the immunosuppressant FK506 (tacrolimus), FK1706 (a nonimmunosuppressant FK506 derivative) and cyclosporin A (CsA) in a chronic relapsing experimental autoimmune encephalomyelitis (EAE) model of MS. Female SJL/J mice were immunized by subcutaneous (s.c.) injection with proteolipid protein 139-151 peptide in complete Freund's adjuvant. At the onset of paralysis, 12-14 days after immunization, mice received daily s.c. injections of FK506 (0.2, 1, and 5 mg/kg), FK1706 (5 mg/kg), CsA (2, 10, and 50 mg/kg), saline or vehicle (30% dimethylsulfoxide) for 30 days. FK506 (at a dose of 5 mg/kg) reduced the severity of the initial disease and suppressed relapses. FK1706 did not significantly alter the clinical course and CsA (at a dose of 50 mg/kg) lessened the severity of the initial episode of EAE but did not alter relapses. In the thoracic spinal cord, FK506 (5 mg/kg), FK1706 (5 mg/kg), and CsA (50 mg/kg) significantly (P < 0.001) reduced the extent of damage in the dorsal, lateral, and ventral white matter by a mean of up to 95, 68, and 30%, respectively. A nonimmunosuppressant dose of FK506 (0.2 mg/kg) also significantly (P < 0.001) reduced the extent of damage in the spinal cord by a mean of up to 45%. Other dosages of these compounds were ineffective. FK506 markedly protects against demyelination and axonal loss in this MS model through immunosuppression and neuroprotection.
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Neuroregenerative and neuroprotective actions of Neuroimmunophilin compounds in traumatic and inflammatory neuropathies
Neurological Research, 2004Co-Authors: Bruce G. Gold, Esther Udina, Dennis Bourdette, Xavier NavarroAbstract:FK506 (tacrolimus, Prograf®) is an immunosuppressant drug that also has profound neuroregenerative and neuroprotective actions independent of its immunosuppressant activity. The separation of these properties has led to the development of non-immunosuppressant derivatives that retain the neurotrophic activity. This review focuses on the peripheral nerve actions of these compounds following mechanical injury (nerve crush or transection with graft repair) and in models of inflammatory neuropathies. Whereas FK506 may be indicative for the treatment of inflammatory neuropathies where its immunosuppressive action would be advantageous, non-immunosuppressant derivatives represent a new class of potential therapeutic agents for the treatment of human neurological conditions in general. Moreover, these studies have led to the discovery of a novel mechanism whereby these compounds activate intrinsic neuroregenerative and neuroprotective pathways in the neuron.
Georg Terstappen - One of the best experts on this subject based on the ideXlab platform.
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solid phase solution phase combinatorial synthesis of Neuroimmunophilin ligands
Bioorganic & Medicinal Chemistry Letters, 2000Co-Authors: Michael H Rabinowitz, Pierfausto Seneci, T Rossi, Michele Dal Cin, Martyn Deal, Georg TerstappenAbstract:A novel solid-phase/solution-phase strategy for the synthesis of Neuroimmunophilin ligands based on GPI 1046 was developed. The synthesis employs a solid-phase esterification strategy followed by a solution-phase pyruvic amide formation to produce multi-milligram quantities of discrete compounds for assay. The protocol was applied to a production library of 880 discrete compounds. A highlight of the strategy is an aqueous extractive purification of the final compounds using a novel liquid/ice extraction system developed for high throughput.
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Solid-phase/solution-phase combinatorial synthesis of Neuroimmunophilin ligands
'Elsevier BV', 2000Co-Authors: M. Rabinowitz, Pierfausto Seneci, T Rossi, Martyn Deal, Dal M. Cin, Georg TerstappenAbstract:A novel solid-phase/solution-phase strategy for the synthesis of Neuroimmunophilin ligands based on GPI 1046 was developed. The synthesis employs a solid-phase esterification strategy followed by a solution-phase pyruvic amide formation to produce multi-milligram quantities of discrete compounds for assay. The protocol was applied to a production library of 880 discrete compounds. A highlight of the strategy is an aqueous extractive purification of the final compounds using a novel liquid/ice extraction system developed for high throughpu
Li Song - One of the best experts on this subject based on the ideXlab platform.
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design synthesis and evaluation of 2 2 dimethyl 1 3 dioxolane 4 5 dicarboxylic acid derivatives as Neuroimmunophilin ligands
Chinese Journal of Medicinal Chemistry, 2007Co-Authors: Li SongAbstract:Aim To design and synthesize novel 2,2-dimethyl-[1,3]-dioxolane-4,5-dicarboxylic acid derivatives as Neuroimmunophilin ligands.Methods Both the sequences and conformation of FK506-binding site in FKBPs(FK506 binding proteins) family are highly conserved.According to this characteristic of FKBPs and the structural feature of ligands binding to FKBP12,CADD(computer-aided drug design) was employed to design and virtually screen the novel 2,2-dimethyl——dioxolane-4,5-dicarboxylic acid derivatives.These compounds were synthesized by a liquid-phase synthetic method.A model of chick embryos dorsal root ganglion(DRG) cultures free of serum and a model of NG108-15 cell injured by H2O2 were applied to evaluate neurotrophic activity of these target compounds.Results and conclusion 27 target compounds were synthesized.In cultured chick DRGs,compound 7o produced a little neurotrophic effect and promoted neurite outgrowth in vitro.In the model of H2O2-induced NG108 cell damage,compound 7d showed a significantly protective effect on NG 108 cell.
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drug discovery based on the structure of fkbp52 design synthesis and evaluation of 2 aza bicyclohept 5 ene 3 carboxy derivatives as Neuroimmunophilin ligands
Chinese Journal of Medicinal Chemistry, 2006Co-Authors: Li SongAbstract:Aim To design and synthesize novel 2-aza-bicyclohept-5-ene-3-carboxy derivatives as Neuroimmunophilin ligands.Methods SYBYL/Composer was used for homology modeling the structure of domain 1(D1) of FKBP52.Based on the structure of FKBP52 D1,CADD(computer-aided drug design) was employed to design and virtual screen the novel 2-aza-bicyclohept-5-ene-3-carboxy derivatives.These compounds were synthesized by liquid-phase synthetic method.Cultured chick DRGs(dorsal root ganglion sensory neurons) was applied to evaluate neurotrophic activity of these target compounds.Results and conclusion Novel 2-aza-bicyclohept-5-ene-3-carboxy derivatives were designed based on the structure of FKBP52 and 21 target compounds were synthesized.In cultured chick DRGs,compound 10k produced potent neurotrophic effects and promoted neurite outgrowth in vitro.
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review on the evolution of Neuroimmunophilin ligands
Chinese Journal of Medicinal Chemistry, 2004Co-Authors: Li SongAbstract:Neuroimmunophilin ligands are a class of compounds t hat hold great promise for the treatment of nerve injuries and neurological dise ase.In this review the evolution of design,synthesis and st ructure-activity relationships of Neuroimmunophilin ligands are introduced.The neuroprotec tive and neuroregenerative properties of these compounds are also summarized.
Edward D. Hall - One of the best experts on this subject based on the ideXlab platform.
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24-Hour Delayed Administration in a Mouse Model of Diffuse Traumatic Brain Injury
2015Co-Authors: Nancy C. Kupina, Megan R. Detloff, Satavisha Dutta, Edward D. HallAbstract:Summary: The authors present two studies that investigate the biochemical and histologic effects of the nonimmunosuppres-sive Neuroimmunophilin (NIMM) ligand V-10,367 in a mouse model of traumatic brain injury (TBI). In study 1, the authors examined the effect of V-10,367 (50 mg/kg × 2 per day, by mouth) on neurofilament M (NFM) protein levels and on -spectrin breakdown products (SBDPs) when dosed for 2 days, starting 24 hours after TBI and killed on day 3. In study 2, V-10,367 was given for 10 days, starting 24 hours after TBI and the mice killed 6 weeks after TBI, to measure the extent of neurodegeneration (amino CuAg stain). The results in study 1 revealed that V-10,367-treatment significantly increased NFM protein levels in both sham and TBI mice. In addition, V-10,367 attenuated SBDP 150 levels in the cortex, striatum, and hippocampus. The results of study 2 indicated that TB
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Neuroimmunophilin ligand v 10 367 is neuroprotective after 24 hour delayed administration in a mouse model of diffuse traumatic brain injury
Journal of Cerebral Blood Flow and Metabolism, 2002Co-Authors: Nancy C. Kupina, Megan R. Detloff, Satavisha Dutta, Edward D. HallAbstract:The authors present two studies that investigate the biochemical and histologic effects of the nonimmunosuppressive Neuroimmunophilin (NIMM) ligand V-10,367 in a mouse model of traumatic brain injury (TBI). In study 1, the authors examined the effect of V-10,367 (50 mg/kg x 2 per day, by mouth) on neurofilament M (NFM) protein levels and on alpha-spectrin breakdown products (SBDPs) when dosed for 2 days, starting 24 hours after TBI and killed on day 3. In study 2, V-10,367 was given for 10 days, starting 24 hours after TBI and the mice killed 6 weeks after TBI, to measure the extent of neurodegeneration (amino CuAg stain). The results in study 1 revealed that V-10,367-treatment significantly increased NFM protein levels in both sham and TBI mice. In addition, V-10,367 attenuated SBDP 150 levels in the cortex, striatum, and hippocampus. The results of study 2 indicated that TBI mice treated with V-10,367 demonstrated significantly less neurodegeneration compared to injured, vehicle-treated mice. In summary, these results suggest that NIMMs may be neuroprotective indirectly through inhibition of calpain-mediated cytoskeletal damage and perhaps via maintenance of neuronal plasticity. In the context of this mouse model of TBI, the therapeutic window for V-10,367's positive effects is at least 24 hours after injury, which, in the case of TBI models, is largely unprecedented for a neuroprotective compound.
Michael H Rabinowitz - One of the best experts on this subject based on the ideXlab platform.
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solid phase solution phase combinatorial synthesis of Neuroimmunophilin ligands
Bioorganic & Medicinal Chemistry Letters, 2000Co-Authors: Michael H Rabinowitz, Pierfausto Seneci, T Rossi, Michele Dal Cin, Martyn Deal, Georg TerstappenAbstract:A novel solid-phase/solution-phase strategy for the synthesis of Neuroimmunophilin ligands based on GPI 1046 was developed. The synthesis employs a solid-phase esterification strategy followed by a solution-phase pyruvic amide formation to produce multi-milligram quantities of discrete compounds for assay. The protocol was applied to a production library of 880 discrete compounds. A highlight of the strategy is an aqueous extractive purification of the final compounds using a novel liquid/ice extraction system developed for high throughput.