Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models

Steiner, Joseph P.; Hamilton, Gregory S.; Ross, Douglas T.; Valentine, Heather; Guo, Hongzhi; Connolly, Maureen A.; Shi, Liang; Ramsey, Cynthia; Li, Jia He J.; Huang, Wei; Howorth, P. J. N.; Soni, Rajat; Fuller, Michael S.; Sauer, Hans R.; Nowotnik, Alison C.; Suzdak, Peter D.

doi:10.1073/pnas.94.5.2019

Cited by 300 publications

(208 citation statements)

References 31 publications

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“…Several studies report that FK506 and related non-immunosuppressive immunophilin ligands, such as GPI-1046 and V10367, have neurotrophic/ neuroprotective effects on dopaminergic neurons following MPTPor 6-OHDA-induced lesion (Steiner et al, 1997;Costantini et al, 1998Costantini et al, , 2001Ross et al, 2001;Zhang et al, 2001a;Tanaka et al, 2002a). Neurotrophic effects to dopaminergic neurons are also observed in vitro (Costantini and Isacson, 2000;Guo et al, 2001).…”

Section: Immunophilin Ligandsmentioning

confidence: 84%

“…Nevertheless, current clinically available immunophilin ligands, including FK506 and cyclosporine A, are immunosuppressive, which limits their chronic use. However, neither calcineurin inhibition nor binding to FKBP-12 were found to be necessary for the neurotrophic effects of immunophilin ligands (Steiner et al, 1997;Costantini et al, 2001;Guo et al, 2001;Klettner et al, 2001;Zhang et al, 2001a;Tanaka et al, 2002b). This fact, together with the neuroprotective effects of immunophilin ligands in models of neurodegenerative disorders (reviewed by Pong and Zaleska, 2003), has led to the design of small ligands that bind to immunophilins, but are not immunosuppressive since they do not interact with calcineurin (e.g.…”

Section: Immunophilin Ligandsmentioning

confidence: 99%

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Driving GDNF expression: The green and the red traffic lights

Saavedra

Baltazar

Duarte

2008

Progress in Neurobiology

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Section: Immunophilin Ligandsmentioning

confidence: 84%

Section: Immunophilin Ligandsmentioning

confidence: 99%

Driving GDNF expression: The green and the red traffic lights

Saavedra

Baltazar

Duarte

2008

Progress in Neurobiology

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“…Interestingly, such effectiveness was recognized with both early and late administration (7 to 28 days after injury) (Steiner et al, 1997b;Zhang et al, 2001). The present study observed a striking colocalization of CyCAP and cyclophilin C mRNAs in the activated macrophages of the ischemic core.…”

Section: Discussionmentioning

confidence: 99%

Cyclophilin C-Associated Protein and Cyclophilin C mRNA are Upregulated in Penumbral Neurons and Microglia after Focal Cerebral Ischemia

Shimizu

Imai

Seki

et al. 2005

J Cereb Blood Flow Metab

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Immunophilin ligands, such as cyclosporin A and FK506, have neuroprotective effects in experimental stroke models, although the precise mechanism is unclear. Cyclophilin C-associated protein (CyCAP) is a natural cellular ligand for the immunophilin, cyclophilin C, and has a protective effect against endotoxins by downmodulating the proinflammatory response. Expressions of CyCAP and cyclophilin C mRNA in a rat middle cerebral artery (MCA) occlusion ischemia model were investigated by Northern blotting and in situ hybridization. Both CyCAP and cyclophilin C mRNAs were ubiquitously distributed in the neurons of the normal brain. Expression increased in neurons of the periinfarct zone up to 7 days after MCA occlusion. The neuronal distribution was confirmed by counterimmunostaining of NeuN. Both mRNAs were predominantly expressed in microglia of the ischemic core at 7 days, confirmed by immunostaining with the microglial marker, ED1. The quantification of CyCAP and cyclophilin C mRNAs at 7 days by Northern blot analysis showed the 8.5-fold increase (Po0.005, n ¼ 6) and 6.8-fold increase (Po0.005, n ¼ 6), respectively, in ischemic core compared with control. The coincidence of CyCAP and cyclophilin C expression in neurons and microglia suggests distinct roles in each cellular population. In particular, the early increase in penumbral neurons might be related to protection in periinfarct neurons.

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“…studies of GPI used in other nerve lesion paradigms have shown that, following oral administration of the compound, increased doses, nearly twice the intraperitoneal or subcutaneous dose are necessary to provide efficacy [13]. Thus, we utilized GPI at a dose of 30 mg/kg to assess the oral efficacy of the compound.…”

Section: Oral Treatment With Gpi Maintains Erectile Function-previousmentioning

confidence: 99%

Neuroimmunophilin Ligands Protect Cavernous Nerves after Crush Injury in the Rat: New Experimental Paradigms

et al. 2007

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Objectives-We investigated the effects of the orally bioavailable non-immunosuppressive immunophilin ligand GPI 1046 (GPI) on erectile function and cavernous nerve (CN) histology following unilateral or bilateral crush injury (UCI, BCI, respectively) of the CNs.Methods-Adult male Sprague-Dawley rats were administered GPI 15 mg/kg intraperitoneally (ip) or 30 mg/kg orally (po), FK506 1 mg/kg, ip, or vehicle controls for each route of administration just prior to UCI or BCI and daily up to 7 d following injury. At day 1 or 7 of treatment, erectile function induced by CN electrical stimulation was measured, and electron microscopic analysis of the injured CN was performed.Results-Intraperitoneal administration of GPI to rats with injured CN protected erectile function, in a fashion similar to the prototypic immunophilin ligand FK506, compared with vehicle-treated animals (93% ± 9% vs. 70% ± 5% vs. 45% ± 1%, p < 0.01, respectively). Oral administration of GPI elicited the same level of significant protection from CN injury. GPI administered PO at 30 mg/kg/ d, dosing either once daily or four times daily with 7.5 mg/kg, provided nearly complete protection of erectile function. In a more severe BCI model, PO administration of GPI maintained erectile function at 24 h after CN injury. Ultrastructural analysis of injured CNs indicated that GPI administered at the time of CN injury prevents degeneration of about 83% of the unmyelinated axons at 7 d after CN injury. Take-home message This study demonstrates that oral or intraperitoneal administration of GPI-1046, a non-immunosuppressive immunophilin ligand, recovers erectile function in rat models of cavernous nerve injury, thus providing a potential therapeutic tool for the treatment of erectile dysfunction related to nerve injury. Disclosure Conflict of interest: Under a licensing agreement between Guilford Pharmaceuticals and the Johns Hopkins University, A.L. Burnett is entitled to a share of royalty received by the university on sales of products described in this article. The university owns Guilford Pharmaceuticals stock, which is subjected to certain restrictions under university policy. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

show abstract

Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models

Cited by 300 publications

References 31 publications

Driving GDNF expression: The green and the red traffic lights

Driving GDNF expression: The green and the red traffic lights

Cyclophilin C-Associated Protein and Cyclophilin C mRNA are Upregulated in Penumbral Neurons and Microglia after Focal Cerebral Ischemia

Neuroimmunophilin Ligands Protect Cavernous Nerves after Crush Injury in the Rat: New Experimental Paradigms

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