Systemic Administration of the Immunophilin Ligand GPI 1046 in MPTP-Treated Monkeys

Emborg, Marina E.; Shin, Peter; Roitberg, Ben; Sramek, Joseph G.; Chu, Yaping; Stebbins, Glenn T.; Hamilton, John; Suzdak, Peter D.; Steiner, Joseph P.; Kordower, Jeffrey H.

doi:10.1006/exnr.2000.7592

Cited by 52 publications

(38 citation statements)

References 45 publications

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“…140,141 On the other hand, there have been many reports that failed to find such benefits in various animal models of PD, including primates. [142][143][144][145] One controlled clinical trial testing neuroimmunophilin in patients was unsuccessful, but a larger one is now underway.…”

Section: Providing Trophic Factorsmentioning

confidence: 99%

Neurodegeneration and neuroprotection in Parkinson disease

Fahn

Sulzer

2004

Neurotherapeutics

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Summary:Many of the motoric features that define Parkinson disease (PD) result primarily from the loss of the neuromelanin (NM)-containing dopamine (DA) neurons of the substantia nigra (SN), and to a lesser extent, other mostly catecholaminergic neurons, and are associated with cytoplasmic "Lewy body" inclusions in some of the surviving neurons. While there are uncommon instances of familial PD, and rare instances of known genetic causes, the etiology of the vast majority of PD cases remains unknown (i.e., idiopathic). Here we outline genetic and environmental findings related to PD epidemiology, suggestions that aberrant protein degradation may play a role in disease pathogenesis, and pathogenetic mechanisms including oxidative stress due to DA oxidation that could underlie the selectivity of neurodegeneration. We then outline potential approaches to neuroprotection for PD that are derived from current notions on disease pathogenesis.

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Section: Providing Trophic Factorsmentioning

confidence: 99%

Neurodegeneration and neuroprotection in Parkinson disease

Fahn

Sulzer

2004

Neurotherapeutics

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“…The nonimmunosuppressive immunophilin ligand, GPI-1046, promotes the regeneration of dopamine cells in association with functional recovery in rodent models of Parkinson's disease (PD), however, it does not have neuroprotective and regenerative effects in MPTP-treated primates [24,25].…”

Section: Neuroprotective and Neurotrophic Effects Of Csa And Fk506mentioning

confidence: 99%

Molecular mechanisms of neuroprotective action of immunosuppressants ‐ facts and hypotheses

Kamińska

Gawęda-Walerych

Zawadzka

2004

J Cellular Molecular Medi

112

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Cyclosporin A (CsA) and FK506 (Tacrolimus) are short polypeptides which block the activation of lymphocytes and other immune system cells. Immunosuppressants exert neuroprotective and neurotrophic action in traumatic brain injury, sciatic nerve injury, focal and global ischemia in animals. Their neuroprotective actions are not understood and many hypotheses have been formed to explain such effects. We discuss a role of drug target -calcineurin in neuroprotective action of immunosuppressants. Protein dephosphorylation by calcineurin plays an important role in neuronal signal transduction due to its ability to regulate the activity of ion channels, glutamate release, and synaptic plasticity. In vitro FK506 protects cortex neurons from NMDA-induced death, augments NOS phosphorylation inhibiting its activity and NO synthesis. However, in vivo experiments demonstrated that FK506 in neuroprotective doses did not block excitotoxic cell death nor did it alter NO production during ischemia/reperfusion. Tissue damage in ischemia is the result of a complex pathophysiological cascade, which comprises a variety of distinct pathological events. Resident non-neuronal brain cells respond rapidly to neuronal cell death and may have both deleterious and useful role in neuronal damage. There is increasing evidence that reactive gliosis and post-ischemic inflammation involving microglia contribute to ischemic damage. We have demonstrated that FK506 modulates hypertrophic/proliferative responses and proinflammatory cytokine expression in astrocytes and microglia in vitro and in focal transient brain ischemia. Our findings suggest that astrocytes and microglia are direct targets of FK506 and modulation of glial response and inflammation is a possible mechanism of FK506-mediated neuroprotection in ischemia.

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“…FK506 and FK520 also accelerate the rate of nerve regeneration (Gold, 2000;Hamilton and Thomas, 2000), being very potent in promoting neurite outgrowth in PC12 cells, SH-SY5Y cells, and primary neuronal cultures (Lyons et al, 1994;Gold et al, 1999). The neurotrophic property of these compounds has been established in a variety of animal models (for review, see Gold, 2000), including, sciatic nerve injury (Gold et al, 1994;Archibald et al, 1999;Doolabh and Mackinnon, 1999;Lee et al, 2000), spinal cord injury (Madsen et al, 1998;Wang and Gold, 1999), and toxic-chemical models of Parkinson's disease (Hamilton et al, 1997;Steiner et al, 1997b;Costantini et al, 1998;Emborg et al, 2001). Nevertheless, for treatment of neurodegenerative diseases, it would clearly be necessary to reduce or eliminate the immunosuppressive effects of these drugs.…”

mentioning

confidence: 99%

Genetically Engineered Analogs of Ascomycin for Nerve Regeneration

Revill¹,

Voda²,

Reeves³

et al. 2002

J Pharmacol Exp Ther

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The polyketides FK506 (tacrolimus) and FK520 (ascomycin) are potent immunosuppressants that function by inhibiting calcineurin phosphatase through formation of an FKBP12-FK506/ 520-calcineurin ternary complex. They also have calcineurinindependent neuroregenerative properties in cell culture and animal models of nervous system disorders. Based on the crystal structure of the FKBP12-FK506-calcineurin complex, we deduced that the 13-and 15-methoxy groups of FK506 or FK520 are important for inhibition of calcineurin phosphatase but not for binding to FKBP12. By genetic modification of the FK520 gene cluster, we generated 13-and 15-desmethoxy analogs of FK520 that contain hydrogen, methyl, or ethyl instead of methoxy at one or both of these positions. These analogs bind FKBP12 tightly, have decreased calcineurin phosphatase inhibition and immunosuppressive properties, and enhance neurite outgrowth in cell cultures. A representative compound was also shown to accelerate nerve regeneration and functional recovery in the rat sciatic nerve crush model.

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Systemic Administration of the Immunophilin Ligand GPI 1046 in MPTP-Treated Monkeys

Cited by 52 publications

References 45 publications

Neurodegeneration and neuroprotection in Parkinson disease

Neurodegeneration and neuroprotection in Parkinson disease

Molecular mechanisms of neuroprotective action of immunosuppressants ‐ facts and hypotheses

Genetically Engineered Analogs of Ascomycin for Nerve Regeneration

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