Calcineurin Inhibitors as Neuroprotectants

Sharkey, John; Jones, Paul A.; McCarter, J. F.; Kelly, John

doi:10.2165/00023210-200013010-00001

Cited by 18 publications

(9 citation statements)

References 159 publications

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“…Several groups reported that both, FK506 and CsA inhibited NMDA-stimulated NOS activity and blocked NMDA neurotoxicity in neuronal cell cultures. Rapamycin antagonized the neuroprotective effects of FK506 [48,58,73], indicating a CaN-dependent mechanism. Unlike NMDA receptor antagonists (e.g.…”

Section: Can and Rosmentioning

confidence: 98%

“…Currently, some of the above-described interactions of FK506 with FKBPs are discussed as mechanisms underlying the multiple effects of this drug on the central and peripheral nervous system [11,12,47,48]. Memory formation, axonal transport, nerve growth and neurodegenerative processes were found to be affected by FKBPs and cyclophilins as could be inferred from the effects of mono-and bifunctional inhibitors as biological probes [4,7,8,49].…”

Section: Immunosuppressive Ppiase Ligands As Neurogenic Agentsmentioning

confidence: 99%

“…Besides protection and regeneration following nerve fiber injury, FK506 and derivatives can exert further beneficial effects including alteration of neurotransmitter release [54], protection against ischemic brain injury [4,48,[55][56][57] and glutamate neurotoxicity in vitro [58], prevention of Nmethyl-D-aspartate (NMDA)-receptor desensitization [59], modulation of long-term potentiation (LTP) [60][61][62] and blockade of long-term depression (LTD) in the rat hippocampus [63], prevention of LTP and LTD in the visual cortex [64,65].…”

Section: Immunosuppressive Ppiase Ligands As Neurogenic Agentsmentioning

confidence: 99%

“…A major issue of ongoing discussion is the role of CaN in neuroprotection, since CaN regulates the activity of various intracellular proteins including nitric oxide synthase (NOS), the NMDA receptor complex, the IP 3 receptor and a variety of ion channels [48]. Noticably, both, FK506 and CsA have been shown to be effective in a wide range of cerebral ischemia models, although conflicting data have also been reported.…”

Section: Can and Rosmentioning

confidence: 99%

“…Recently, FK506 as well as rapamycin were reported to significantly decrease the infarct volume when administered 10 min after occlusion of the left middle cerebral artery in rats, whereas the monofunctional FKBP ligand GPI-1046 was completely inactive [69]. The poor blood-brain barrier permeability of CsA requires the use of relatively high dosages for neuroprotection and may contribute for the observed ineffectiveness in some experimental models of ischemia [4,48].…”

Section: Can and Rosmentioning

confidence: 99%

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FKBP Ligands as Novel Therapeutics for Neurological Disorders

Christner¹,

Herdegen²,

Fischer³

2001

MRMC

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Given their clinical importance for the treatment of acute and chronic neurodegenerative diseases in humans including nerve injuries (e.g. Alzheimer's disease, Parkinson's disease, diabetic neuropathy) a number of different approaches were pursued to obtain selectively acting FK506-binding protein (FKBP) ligands: computational methods and target-oriented screening of natural compound and synthetic product libraries. The resulting monofunctional ligands, which inhibit the peptidyl prolyl cis/trans isomerase activity of FKBPs, highlight the role of these enzymes in neuronal signaling. The exploration of the mechanisms of neuroregenerative and neuroprotective action of some of these compounds is the main focus of ongoing neuropharmaceutical research.

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Section: Can and Rosmentioning

confidence: 98%

Section: Immunosuppressive Ppiase Ligands As Neurogenic Agentsmentioning

confidence: 99%

Section: Immunosuppressive Ppiase Ligands As Neurogenic Agentsmentioning

confidence: 99%

Section: Can and Rosmentioning

confidence: 99%

Section: Can and Rosmentioning

confidence: 99%

See 3 more Smart Citations

FKBP Ligands as Novel Therapeutics for Neurological Disorders

Christner¹,

Herdegen²,

Fischer³

2001

MRMC

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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

Gold

Voda

et al. 2004

J of Neuroscience Research

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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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The Calcineurin Inhibitor Ascomicin Interferes with the Early Stage of the Epileptogenic Process Induced by Latrunculin A Microperfusion in Rat Hippocampus

Freire-Cobo

Sierra-Paredes

Freire

et al. 2014

J Neuroimmune Pharmacol

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Latrunculin A microperfusion in rat hippocampus has shown to be an effective model of acute and chronic seizures for neurochemical studies. The intervention over early synaptic plasticity changes after the epileptogenesis onset represents a big challenge on the design of a suitable therapy to impair the epilepsy development. We previously suggested that receptor location might be essential for controlling neuronal excitability, and that disruption of local cytoskeletal dynamics followed by drastic changes in the synaptic/extrasynaptic ratio of NMDA, AMPA receptors and their subsequent downstream signalling may play an important role in the pathogenesis of seizures. In the present study, we performed a pharmacological intervention in the Latrunculin model by using Ascomicin (ASC) and Phenytoin (PHT). We pointed out the inhibitory action of ASC over the protein phosphatase 2B (PP2B). PP2B pathological mechanism involves changes in actin cytoskeleton and showed to avoid those subsequent changes previously observed in PSD components. On the contrary, PHT didn't seem to modify the F-actin depolymerization process induced, showing a similar redistribution pattern from the PSD towards the extrasynaptic site of several molecular components with more or less dependence on actin for their location, including glutamate receptors. Overall, we propose that the early intervention over changes on the synapse during the epileptogenic process might represent the best approach to avoid the onset of chronic refractory seizures our model. On this regard, the therapeutic potential of ASC, FK506 and derivatives should be further explored as a possible tool in the intervention over epilepsy and other brain diseases.

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Calcineurin Inhibitors as Neuroprotectants

Cited by 18 publications

References 159 publications

FKBP Ligands as Novel Therapeutics for Neurological Disorders

FKBP Ligands as Novel Therapeutics for Neurological Disorders

FK506 and a nonimmunosuppressant derivative reduce axonal and myelin damage in experimental autoimmune encephalomyelitis: Neuroimmunophilin ligand‐mediated neuroprotection in a model of multiple sclerosis

The Calcineurin Inhibitor Ascomicin Interferes with the Early Stage of the Epileptogenic Process Induced by Latrunculin A Microperfusion in Rat Hippocampus

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