Immunosupressants and calcineurin inhibitors, cyclosporin A and FK506, reversibly inhibit epileptogenesis in amygdaloid kindled rat

Moia, Lizomar J.M.P.; Matsui, Hideki; Barros, Guilherme Antônio Moreira de; Tomizawa, Kazuhito; Miyamoto, Kazuhiro; Kuwata, Yoshihiro; Tokuda, Masaaki; Itano, Toshifumi; Hatase, Osamu

doi:10.1016/0006-8993(94)91138-x

Cited by 52 publications

(16 citation statements)

References 23 publications

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“…Regarding to the Epileptic mechanism, the role of PP2B on the development and propagation of epileptic seizures has been the main focus of many preclinical studies. Moia et al (1994) showed that the concentration of PP2B in the rat brain, as detected immunohistochemically, increases after completion of electrical kindling. Kurz et al (2001) have reported a significant increase in PP2B activity in the rat pilocarpine model of status epilepticus, occurring through a NMDA-dependent mechanism.…”

Section: Introductionmentioning

confidence: 98%

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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Section: Introductionmentioning

confidence: 98%

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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“…Briefly, the polyclonal antibodies against CnA were from StressGen Biotech (Victoria, BC, Canada); the monoclonal CnB antibodies were produced as described previously (26); the polyclonal antibodies against cabin-1 and non-erythroid ␣-spectrin mouse monoclonal antibodies were from Chemicon (Temecula, CA). After incubation with the appropriate secondary antibodies conjugated with horseradish peroxidase (Sigma), positive bands were visualized using an enhanced chemiluminescence (ECL) detection system (Amersham Biosciences).…”

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confidence: 99%

Critical Role of Calpain-mediated Cleavage of Calcineurin in Excitotoxic Neurodegeneration

Tomizawa

Oda

et al. 2004

Journal of Biological Chemistry

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212

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Calcineurin and calpain, a Ca2؉ /calmodulin-dependent protein phosphatase and a Ca 2؉ -dependent cysteine protease, respectively, mediate neuronal cell death through independent cascades. Here, we report that during neuroexcitotoxicity, calcineurin A (CnA) is directly cleaved by calpain in vitro and in vivo, resulting in the enzyme being converted to an active form. Mass spectrometry identified three cleavage sites in CnA, two of which were constitutively active forms. Overexpression of the cleaved CnA induced caspase activity and neuronal cell death. Calpain inhibitors and membranepermeable calpastatin peptides not only blocked the cleavage of CnA, but also protected against excitotoxic neuronal cell death in vitro and in vivo. These results indicate that CnA is a crucial target for calpain, and the calpain-mediated activation of CnA triggers excitotoxic neurodegeneration. This study established a molecular link between calpain and calcineurin, thereby demonstrating a new mechanism for proteolytical regulation of calcineurin by calpain in response to certain pathological states.

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“…Ca also plays a role in the induction of an endonuclease responsible for internucleosomal DNA cleavage, yielding the characteristic apoptotic DNA ladders (Shiokawaet al, 1994), and recent studies have shown that the apoptotic endonuclease AP-24 is activated via CaM-dependent protein kinase II (Wrightet al, 1997a). If we observe changes in the phosphorylation patterns of the Bcl-2-related proteins, then we will directly assay for changes in calcineurin expression and activity, utilizing specific inhibitors of this enzyme, Cyclosporin A and FK506 (Moia et al, 1994). In addition, we will test the expression and role of the serine protease AP-24 utilizing specific inhibitors as described (Wright et al, 1997b), and if it is positive we will investigate the potential role of CaM kinase II utilizing specific inhibitors KN62 and KN93 (Marley andThomson, 1996) (Wrightet al, 1997a).…”

Section: +mentioning

confidence: 99%

Characterization and Modulation of Proteins Involved in SM Vesication

Rosenthal¹

2005

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Immunosupressants and calcineurin inhibitors, cyclosporin A and FK506, reversibly inhibit epileptogenesis in amygdaloid kindled rat

Cited by 52 publications

References 23 publications

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

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

Critical Role of Calpain-mediated Cleavage of Calcineurin in Excitotoxic Neurodegeneration

Characterization and Modulation of Proteins Involved in SM Vesication

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