Different preparations, doses, and treatment regimens of cyclosporine A cause adverse effects but no robust changes in seizure thresholds in rats

Handreck, Annelie; Mall, Eva Maria; Elger, Deborah Annina; Gey, Laura; Gernert, Manuela

doi:10.1016/j.eplepsyres.2015.02.006

Cited by 4 publications

(3 citation statements)

References 81 publications

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“…However, the present data show that the lower efficacies of AMPAR antagonists to the PP2B-ERK1/2-SGK1-NEDD4-2-mediated GRIA1 ubiquitination and the inhibition of spontaneous seizure activities (presumably due to the higher clearance of AMPAR antagonists or the lower affinities of AMPAR antagonists on GRIA1 [23][24][25]) in non-responders were improved by CsA co-treatment. If the upregulated GRIA2-lacking AMPAR expression resulted in refractory seizures to AMPAR antagonists, CsA co-treatment would not inhibit seizure activity in non-responders, since a lack of effects of CsA on neuronal excitability and seizure activity is well known [30,58,59]. Therefore, our findings suggest that the upregulated GRIA2-lacking AMPAR expression in non-responders may not be a primary cause of intractable seizures to AMPAR antagonists (although it may be relevant to ictogenesis), but may be a consequence of the irresponsiveness to AMPAR antagonists.…”

Section: Discussionmentioning

confidence: 99%

AMPA Receptor Antagonists Facilitate NEDD4-2-Mediated GRIA1 Ubiquitination by Regulating PP2B-ERK1/2-SGK1 Pathway in Chronic Epilepsy Rats

et al. 2021

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The neural precursor cell expressed by developmentally downregulated gene 4-2 (NEDD4-2) is a ubiquitin E3 ligase that has a high affinity toward binding and ubiquitinating glutamate ionotropic receptor α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type subunit 1 (GRIA1, also referred to GluR1 or GluA1). Since dysregulation of GRIA1 surface expression is relevant to the responsiveness to AMPA receptor (AMPAR) antagonists (perampanel and GYKI 52466) in chronic epilepsy rats, it is likely that NEDD4-2 may be involved in the pathogenesis of intractable epilepsy. However, the role of NEDD4-2-mediated GRIA1 ubiquitination in refractory seizures to AMPAR antagonists is still unknown. In the present study, both AMPAR antagonists recovered the impaired GRIA1 ubiquitination by regulating protein phosphatase 2B (PP2B)-extracellular signal-regulated kinase 1/2 (ERK1/2)-serum and glucocorticoid-regulated kinase 1 (SGK1)-NEDD4-2 signaling pathway in responders (whose seizure activities are responsive to AMPAR), but not non-responders (whose seizure activities were uncontrolled by AMPAR antagonists). In addition, cyclosporin A (CsA, a PP2B inhibitor) co-treatment improved the effects of AMPAR antagonists in non-responders, independent of AKT signaling pathway. Therefore, our findings suggest that dysregulation of PP2B-ERK1/2-SGK1-NEDD4-2-mediated GRIA1 ubiquitination may be responsible for refractory seizures and that this pathway may be a potential therapeutic target for improving the treatment of intractable epilepsy in response to AMPAR antagonists.

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Section: Discussionmentioning

confidence: 99%

AMPA Receptor Antagonists Facilitate NEDD4-2-Mediated GRIA1 Ubiquitination by Regulating PP2B-ERK1/2-SGK1 Pathway in Chronic Epilepsy Rats

et al. 2021

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“…The amygdala‐kindling model is highly predictive for detecting clinically effective drugs for the treatment of focal onset seizures as in temporal lobe epilepsies 21 and is thus considered a model for difficult‐to‐treat types of seizures. We previously published kindling protocols comparable to the one used here, 22,35,38,39 which is described in detail in the Supplement. Briefly, rats were electrically kindled via a chronically implanted electrode in the right amygdala.…”

Section: Methodsmentioning

confidence: 99%

“…Thus, the ivPTZ‐ST test is particularly sensitive to drugs that increase GABAergic inhibition, 20 such as GABA‐AT inactivators, and can be used to determine the ability of drugs to alter seizure thresholds by applying the drug at the appropriate time before onset of PTZ infusion. To avoid a kindling effect, the number of ivPTZ‐ST tests was limited to a maximum of five in the same individual, which has been proven not to change seizure thresholds 34,35 …”

Section: Methodsmentioning

confidence: 99%

OV329, a novel highly potent γ‐aminobutyric acid aminotransferase inactivator, induces pronounced anticonvulsant effects in the pentylenetetrazole seizure threshold test and in amygdala‐kindled rats

Feja¹,

Meller²,

Deking³

et al. 2021

Epilepsia

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Summary Objective An attractive target to interfere with epileptic brain hyperexcitability is the enhancement of γ‐aminobutyric acidergic (GABAergic) inhibition by inactivation of the GABA‐metabolizing enzyme GABA aminotransferase (GABA‐AT). GABA‐AT inactivators were designed to control seizures by raising brain GABA levels. OV329, a novel drug candidate for the treatment of epilepsy and addiction, has been shown in vitro to be substantially more potent as a GABA‐AT inactivator than vigabatrin, an antiseizure drug approved as an add‐on therapy for adult patients with refractory complex partial seizures and monotherapy for pediatric patients with infantile spasms. Thus, we hypothesized that OV329 should produce pronounced anticonvulsant effects in two different rat seizure models. Methods We therefore examined the effects of OV329 (5, 20, and 40 mg/kg ip) on the seizure threshold of female Wistar Unilever rats, using the timed intravenous pentylenetetrazole (ivPTZ) seizure threshold model as a seizure test particularly sensitive to GABA‐potentiating manipulations, and amygdala‐kindled rats as a model of difficult‐to‐treat temporal lobe epilepsy. Results GABA‐AT inactivation by OV329 clearly increased the threshold of both ivPTZ‐induced and amygdala‐kindled seizures. OV329 further showed a 30‐fold greater anticonvulsant potency on ivPTZ‐induced myoclonic jerks and clonic seizures compared to vigabatrin investigated previously. Notably, all rats were responsive to OV329 in both seizure models. Significance These results reveal an anticonvulsant profile of OV329 that appears to be superior in both potency and efficacy to vigabatrin and highlight OV329 as a highly promising candidate for the treatment of seizures and pharmacoresistant epilepsies.

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A new model for biofilm formation and inflammatory tissue reaction: intraoperative infection of a cranial implant with Staphylococcus aureus in rats

et al. 2017

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Different preparations, doses, and treatment regimens of cyclosporine A cause adverse effects but no robust changes in seizure thresholds in rats

Cited by 4 publications

References 81 publications

AMPA Receptor Antagonists Facilitate NEDD4-2-Mediated GRIA1 Ubiquitination by Regulating PP2B-ERK1/2-SGK1 Pathway in Chronic Epilepsy Rats

AMPA Receptor Antagonists Facilitate NEDD4-2-Mediated GRIA1 Ubiquitination by Regulating PP2B-ERK1/2-SGK1 Pathway in Chronic Epilepsy Rats

OV329, a novel highly potent γ‐aminobutyric acid aminotransferase inactivator, induces pronounced anticonvulsant effects in the pentylenetetrazole seizure threshold test and in amygdala‐kindled rats

A new model for biofilm formation and inflammatory tissue reaction: intraoperative infection of a cranial implant with Staphylococcus aureus in rats

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