Pregabalin activates ROMK1 channels via cAMP-dependent protein kinase and protein kinase C

Lee, Chien-Hsing; Liou, Horng-Huei

doi:10.1016/j.ejphar.2014.06.049

Cited by 5 publications

(3 citation statements)

References 49 publications

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“…However, in conventional AED screening models, K ir 6-targeting AEDs have proven ineffective (Wickenden 2002). In this context, it is also worth noting that the approved AED pregabaline also activates K ir 1.1 channels, which may be responsible for heartrelated side effects (Lee and Liou 2014). The proposal that K ir 2 channels could function as antiepileptic channels (Young et al 2009; Wolfart and Laker 2015) is supported by the finding that the anti-inflammatory drug tenidap, which was found to open K ir 2.3 channels (Liu et al 2002), is also quite effective in abolishing epileptic seizures in standard AED testing models (Xu et al 2013).…”

Section: Inward Rectifier Potassium Channelsmentioning

confidence: 99%

Potassium Channels in Epilepsy

Köhling

Wolfart

2016

Cold Spring Harb Perspect Med

121

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This review attempts to give a concise and up-to-date overview on the role of potassium channels in epilepsies. Their role can be defined from a genetic perspective, focusing on variants and de novo mutations identified in genetic studies or animal models with targeted, specific mutations in genes coding for a member of the large potassium channel family. In these genetic studies, a demonstrated functional link to hyperexcitability often remains elusive. However, their role can also be defined from a functional perspective, based on dynamic, aggravating, or adaptive transcriptional and posttranslational alterations. In these cases, it often remains elusive whether the alteration is causal or merely incidental. With ∼80 potassium channel types, of which ∼10% are known to be associated with epilepsies (in humans) or a seizure phenotype (in animals), if genetically mutated, a comprehensive review is a challenging endeavor. This goal may seem all the more ambitious once the data on posttranslational alterations, found both in human tissue from epilepsy patients and in chronic or acute animal models, are included. We therefore summarize the literature, and expand only on key findings, particularly regarding functional alterations found in patient brain tissue and chronic animal models.

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Section: Inward Rectifier Potassium Channelsmentioning

confidence: 99%

Potassium Channels in Epilepsy

Köhling

Wolfart

2016

Cold Spring Harb Perspect Med

121

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“…A number of drugs, originally approved for a different action, were later found to enhance K ir channel function; e.g., K ir 1.1 (Pregabaline) and K ir 2.3 (Tenidap; Liu et al, 2002; Lee and Liou, 2014). Furthermore, supporting K ir 3 channel (Kaufmann et al, 2013) and K ir 2 channel (Xu et al, 2013a) function in vivo is effective against seizures of certain epilepsy models (Table 2).…”

Section: Ion Channel-related Antiepileptic Drug and Gene Therapy Mechmentioning

confidence: 99%

Homeostasis or channelopathy? Acquired cell type-specific ion channel changes in temporal lobe epilepsy and their antiepileptic potential

Wolfart

Laker

2015

Front. Physiol.

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Neurons continuously adapt the expression and functionality of their ion channels. For example, exposed to chronic excitotoxicity, neurons homeostatically downscale their intrinsic excitability. In contrast, the “acquired channelopathy” hypothesis suggests that proepileptic channel characteristics develop during epilepsy. We review cell type-specific channel alterations under different epileptic conditions and discuss the potential of channels that undergo homeostatic adaptations, as targets for antiepileptic drugs (AEDs). Most of the relevant studies have been performed on temporal lobe epilepsy (TLE), a widespread AED-refractory, focal epilepsy. The TLE patients, who undergo epilepsy surgery, frequently display hippocampal sclerosis (HS), which is associated with degeneration of cornu ammonis subfield 1 pyramidal cells (CA1 PCs). Although the resected human tissue offers insights, controlled data largely stem from animal models simulating different aspects of TLE and other epilepsies. Most of the cell type-specific information is available for CA1 PCs and dentate gyrus granule cells (DG GCs). Between these two cell types, a dichotomy can be observed: while DG GCs acquire properties decreasing the intrinsic excitability (in TLE models and patients with HS), CA1 PCs develop channel characteristics increasing intrinsic excitability (in TLE models without HS only). However, thorough examination of data on these and other cell types reveals the coexistence of protective and permissive intrinsic plasticity within neurons. These mechanisms appear differentially regulated, depending on the cell type and seizure condition. Interestingly, the same channel molecules that are upregulated in DG GCs during HS-related TLE, appear as promising targets for future AEDs and gene therapies. Hence, GCs provide an example of homeostatic ion channel adaptation which can serve as a primer when designing novel anti-epileptic strategies.

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“…Previous reports showed that PG can affect cAMP‐dependent protein kinase pathways in renal epithelial cells (Lee & Liou, 2014). This could support our hypothesis regarding the possible effects of PG on signalling molecules in testicular cells.…”

Section: Discussionmentioning

confidence: 98%

Pregabalin administration and withdrawal affect testicular structure and functions in rats

et al. 2020

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The aim of this prospective experimental study was to investigate the effects of pregabalin (PG) administration and withdrawal on testicular structures and functions in rats. A total of 24 male Wistar rats were divided into two groups (n = 12 each): a control group received normal saline, and PG‐treated group received 62 mg kg‐1 day‐1 PG for 2 months. Half the animals of each group were sacrificed for the collection of blood and testicular samples. The remaining animals were bred for another 2 months without treatment before collection of blood and testicular samples. PG administration decreased testosterone and increased luteinising hormone (LH) and follicle‐stimulating hormone (FSH) levels versus controls. PG withdrawal led to a decrease in both FSH and LH and an increase in testosterone levels versus saline withdrawal. Compared to controls, PG administration caused degeneration of seminiferous tubules and decreased the number of spermatogenic but increased the number of Leydig cells. After PG withdrawal, these cells showed a rebound reverse. Reduced glutathione levels increased with PG administration while PG withdrawal increased malondialdehyde levels. Conclusion: PG administration affected testicular morphometry, gonadotrophic and sex hormones; however, there was a rebound reversal in all these parameters and a significant oxidative stress in PG withdrawal.

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Pregabalin activates ROMK1 channels via cAMP-dependent protein kinase and protein kinase C

Cited by 5 publications

References 49 publications

Potassium Channels in Epilepsy

Potassium Channels in Epilepsy

Homeostasis or channelopathy? Acquired cell type-specific ion channel changes in temporal lobe epilepsy and their antiepileptic potential

Pregabalin administration and withdrawal affect testicular structure and functions in rats

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