Decreased CREB levels suppress epilepsy

Zhu, Xinjian; Han, Xiao; Blendy, Julie A.; Porter, Brenda E.

doi:10.1016/j.nbd.2011.08.009

Cited by 79 publications

(80 citation statements)

References 33 publications

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“…Holst et al [34] reported that the GHSR ligand-independently signals through the CREB pathway. CREB phosphorylation has been found to be increased in rodent epilepsy models, and a reduction in CREB levels led to the suppression of seizures [47]. Activation of the G q pathway inherently results in inositol phosphate-3 (IP 3 )-dependent Ca 2+ release from intracellular Ca 2+ stores, leading to increased cytosolic Ca 2+ concentrations, which is synonymous with increased membrane excitability, as well as triggering and maintaining seizures [48][49][50].…”

Section: Possible Downstream Molecular Pathways For Ghsr-mediated Antmentioning

confidence: 99%

Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

et al. 2012

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Ghrelin is a pleiotropic neuropeptide that has been recently implicated in epilepsy. Animal studies performed to date indicate that ghrelin has anticonvulsant properties; however, its mechanism of anticonvulsant action is unknown. Here we show that the anticonvulsant effects of ghrelin are mediated via the growth hormone secretagogue receptor (GHSR). To our surprise, however, we found that the GHSR knockout mice had a higher seizure threshold than their wild-type littermates when treated with pilocarpine. Using both in vivo and in vitro models, we further discovered that inverse agonism and desensitization/internalization of the GHSR attenuate limbic seizures in rats and epileptiform activity in hippocampal slices. This constitutes a novel mechanism of anticonvulsant action, whereby an endogenous agonist reduces the activity of a constitutively active receptor.

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Section: Possible Downstream Molecular Pathways For Ghsr-mediated Antmentioning

confidence: 99%

Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

et al. 2012

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“…The increased abundance of GABA A subunit α1 after Hip-LFS might be associated with the decrease in CREB expression. Recently, studies have suggested that altering CREB activity might modify epileptogenensis [25]. Our experiments suggested that inhibiting CREB activity might provide a therapeutic strategy for pharmacoresistant epilepsy.…”

Section: Discussionmentioning

confidence: 58%

“…/increased expression of p-CREB was observed in epilepsy rats and in the seizure onset region of humans with medically intractable epilepsy [25,26]. Epileptic brain regions prone to seizures showed persistent activation of CREB [24].…”

Section: Discussionmentioning

confidence: 99%

“…Simultaneously, the degree and duration of seizures were decreased remarkably, as well as the amygdala EEG frequency. Mice with decreased CREB levels have a ~50% reduction in spontaneous seizures following pilocarpine-induced status epilepticus and require more stimulation to electrically kindle [25]. The gene encoding GABA A subunit α1 contains the cAMP response element in its promoter [27], and surface expression of GABA A receptors is transcriptionally controlled by a system of interactions involving CREB [29].…”

Section: Discussionmentioning

confidence: 99%

“…Epileptic brain regions prone to seizure activity exhibit persistent activation of CREB [24], and increased expression of phosphorylated CREB (p-CREB) has been observed in epileptic rats and patients with medically intractable epilepsy [25,26]. Mice with decreased CREB levels exhibit an approximately 50% reduction in spontaneous seizures following pilocarpineinduced status epilepticus and require greater stimulation to electrically kindle seizures [25].…”

mentioning

confidence: 99%

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Hippocampal Low-Frequency Stimulation Decreased cAMP Response Element-Binding Protein and Increased GABAA Receptor Subunit α1 in Amygdala-Kindled Pharmacoresistant Epileptic Rats

Wu¹,

Wang²,

Zhou³

et al. 2017

Neuropsychiatry

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Aim: To observe the changes in cAMP response element-binding protein (CREB) and GABA A receptor subunit α1 in amygdala-kindled pharmacoresistant epileptic rats subjected to hippocampal low-frequency stimulation (Hip-LFS). Methods:A total of sixteen pharmacoresistant epileptic rats were selected from fifty rats with amygdalakindled epilepsy by testing their seizure response to phenytoin (PHT) and phenobarbital (PB). The pharmacoresistant epileptic rats were assigned to a pharmacoresistant control group (PRC group) or a pharmacoresistant stimulation group (PRS group), each of which included 8 rats. The same number of pharmacosensitive epileptic rats was assigned to a pharmacosensitive control group (PSC group, 8 rats). A normal rat control (NRC) group of 8 rats was also used in the study. A stimulation electrode was implanted in the hippocampus of each rat from each of the four groups. Hip-LFS was administered to the PRS group twice per day for 2 weeks. The other three groups only received hippocampal sham stimulation. Following 2 weeks of Hip-LFS, seizure degree and amygdala EEG were recorded. The levels of CREB protein and GABA A receptor subunit α1 in the hippocampal tissues were measured by a Western blot. Results:The CREB level increased remarkably and the GABA A receptor subunit α1 level decreased in the pharmacoresistant epileptic rats compared with the control. Following two weeks of Hip-LFS, stimulation-induced seizures and amygdala EEG were inhibited significantly. The CREB and p-CREB level decreased significantly in the PRS group compared with the PRC group. However, the GABA A α1 subunit level in the PRS group increased dramatically compared with that in the PRC group. Conclusions:Hip-LFS might increase the expression of the GABA A α1 subunit and decrease the level of CREB. The Hip-LFS-induced increase in the level of the GABA A receptor α1 subunit might be associated with the decreases in CREB and p-CREB in the treatment of amygdala-kindled pharmacoresistant epileptic rats.

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Physical exercise alters the activation of downstream proteins related to BDNF‐TrkB signaling in male Wistar rats with epilepsy

Almeida

Silva

Lopim

et al. 2017

J of Neuroscience Research

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There are a considerable number of studies concerning the behavioral effects of physical exercise on the epileptic brain; however, the intracellular signaling mechanisms involved remain unclear. We investigated the effects of aerobic exercise on hippocampal levels of brain-derived neurotrophic factor (BDNF), expression of its receptor tropomyosin receptor kinase B (TrkB), and activation of intracellular proteins related to BDNF-TrkB signaling in male Wistar rats with pilocarpine-induced epilepsy. Thirty days after the first spontaneous seizure, rats from the exercise group undertook a 30-day physical exercise program on the treadmill. Thereafter, BDNF levels, expression of TrkB, and activation of intracellular proteins were quantified by enzyme-linked immunosorbent assay, Western blotting, and multiplex assay, respectively. Statistical analyses were conducted using nonparametric tests. Rats with epilepsy presented decreased BDNF levels compared with control rats. BDNF levels increased significantly in the exercise group compared with the epileptic and control groups. Expression of full-length and truncated TrkB was increased in rats with epilepsy, and physical exercise restored its expression to control levels. RAC-alpha serine/threonine-protein kinase, mammalian target of rapamycin, and extracellular signal-regulated kinase activation were reduced in rats with epilepsy, and exercise increased activation compared with control and epilepsy groups. Increased cAMP response element binding protein activation was observed in the exercise group compared with the epilepsy group. Our findings indicate that the beneficial effects of exercise in the epileptic brain can be in part related to alterations in the activation of proteins related to the BDNF-TrkB signaling pathway.

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Decreased CREB levels suppress epilepsy

Cited by 79 publications

References 33 publications

Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

Hippocampal Low-Frequency Stimulation Decreased cAMP Response Element-Binding Protein and Increased GABAA Receptor Subunit α1 in Amygdala-Kindled Pharmacoresistant Epileptic Rats

Physical exercise alters the activation of downstream proteins related to BDNF‐TrkB signaling in male Wistar rats with epilepsy

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