Dynamic up‐regulation of prodynorphin transcription in temporal lobe epilepsy

Pirker, Susanne; Gasser, Elisabeth; Czech, Thomas; Baumgartner, Christoph; Schuh, Elisabeth; Feucht, Martha; Novak, Klaus; Zimprich, Fritz; Sperk, Günther

doi:10.1002/hipo.20633

Cited by 21 publications

(16 citation statements)

References 19 publications

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“…In most animal models of temporal lobe epilepsy (TLE; comprising epilepsies arising cortical = lateral TLE and mTLE), cortical and hippocampal prodynorphin expression is reduced after an initial, short peak of over-expression (see Simonato and Romualdi, 1996;Schwarzer, 2009). This is in line with significantly increased prodynorphin mRNA in hippocampal granule cells of patients displaying seizures within the last 48 h before surgical removal of the hippocampus, compared with those with a longer seizure-free period (Pirker et al, 2009) accompanied by an overall reduction of dynorphin immunoreactivity in surgically removed tissue obtained from mTLE patients (de Lanerolle et al, 1997).…”

Section: Introductionmentioning

confidence: 87%

The G‐protein biased partial κ opioid receptor agonist 6′‐GNTI blocks hippocampal paroxysmal discharges without inducing aversion

Zangrandi

Burtscher

Mackay

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSEWith a prevalence of 1-2%, epilepsies belong to the most frequent neurological diseases worldwide. Although antiepileptic drugs are available since several decades, the incidence of patients that are refractory to medication is still over 30%. Antiepileptic effects of κ opioid receptor (κ receptor) agonists have been proposed since the 1980s. However, their clinical use was hampered by dysphoric side effects. Recently, G-protein biased κ receptor agonists were developed, suggesting reduced aversive effects. EXPERIMENTAL APPROACHWe investigated the effects of the κ receptor agonist U-50488H and the G-protein biased partial κ receptor agonist 6′-GNTI in models of acute seizures and drug-resistant temporal lobe epilepsy and in the conditioned place avoidance (CPA) test. Moreover, we performed slice electrophysiology to understand the functional mechanisms of 6′-GNTI. KEY RESULTSAs previously shown for U-50488H, 6′-GNTI markedly increased the threshold for pentylenetetrazole-induced seizures. All treated mice displayed reduced paroxysmal activity in response to U-50488H (20 mg·kg À1 ) or 6′-GNTI (10-30 nmoles) treatment in the mouse model of intra-hippocampal injection of kainic acid. Single cell recordings on hippocampal pyramidal cells revealed enhanced inhibitory signalling as potential mechanisms causing the reduction of paroxysmal activity. Effects of 6′-GNTI were blocked in both seizure models by the κ receptor antagonist 5′-GNTI. Moreover, 6′-GNTI did not induce CPA, a measure of aversive effects, while U-50488H did. CONCLUSIONS AND IMPLICATIONSOur data provide the proof of principle that anticonvulsant/antiseizure and aversive effects of κ receptor activation can be pharmacologically separated in vivo.

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Section: Introductionmentioning

confidence: 87%

The G‐protein biased partial κ opioid receptor agonist 6′‐GNTI blocks hippocampal paroxysmal discharges without inducing aversion

Zangrandi

Burtscher

Mackay

et al. 2016

British J Pharmacology

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“…Status epilepticus induced by intermittent stimulation of the perforant path also decreased the dynorphin-like immunoreactivity in the dentate gyrus and CA3 [118]. However, an up-regulation of prodynorphin transcription was found in human temporal lobe epilepsy [119]. The acute changes in the level of opioid peptides may contribute to increased excitation during induction of seizures, while the chronic changes may contribute directly to persistently increased excitability in the hippocampus and possibly other brain regions, too [112].…”

Section: Dynorphin and Enkephalinmentioning

confidence: 93%

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Dobolyi¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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Neuropeptides are signaling molecules participating in the modulation of synaptic transmission. Neuropeptides are stored in dense core synaptic vesicles, the release of which requires profound excitation. Only in the extracellular space, neuropeptides act on G-protein coupled receptors to exert a relatively slow action both pre-and postsynaptically. Consequently, neuropeptide modulators are ideal candidates to influence epileptic tissue overexcited during seizures. Indeed, a number of neuropeptides have been implicated in epilepsy and many of them are considered to have endogenous neuroprotective actions. Neuropeptides, present in the hippocampus, the most frequent focus of seizures in temporal lobe epilepsy, received the largest attention as potential anti-epileptic substances. Hippocampal neuropeptides, somatostatin, neuropeptide Y, galanin, dynorphin, enkephalin, substance P, cholecystokinin, vasoactive intestinal polypeptide, and some neuropeptides, which are also hormones such as ghrelin, angiotensins, corticotropin-releasing hormone, adrenocorticotropin, thyrotropin-releasing hormone, oxytocin and vasopressin involved in epilepsy are discussed in the review article. Oral application of neuropeptides as drugs is typically not efficient because of low bioavailability: rapid degradation and insufficient penetration through the blood-brain barrier. Recent progress in the development of non-peptide agonists and antagonists of neuropeptide receptors as well as gene therapeutic approaches leading to the local production of neuropeptides within the central nervous system will also be discussed.

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“…Administration of a KOR agonist prevents drug-induced seizures in mice, possibly indicating the presence of a regulatory dynorphin ton in the HIPP (Solbrig et al 2006). In the clinical population, prodynorphin transcription is upregulated in patients with temporal lobe epilepsy (Pirker et al 2009). In line with this information, researchers have speculated that KOR activation may be a potential treatment for seizures, treating abhorrent dynorphin release/KOR activation in the hippocampus (Bortolato & Solbrig 2007).…”

Section: Circuitrymentioning

confidence: 99%

Kappa opioid receptor signaling in the brain: Circuitry and implications for treatment

Crowley

Kash

2015

Progress in Neuro-Psychopharmacology and Biological Psychiatry

103

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Kappa opioid receptors (KORs) in the central nervous system have been known to be important regulators of a variety of psychiatry illnesses, including anxiety and addiction, but their precise involvement in these behaviors is complex and has yet to be fully elucidated. Here, we briefly review the pharmacology of KORs in the brain, including KOR's involvement in anxiety, depression, and alcohol addiction. We also review the known neuronal circuitry impacted by KOR signaling, and interactions with corticotrophin-releasing factor (CRF), another key peptide in anxiety-related illnesses, as well as the role of glucocorticoids. We suggest that KORs are a promising therapeutic target for a host of neuropsychiatric conditions.

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Dynamic up‐regulation of prodynorphin transcription in temporal lobe epilepsy

Cited by 21 publications

References 19 publications

The G‐protein biased partial κ opioid receptor agonist 6′‐GNTI blocks hippocampal paroxysmal discharges without inducing aversion

The G‐protein biased partial κ opioid receptor agonist 6′‐GNTI blocks hippocampal paroxysmal discharges without inducing aversion

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Kappa opioid receptor signaling in the brain: Circuitry and implications for treatment

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