“…This is in agreement with the findings of Luchowska et al (2001), that showed an anti-epileptiform effect against maximal electroshock-induced seizures in mice by antagonizing the β-adrenergic receptor. Additionally, β-adrenergic receptors have been implicated in audiogenic seizures and pindolol, a potent β-antagonist, was found to attenuate audiogenic seizures in DBA/2 mice (Lints and Nyquist-Battie, 1985). Nevertheless, in this work we show that the percentage of scn1a mutant larvae with decreased epileptiform activity was not significantly changed.…”
Dravet syndrome (DS) is a genetic encephalopathy that is characterized by severe seizures and prominent co-morbidities (e.g., physical, intellectual disabilities). More than 85% of the DS patients carry an SCN1A mutation (sodium channel, voltage gated, type I alpha subunit). Although numerous anti-epileptic drugs have entered the market since 1990, these drugs often fail to adequately control seizures in DS patients. Nonetheless, current clinical data shows significant seizure reduction in DS patients treated with the serotonergic (5-hydroxytryptamine, 5-HT) drug fenfluramine (FA). Recent preclinical research confirmed the anti-epileptiform activity of FA in homozygous scn1a mutant zebrafish larvae that mimic DS well. Here we explored the anti-epileptiform mechanisms of FA by investigating whether selective agonists/antagonists of specific receptor subtypes were able to counteract the FA-induced inhibition of seizures and abnormal brain discharges observed in the scn1a mutants. We show that antagonists of 5-HT1D and 5-HT2C receptor subtypes were able to do so (LY 310762 and SB 242084, respectively), but notably, a 5-HT2A-antagonist (ketanserin) was not. In addition, exploring further the mechanism of action of FA beyond its serotonergic profile, we found that the anti-epileptiform brain activity of FA was significantly abolished when it was administered in combination with a σ1-agonist (PRE 084). Our study therefore provides the first evidence of an involvement of the σ1 receptor in the mechanism of FA. We further show that the level of some neurotransmitters [i.e., dopamine and noradrenaline (NAD)] in head homogenates was altered after FA treatment, whereas γ-aminobutyric acid (GABA) and glutamate levels were not. Of interest, NAD-decreasing drugs have been employed successfully in the treatment of neurological diseases; including epilepsy and this effect could contribute to the therapeutic effect of the compound. In summary, we hypothesize that the anti-epileptiform activity of FA not only originates from its 5-HT1D- and 5-HT2C-agonism, but likely also from its ability to block σ1 receptors. These findings will help in better understanding the pharmacological profile of compounds that is critical for their applicability in the treatment of DS and possibly also other drug-resistant epilepsies.
“…This is in agreement with the findings of Luchowska et al (2001), that showed an anti-epileptiform effect against maximal electroshock-induced seizures in mice by antagonizing the β-adrenergic receptor. Additionally, β-adrenergic receptors have been implicated in audiogenic seizures and pindolol, a potent β-antagonist, was found to attenuate audiogenic seizures in DBA/2 mice (Lints and Nyquist-Battie, 1985). Nevertheless, in this work we show that the percentage of scn1a mutant larvae with decreased epileptiform activity was not significantly changed.…”
Dravet syndrome (DS) is a genetic encephalopathy that is characterized by severe seizures and prominent co-morbidities (e.g., physical, intellectual disabilities). More than 85% of the DS patients carry an SCN1A mutation (sodium channel, voltage gated, type I alpha subunit). Although numerous anti-epileptic drugs have entered the market since 1990, these drugs often fail to adequately control seizures in DS patients. Nonetheless, current clinical data shows significant seizure reduction in DS patients treated with the serotonergic (5-hydroxytryptamine, 5-HT) drug fenfluramine (FA). Recent preclinical research confirmed the anti-epileptiform activity of FA in homozygous scn1a mutant zebrafish larvae that mimic DS well. Here we explored the anti-epileptiform mechanisms of FA by investigating whether selective agonists/antagonists of specific receptor subtypes were able to counteract the FA-induced inhibition of seizures and abnormal brain discharges observed in the scn1a mutants. We show that antagonists of 5-HT1D and 5-HT2C receptor subtypes were able to do so (LY 310762 and SB 242084, respectively), but notably, a 5-HT2A-antagonist (ketanserin) was not. In addition, exploring further the mechanism of action of FA beyond its serotonergic profile, we found that the anti-epileptiform brain activity of FA was significantly abolished when it was administered in combination with a σ1-agonist (PRE 084). Our study therefore provides the first evidence of an involvement of the σ1 receptor in the mechanism of FA. We further show that the level of some neurotransmitters [i.e., dopamine and noradrenaline (NAD)] in head homogenates was altered after FA treatment, whereas γ-aminobutyric acid (GABA) and glutamate levels were not. Of interest, NAD-decreasing drugs have been employed successfully in the treatment of neurological diseases; including epilepsy and this effect could contribute to the therapeutic effect of the compound. In summary, we hypothesize that the anti-epileptiform activity of FA not only originates from its 5-HT1D- and 5-HT2C-agonism, but likely also from its ability to block σ1 receptors. These findings will help in better understanding the pharmacological profile of compounds that is critical for their applicability in the treatment of DS and possibly also other drug-resistant epilepsies.
“…Although propranolol and other p blockers are not routinely employed as anticonvulsant agents, a number of studies have shown that p blockers do possess anticonvulsant action (Papanicolou et al, 1982;Lints and Nyquist-Battie, 1985). We established that the intracerebroventricular and/or i.v.…”
Section: Discussionmentioning
confidence: 74%
“…Timolol blocked the proconvulsant activity of 2-fluoronorepinephrine and 1-isoproterenol in in vitro hippocampal slice preparations superfused with penicillin and elevated levels of potassium (Mueller and Dunwiddie, 1983). The anticonvulsant action of p-blocking agents may be due to a membranestabilizing action, although other mechanisms have been proposed (Lints and Nyquist-Battie, 1985).…”
Section: Discussionmentioning
confidence: 97%
“…administration of timolol suppressed seizure activity elicited by PTZ administered to anesthetized cats (StauRer et al, 1987). The anticonvulsant action of p-blocking agents may be due to a membranestabilizing action, although other mechanisms have been proposed (Lints and Nyquist-Battie, 1985). Timolol blocked the proconvulsant activity of 2-fluoronorepinephrine and 1-isoproterenol in in vitro hippocampal slice preparations superfused with penicillin and elevated levels of potassium (Mueller and Dunwiddie, 1983).…”
Intravenous (i.v.) access for administration of antiepileptic drugs can be time-consuming and difficult in an infant during a seizure. This study examined the intraosseous (i.o.) route as an alternative means of vascular access for drug administration in an animal-seizure model. Domestic swine (13-20 kg) were anesthetized with ketamine (20 mg/kg i.m.) and alpha-chloralose (80 mg/kg i.v.) and given gallamine (4 mg/kg i.v.) to prevent muscle fasciculations. Tracheosotomies were performed and the animals were ventilated with a Harvard respirator. The left femoral vein was cannulated and pentylenetetrazol (PTZ) (100 mg/kg) was given to elicit epileptogenic activity. Sixty seconds after onset of epileptogenic activity, the animals received saline or diazepam (DZP) (0.1 mg/kg) or propranolol (2.5 mg/kg) i.v. or via the i.o. route (18-gauge spinal needle placed in the right proximal tibia). Both DZP and propranolol were effective in suppressing epileptogenic activity via the i.v. or i.o. routes. Thus, the i.o. route is a rapid and effective alternative route for the administration of antiepileptic drugs when an i.v. route cannot be readily established.
“…When comparing migraine prevalence, this is significantly higher in the population of patients with epilepsy. Comments : From the home institution of our Editor‐in Chief I contribute a nice review of Migraine and Epilepsy should you by chance have missed it. 1 The interrelationship of these two disorders couldn't be more evident than from (1) hemiplegic migraine sufferers when different mutations produce migraine, epilepsy or both and (2) a child with epilepsy (not masquerading as prolonged QT syndrome) responding to a beta‐blocker (anesthetic‐like effects) 2 and any age migraineur responding to one or another anti‐epilepsy drug, which we of course may refer to as a neuronal stabilizing agent. …”
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