Receptors and channels possibly mediating the effects of phytocannabinoids on seizures and epilepsy

Epilepsy contributes to approximately 1% of the global disease burden. By affecting especially young children as well as older persons of all social and racial variety, epilepsy is a present disorder worldwide. Currently, only 65% of epileptic patients can be successfully treated with antiepileptic drugs. For this reason, alternative medicine receives more attention. Cannabis has been cultivated for over 6000 years to treat pain and insomnia and used since the 19th century to suppress epileptic seizures. The two best described phytocannabinoids, (−)-trans-Δ9- tetrahydrocannabinol (THC) and cannabidiol (CBD) are claimed to have positive effects on different neurological as well as neurodegenerative diseases, including epilepsy. There are different cannabinoids which act through different types of receptors and channels, including the cannabinoid receptor 1 and 2 (CB1, CB2), G protein-coupled receptor 55 (GPR55) and 18 (GPR18), opioid receptor μ and δ, transient receptor potential vanilloid type 1 (TRPV1) and 2 (TRPV2), type A γ-aminobutyric acid receptor (GABAAR) and voltage-gated sodium channels (VGSC). The mechanisms and importance of the interaction between phytocannabinoids and their different sites of action regarding epileptic seizures and their clinical value are described in this review

Uso di agonisti e antagonisti dei recettori per i growth hormone secretagogues per la prevenzione e il trattamento di convulsioni ed epilessia

L\u2019invenzione riguarda l\u2019uso di agonisti e antagonisti dei recettori per i Growth Hormone Secretagogues utili nella prevenzione e nel trattamento di convulsioni, ad esempio acute, ricorrenti, a grappolo, associate o non associate ad epilessia, e di stati epilettici, come ad esempio le crisi motorie associate ad epilessia del lobo temporale. Tali composti possono essere somministrati da soli o in associazione con uno o pi\uf9 composti anticonvulsivanti o antiepilettici per la prevenzione e il trattamento delle convulsioni e dell\u2019epilessia

Neurosteroids and focal epileptic disorders

Neurosteroids are a family of compounds that are synthesized in principal excitatory neurons and glial cells, and derive from the transformation of cholesterol into pregnenolone. The most studied neurosteroids—allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC)—are known to modulate GABAA receptor-mediated transmission, thus playing a role in controlling neuronal network excitability. Given the role of GABAA signaling in epileptic disorders, neurosteroids have profound eects on seizure generation and play a role in the development of chronic epileptic conditions (i.e., epileptogenesis). We review here studies showing the eects induced by neurosteroids on epileptiform synchronization in in vitro brain slices, on epileptic activity in in vivo models, i.e., in animals that were made epileptic with chemoconvulsant treatment, and in epileptic patients. These studies reveal that neurosteroids can modulate ictogenesis and the occurrence of pathological network activity such as interictal spikes and high-frequency oscillations (80–500 Hz). Moreover, they can delay the onset of spontaneous seizures in animal models of mesial temporal lobe epilepsy. Overall, this evidence suggests that neurosteroids represent a new target for the treatment of focal epileptic disorders

Lacosamide: a new approach to target voltage-gated sodium currents in epileptic disorders

The mechanism of action of several antiepileptic drugs (AEDs) rests on their ability tomodulate the activity of voltage-gated sodium currents that are responsible for fast action potentialgeneration. Recent data indicate that lacosamide - a compound with analgesic and anticonvulsanteffects in animal models - shares a similar mechanism. When compared with other AEDs, lacosamidehas the unique ability to interact with sodium channel slow inactivation without affecting fastinactivation. This article reviews these findings and discusses their relevance within the context ofneuronal activity seen during epileptiform discharges generated by limbic neuronal networks in thepresence of chemical convulsants. These seizure-like events are characterized by sustained dischargesof sodium-dependent action potentials supported by robust depolarizations thus providingsynchronization within neuronal networks. Generally, AEDs such as phenytoin, carbamazepine andlamotrigine block sodium channels when activated. By contrasts, lacosamide facilitates slowinactivation of sodium channels both in term of kinetics and voltage-dependency. This effect may berelatively selective for repeatedly depolarized neurons such as those participating in seizure activity inwhich the persistence of sodium currents is more pronounced and promotes neuronal excitation. Theclinical effectiveness of lacosamide has been demonstrated in randomized placebo-controlled doubleblindparallel-group, adjunctive-therapy trials in patients with refractory partial seizures. Furtherstudies should determine whether lacosamide effects in animal models and in clinical settings are fullyexplained by its selective action on sodium current slow inactivation or whether other effects (e.g.,interactions with the collapsin-response mediator protein 2) play a contributory role

Neuroactive Peptides as Putative Mediators of Antiepileptic Ketogenic Diets

Various ketogenic diet (KD) therapies, including classic KD, medium chain triglyceride administration, low glycemic index treatment, and a modified Atkins diet, have been suggested as useful in patients affected by pharmacoresistant epilepsy. A common goal of these approaches is to achieve an adequate decrease in the plasma glucose level combined with ketogenesis, in order to mimic the metabolic state of fasting. Although several metabolic hypotheses have been advanced to explain the anticonvulsant effect of KDs, including changes in the plasma levels of ketone bodies, polyunsaturated fatty acids, and brain pH, direct modulation of neurotransmitter release, especially purinergic (i.e., adenosine) and γ-aminobutyric acidergic neurotransmission, was also postulated. Neuropeptides and peptide hormones are potent modulators of synaptic activity, and their levels are regulated by metabolic states. This is the case for neuroactive peptides such as neuropeptide Y, galanin, cholecystokinin and peptide hormones such as leptin, adiponectin, and growth hormone-releasing peptides (GHRPs). In particular, the GHRP ghrelin and its related peptide des-acyl ghrelin are well-known controllers of energy homeostasis, food intake, and lipid metabolism. Notably, ghrelin has also been shown to regulate the neuronal excitability and epileptic activation of neuronal networks. Several lines of evidence suggest that GHRPs are upregulated in response to starvation and, particularly, in patients affected by anorexia and cachexia, all conditions in which also ketone bodies are upregulated. Moreover, starvation and anorexia nervosa are accompanied by changes in other peptide hormones such as adiponectin, which has received less attention. Adipocytokines such as adiponectin have also been involved in modulating epileptic activity. Thus, neuroactive peptides whose plasma levels and activity change in the presence of ketogenesis might be potential candidates for elucidating the neurohormonal mechanisms involved in the beneficial effects of KDs. In this review, we summarize the current evidence for altered regulation of the synthesis of neuropeptides and peripheral hormones in response to KDs, and we try to define a possible role for specific neuroactive peptides in mediating the antiepileptic properties of diet-induced ketogenesis

Repeated 6-Hz Corneal Stimulation Progressively Increases FosB/\u394FosB Levels in the Lateral Amygdala and Induces Seizure Generalization to the Hippocampus

Exposure to repetitive seizures is known to promote convulsions which depend on specific patterns of network activity. We aimed at evaluating the changes in seizure phenotype and neuronal network activation caused by a modified 6-Hz corneal stimulation model of psychomotor seizures. Mice received up to 4 sessions of 6-Hz corneal stimulation with fixed current amplitude of 32 mA and inter-stimulation interval of 72 h. Video-electroencephalography showed that evoked seizures were characterized by a motor component and a non-motor component. Seizures always appeared in frontal cortex, but only at the fourth stimulation they involved the hippocampus, suggesting the establishment of an epileptogenic process. Duration of seizure non-motor component progressively decreased after the second session, whereas convulsive seizures remained unchanged. In addition, a more severe seizure phenotype, consisting of tonic-clonic generalized convulsions, was predominant after the second session. Immunohistochemistry and double immunofluorescence experiments revealed a significant increase in neuronal activity occurring in the lateral amygdala after the fourth session, most likely due to activity of principal cells. These findings indicate a predominant role of amygdala in promoting progressively more severe convulsions as well as the late recruitment of the hippocampus in the seizure spread. We propose that the repeated 6-Hz corneal stimulation model may be used to investigate some mechanisms of epileptogenesis and to test putative antiepileptogenic drugs

Seizure progression is slowed by enhancing neurosteroid availability in the brain of epileptic rats

Trilostane is a 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase inhibitor able to produce a manyfold increase in brain levels of various neurosteroids, including allopregnanolone. We previously found that treatment with trilostane can slow down epileptogenesis in the kainic acid (KA) model of temporal lobe epilepsy. It is unknown whether trilostane may have a similar effect on the progression of epilepsy severity, as observed in KA-treated rats. Consequently, we investigated the effects of trilostane (50 mg/kg/day, 1 week) in epileptic rats, given 64 days after KA administration. Seizures were monitored by video-electrocorticographic recordings before and during the treatment with trilostane or vehicle (sesame oil), and neurosteroid levels were measured in serum and cerebral tissue using liquid chromatography–electrospray tandem mass spectrometry after treatment. Pregnenolone sulfate, pregnenolone, progesterone, 5α-dihydroprogesterone, and allopregnanolone peripheral levels were massively increased by trilostane. With the only exception of hippocampal pregnenolone sulfate, the other neurosteroids augmented in both the neocortex and hippocampus. Only pregnanolone levels were not upregulated by trilostane. As expected, a significant increase in the seizure occurrence was observed in rats receiving the vehicle, but not in the trilostane group. This suggests that the increased availability of neurosteroids produced a disease-modifying effect in the brain of epileptic rats

Antiseizure effects of cannabidiol leading to increased peroxisome proliferator-activated receptor gamma levels in the hippocampal CA3 subfield of epileptic rats

We evaluated the effects of cannabidiol (CBD) on seizures and peroxisome proliferator activated receptor gamma (PPAR) levels in an animal model of temporal lobe epilepsy (TLE). Adult male Sprague-Dawley rats were continuously monitored by video-electrocorticography up to 10 weeks after an intraperitoneal kainic acid (15 mg/kg) injection. Sixty-seven days after the induction of status epilepticus and the appearance of spontaneous recurrent seizures in all rats, CBD was dissolved in medium-chain triglyceride (MCT) oil and administered subcutaneously at 120 mg/kg (n = 10) or 12 mg/kg (n = 10), twice a day for three days. Similarly, the vehicle was administered to ten epileptic rats. Brain levels of PPAR immunoreactivity were compared to those of six healthy controls. CBD at 120 mg/kg abolished the seizures in 50% of rats (p = 0.033 vs. pretreatment, Fisher’s exact test) and reduced total seizure duration (p < 0.05, Tukey Test) and occurrence (p < 0.05). PPAR levels increased with CBD in the hippocampal CA1 subfield and subiculum (p < 0.05 vs. controls, Holm–Šidák test), but only the highest dose increased the immunoreactivity in the hippocampal CA3 subfield (p < 0.001), perirhinal cortex, and amygdala (p < 0.05). Overall, these results suggest that the antiseizure effects of CBD are associated with upregulation of PPAR in the hippocampal CA3 region

Diminished presynaptic GABA(B) receptor function in the neocortex of a genetic model of absence epilepsy

Changes in GABA(B) receptor subunit expression have been recently reported in the neocortexof epileptic WAG/Rij rats that are genetically prone to experience absence seizures.These alterations may lead to hyperexcitability by downregulating the function of presynapticGABA(B) receptors in neocortical networks as suggested by a reduction in paired-pulsedepression. Here, we tested further this hypothesis by analyzing the effects induced by theGABA(B) receptor agonist baclofen (0.1-10 μM) on the inhibitory events recorded in vitro fromneocortical slices obtained from epileptic (>180 day-old) WAG/Rij and age-matched, nonepilepticcontrol (NEC) rats. We found that higher doses of baclofen were required todepress pharmacologically isolated, stimulus-induced IPSPs generated by WAG/Rij neuronsas compared to NEC. We also obtained similar evidence by comparing the effects ofbaclofen on the rate of occurrence of synchronous GABAergic events recorded by WAG/Rijand NEC neocortical slices treated with 4-aminopyridine+glutamatergic receptor antagonists.In conclusion, these data highlight a decreased function of presynaptic GABA(B) receptorsin the WAG/Rij rat neocortex. We propose that this alteration may contribute toneocortical hyperexcitability and thus to absence seizures

The pilocarpine model of temporal lobe epilepsy

Understanding the pathophysiogenesis of temporal lobe epilepsy (TLE) largely rests on the use of modelsof status epilepticus (SE), as in the case of the pilocarpine model. The main features of TLE are: (i) epilepticfoci in the limbic system; (ii) an “initial precipitating injury”; (iii) the so-called “latent period”; and (iv)the presence of hippocampal sclerosis leading to reorganization of neuronal networks. Many of thesecharacteristics can be reproduced in rodents by systemic injection of pilocarpine; in this animal model, SEis followed by a latent period and later by the appearance of spontaneous recurrent seizures (SRSs). Theseprocesses are, however, influenced by experimental conditions such as rodent species, strain, gender, age,doses and routes of pilocarpine administration, as well as combinations with other drugs administeredbefore and/or after SE. In the attempt to limit these sources of variability,we evaluated themethodologicalprocedures used by several investigators in the pilocarpine model; in particular, we have focused on thebehavioural, electrophysiological and histopathological findings obtained with different protocols. Weaddressed the various experimental approaches published to date, by comparing mortality rates, onset ofSRSs, neuronal damage, and network reorganization. Based on the evidence reviewed here, we proposethat the pilocarpine model can be a valuable tool to investigate the mechanisms involved in TLE, and evenmore so when standardized to reduce mortality at the time of pilocarpine injection, differences in latentperiod duration, variability in the lesion extent, and SRS frequency