Involvement of PPAR receptors in the anticonvulsant effects of a cannabinoid agonist, WIN 55,212-2 (original) (raw)
Related papers
Epilepsy Research, 2008
Cannabinoid compounds are anticonvulsant since they have inhibitory effects at micromolar doses, which are mediated by activated receptors coupling to G i/o proteins. Surprisingly, both the analgesic and anticonvulsant effects of opioids are enhanced by ultra-low doses (nanomolar to picomolar) of the opioid antagonist naltrexone and as opioid and cannabinoid systems interact, it has been shown that ultra-low dose naltrexone also enhances cannabinoidinduced antinociception. Thus, concerning the seizure modulating properties of both classes of receptors this study investigated whether the ultra-low dose opioid antagonist naltrexone influences cannabinoid anticonvulsant effects. The clonic seizure threshold was tested in separate groups of male NMRI mice following injection of vehicle, the cannabinoid selective agonist arachidonyl-2-chloroethylamide (ACEA) and ultra-low doses of the opioid receptor antagonist naltrexone and a combination of ACEA and naltrexone doses in a model of clonic seizure induced by pentylenetetrazole (PTZ). Systemic injection of ultra-low doses of naltrexone (1 pg/kg to 1 ng/kg, i.p.) significantly potentiated the anticonvulsant effect of ACEA (1 mg/kg, i.p.). Moreover, the very low dose of naltrexone (500 pg/kg) unmasked a strong anticonvulsant effect for very low doses of ACEA (10 and 100 g/kg). A similar potentiation by naltrexone (500 pg/kg) of anticonvulsant effects of non-effective dose of ACEA (1 mg/kg) was also observed in the generalized tonic-clonic model of seizure. The present data indicate that the interaction between opioid and cannabinoid systems extends to ultra-low dose levels and ultra-low doses of opioid receptor antagonist in conjunction with very low doses of cannabinoids may provide a potent strategy to modulate seizure susceptibility.
Epilepsy Research, 2013
Cannabinoids and drugs that increase endocannabinoid levels inhibit neuronal excitability and restrain epileptic seizures through CB1 receptor activation. Nevertheless, the results have not been entirely consistent, since pro-convulsant effects have also been reported. The present study aimed to further investigate the effects of cannabinoid-related compounds on seizures induced by pentylenetetrazole (PTZ) in rats. Video-EEG recordings were used to determine both electrographic and behavioral thresholds to ictal activity. The animals received injections of WIN-55,212-2 (0.3-3 mg/kg, non-selective) or ACEA (1-4 mg/kg, CB1-selective), two synthetic cannabinoids, or URB-597 (0.3-3 mg/kg), an anandamide-hydrolysis inhibitor (FAAH enzyme inhibitor), followed by PTZ. Both WIN-55,212-2 (1 mg/kg) and ACEA (1-4 mg/kg) reduced the threshold for myoclonic seizures and enhanced epileptiform EEG activity, typical pro-convulsive effects. On the contrary, URB-597 (1 mg/kg) had an anti-convulsive effect, as it increased the threshold for the occurrence of minimal seizures and reduced EEG epileptiform activity. None of the drugs tested altered the tonic-clonic maximal seizure threshold. These data suggest that the effects of CB1 signaling upon seizure activity may depend on how this receptor is activated. Contrary to direct agonists, drugs that increase anandamide levels seem to promote an optimal tonus and represent a promising strategy for treating myoclonic seizures.
Journal of Neural Transmission, 2014
The aim of this study was to characterize the influence of WIN 55,212-2 (WIN-a non-selective cannabinoid CB 1 and CB 2 receptor agonist) on the anticonvulsant effects of various classical antiepileptic drugs (clobazam, clonazepam, phenobarbital and valproate) in the mouse 6 Hz-induced psychomotor seizure model. Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via ocular electrodes. Drug-related adverse effects were ascertained by use of the chimney test (evaluating motor performance), step-through passive avoidance task (assessing learning) and grip-strength test (evaluating skeletal muscular strength). Total brain concentrations of antiepileptic drugs were measured by fluorescence polarization immunoassay to ascertain any pharmacokinetic contribution to the observed antiseizure effect. Results indicate that WIN (5 mg/kg, administered intraperitoneally) significantly enhanced the anticonvulsant action of clonazepam (P \ 0.001), phenobarbital (P \ 0.05) and valproate (P \ 0.05), but not that of clobazam in the mouse 6 Hz model. Moreover, WIN (2.5 mg/ kg) significantly potentiated the anticonvulsant action of clonazepam (P \ 0.01), but not that of clobazam, phenobarbital or valproate in the 6 Hz test in mice. None of the investigated combinations of WIN with antiepileptic drugs was associated with any concurrent adverse effects with regard to motor performance, learning or muscular strength. Pharmacokinetic experiments revealed that WIN had no impact on total brain concentrations of antiepileptic drugs in mice. These preclinical data would suggest that WIN in combination with clonazepam, phenobarbital and valproate is associated with beneficial anticonvulsant pharmacodynamic interactions in the mouse 6 Hz-induced psychomotor seizure test. Keywords 6 Hz psychomotor seizure model Á Antiepileptic drugs Á Cannabinoids Á Drug interactions Á WIN 55,212-2 Abbreviations MES Maximal electroshock-induced seizures PTZ Pentylenetetrazole-induced seizures WIN WIN 55,212-2
Neuropharmacology, 2007
Several lines of evidence suggest that cannabinoid compounds are anticonvulsant since they have inhibitory effects at micromolar doses, which are mediated by activated receptors coupling to G i/o proteins. Surprisingly, both the analgesic and anticonvulsant effects of opioids are enhanced by ultra-low doses (nanomolar to picomolar) of the opioid antagonist naltrexone and as opioid and cannabinoid systems interact, it has been shown that ultra-low dose naltrexone also enhances cannabinoid-induced antinociception. However, regarding the seizure modulating properties of both classes of receptors this study investigated whether ultra-low dose cannabinoid antagonist AM251 influences cannabinoid anticonvulsant effects. The clonic seizure threshold (CST) was tested in separate groups of male NMRI mice following injection of vehicle, the cannabinoid selective agonist arachidonyl-2-chloroethylamide (ACEA) and ultra-low doses of the cannabinoid CB 1 antagonist AM251 and a combination of ACEA and AM251 doses in a model of clonic seizure induced by pentylenetetrazole (PTZ). Systemic administration of ultra-low doses of AM251 (10 fg/kge100 ng/kg) significantly potentiated the anticonvulsant effect of ACEA at 0.5 and 1 mg/kg. Moreover, inhibition of cannabinoid induced excitatory signaling by AM251 (100 pg/kg) unmasked a strong anticonvulsant effect for very low doses of ACEA (100 ng/kge100 mg/kg), suggesting that a presumed inhibitory component of cannabinoid receptor signaling can exert strong seizureprotective effects even at very low levels of cannabinoid receptor activation. A similar potentiation by AM251 (100 pg/kg and 1 ng/kg) of anticonvulsant effects of non-effective dose of ACEA (0.5 and 1 mg/kg) was also observed in the generalized toniceclonic model of seizure. The present data suggest that ultra-low doses of cannabinoid receptor antagonists may provide a potent strategy to modulate seizure susceptibility, especially in conjunction with very low doses of cannabinoids.
Assessing the role of serotonergic receptors in cannabidiol's anticonvulsant efficacy
Epilepsy & Behavior, 2017
Cannabidiol (CBD) is a phytocannabinoid that has demonstrated anticonvulsant efficacy in several animal models of seizure. The current experiment validated CBD's anticonvulsant effect using the acute pentylenetetrazol (PTZ) model. Furthermore, it tested whether CBD reduces seizure activity by interacting with either the serotonergic 5HT1A or 5HT2A receptor. 120 male adolescent Wistar-Kyoto rats were randomly assigned to 8 treatment groups in two consecutive experiments. In both experiments, subjects received either CBD (100 mg/kg) or vehicle 60 min prior to seizure testing. In Experiment 1, subjects received either WAY-100635 (1 mg/kg), a 5HT1A antagonist, or saline vehicle injection 80 min prior to seizure testing. In Experiment 2, subjects received either MDL-100907 (0.3 mg/kg), a specific 5HT2A antagonist, or 40% DMSO vehicle 80 min prior to seizure testing. 85 mg/kg of PTZ was administered to induce seizure, and behavior was recorded for 30 min. Seizure behaviors were subsequently coded using a 5-point scale of severity. Across both experiments, subjects in the vehicle control groups exhibited high levels of seizure activity and mortality. In both experiments, CBD treatment significantly attenuated seizure activity. Pre-treatment with either WAY-100635 or MDL-100907 did not block CBD's anticonvulsant effect. WAY-100635 administration, by itself, also led to a significant attenuation of seizure activity. These results do not support the hypothesis that CBD attenuates seizure activity through activation of the 5HT1A or 5HT2A receptor. While this work further confirms the anticonvulsant efficacy of CBD and supports its application in the treatment of human seizure disorders, additional research on CBD's mechanism of action must be conducted.
Cannabis and Cannabinoid Research, 2019
Introduction: Highly purified cannabidiol (CBD) (approved as Epidiolex Ò in the United States) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut or Dravet syndrome in four randomized controlled trials. CBD possesses affinity for many target classes with functional effects relevant to the pathophysiology of many disease types, including epilepsy. Although the mechanism of action of CBD underlying the reduction of seizures in humans is unknown, transient receptor potential vanilloid 1 (TRPV1) represents a plausible target because (1) CBD activates and then desensitizes TRPV1, (2) TRPV1 is overexpressed in models of temporal lobe epilepsy and patients with epilepsy, (3) and TRPV1 modulates neuronal excitability. Methods: To investigate a potential role of TRPV1 in the anticonvulsive effects of CBD, the effect of CBD on seizure threshold was assessed using a mouse maximal electroshock threshold model of generalized seizure in TRPV1 knockout and wildtype mice. The dose dependence of the CBD effect was determined and compared with that of the positive comparator diazepam and vehicle. Results: At 50 and 100 mg/kg, CBD significantly (p < 0.0001) increased seizure threshold in wildtype mice compared with TRPV1 knockout and vehicle controls. This effect was observed only at 100 mg/kg in TRPV1 knockout mice compared with knockout vehicle mice, in which gene deletion partially attenuated the CBD-increased seizure threshold. The effect of high-dose CBD in wildtype mice was nevertheless significantly different from vehicle-treated TRPV1 knockout mice (p < 0.0001). Bioanalysis confirmed that genotype-specific differential brain exposure to CBD was not responsible for the observed effect on seizure threshold. Conclusion: These data strongly implicate TRPV1 in the potential mechanisms of action for the anticonvulsive effects of CBD. The partial inhibition of the anticonvulsive effect of high-dose CBD in TRPV1 knockout mice may indicate the involvement of targets other than TRPV1. Further characterization of TRPV1 in the anticonvulsive effect of CBD in validated models of seizure is warranted, as is pharmacological investigation of the molecular interaction between CBD and TRPV1.
Seizure-european Journal of Epilepsy, 2018
Activation of CB1 receptors, produces anticonvulsant effect accompanied by memory disturbance both in animal seizure tests and in patients with epilepsy. Few reports considered the role of CB2 receptor on seizure susceptibility and cognitive functions. The aim of the present study was to explore the effect of a selective CB2 receptor agonist b-caryophyllene (BCP) in models of seizures and cognition in mice. Methods: Dose-dependent effects of BCP was studied in maximal electroshock seizure (MES) test, subcutaneous pentylenetetrazole (scPTZ) test and Morris water maze test. Phenytoin and diazepam were used as reference drugs in seizure tests. The effect of sub-chronic treatment with BCP for 7 days (50 and 100 mg kg À1) was assessed on status epilepticus (SE) induced by kainic acid (KA) model and oxidative stress through measurement of malondialdehyde (MDA) level in the hippocampus. The acute neurotoxicity was determined by a rotarod test. Results: The BCP exerted a protection in the MES test at the lowest dose of 30 mg kg À1 at the 4-h interval tested comparable to that of the referent drug phenytoin. The CB2 agonist was ineffective in the scPTZ test. The BCP displayed no neurotoxicity in the rotarod test. The BCP decreased the seizure scores in the KA-induced SE, which effect correlated with a diminished lipid peroxidation. The CB2 agonist exerted a dose-dependent decrease of latency to cross the target area during the three days of testing in the Morris water maze test. Conclusion: Our results suggest that the CB2 receptor agonists might be clinically useful as an adjunct treatment against seizure spread and status epilepticus and concomitant oxidative stress, neurotoxicity and cognitive impairments.