cannabidivarin and Disease-Models--Animal

Antiepileptic drugs often produce serious adverse effects, and many patients do not respond to them properly. Phytocannabinoids produce anticonvulsant effects in preclinical and preliminary human studies, and appear to produce fewer adverse effects than available antiepileptic drugs. The present review summarizes studies on the anticonvulsant properties of phytocannabinoids.. Literature search using the PubMed database to identify studies on phytocannabinoids and epilepsy.. Preclinical studies suggest that phytocannabinoids, especially cannabidiol and cannabidivarin, have potent anticonvulsant effects which are mediated by the endocannabinoid system. Human studies are limited in number and quality, but suggest that cannabidiol has anticonvulsant effects in adult and infantile epilepsy and is well tolerated after prolonged administration.. Phytocannabinoids produce anticonvulsant effects through the endocannabinoid system, with few adverse effects. Cannabidiol and cannabidivarin should be tested in randomized, controlled clinical trials, especially in infantile epileptic syndromes.

Topics: Animals; Anticonvulsants; Cannabidiol; Cannabinoids; Cerebral Cortex; Clinical Trials as Topic; Disease Models, Animal; Dose-Response Relationship, Drug; Dronabinol; Drug Evaluation, Preclinical; Endocannabinoids; Epilepsy; Humans; Phytotherapy; Plant Extracts

A significant proportion of neonatal and childhood seizures are poorly controlled by existing anti-seizure drugs (ASDs), likely due to prominent differences in ionic homeostasis and network connectivity between the immature and mature brain. In addition to the poor efficacy of current ASDs, many induce apoptosis, impair synaptic development, and produce behavioral deficits when given during early postnatal development. There is growing interest in new targets, such as cannabidiol (CBD) and its propyl analog cannabidivarin (CBDV) for early life indications. While CBD was recently approved for treatment of refractory childhood epilepsies, little is known about the efficacy or safety of CBDV. Here, we addressed this gap through a systematic evaluation of CBDV against multiple seizure models in postnatal day (P) 10 and 20 animals. We also evaluated the impact of CBDV on acute neurotoxicity in immature rats. CBDV (50-200 mg/kg) displayed an age and model-specific profile of anticonvulsant action. In P10 rats, CBDV suppressed seizures only in the pentylenetetrazole model. In P20 rats, CBDV suppressed seizures in the pentylenetetrazole, DMCM, and maximal electroshock models. Between P10 and P20, we identified significant increases in mRNA expression of TRPV1 in multiple brain regions; when CBDV was tested in P20 TRPV1 knockout mice, anticonvulsant effects were attenuated. Finally, CBDV treatment generally avoided induction of neuronal degeneration in immature rats. Together, the efficacy and safety profile of CBDV suggest it may have therapeutic value for early life seizures.

Topics: Age Factors; Animals; Brain; Cannabinoids; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Male; Mice; Mice, Knockout; Nerve Degeneration; Rats; Seizures; TRPV Cation Channels

Epilepsy is the most prevalent neurological disease and is characterized by recurrent seizures. Here, we investigate (i) the anticonvulsant profiles of cannabis-derived botanical drug substances (BDSs) rich in cannabidivarin (CBDV) and containing cannabidiol (CBD) in acute in vivo seizure models and (ii) the binding of CBDV BDSs and their components at cannabinoid CB1 receptors.. The anticonvulsant profiles of two CBDV BDSs (50-422 mg·kg(-1) ) were evaluated in three animal models of acute seizure. Purified CBDV and CBD were also evaluated in an isobolographic study to evaluate potential pharmacological interactions. CBDV BDS effects on motor function were also investigated using static beam and grip strength assays. Binding of CBDV BDSs to cannabinoid CB1 receptors was evaluated using displacement binding assays.. CBDV BDSs exerted significant anticonvulsant effects in the pentylenetetrazole (≥100 mg·kg(-1) ) and audiogenic seizure models (≥87 mg·kg(-1) ), and suppressed pilocarpine-induced convulsions (≥100 mg·kg(-1) ). The isobolographic study revealed that the anticonvulsant effects of purified CBDV and CBD were linearly additive when co-administered. Some motor effects of CBDV BDSs were observed on static beam performance; no effects on grip strength were found. The Δ(9) -tetrahydrocannabinol and Δ(9) -tetrahydrocannabivarin content of CBDV BDS accounted for its greater affinity for CB1 cannabinoid receptors than purified CBDV.. CBDV BDSs exerted significant anticonvulsant effects in three models of seizure that were not mediated by the CB1 cannabinoid receptor and were of comparable efficacy with purified CBDV. These findings strongly support the further clinical development of CBDV BDSs for the treatment of epilepsy.

Topics: Animals; Anticonvulsants; Brain; Cannabidiol; Cannabinoids; Cannabis; Disease Models, Animal; Dose-Response Relationship, Drug; Hand Strength; Male; Mice; Mice, Inbred DBA; Motor Activity; Noise; Pentylenetetrazole; Phytotherapy; Pilocarpine; Plant Extracts; Plants, Medicinal; Protein Binding; Rats; Rats, Inbred WKY; Receptor, Cannabinoid, CB1; Seizures

The cannabinoid 1 (CB1 ) receptor inverse agonists/antagonists, rimonabant (SR141716, SR) and AM251, produce nausea and potentiate toxin-induced nausea by inverse agonism (rather than antagonism) of the CB1 receptor. Here, we evaluated two phytocannabinoids, cannabidivarin (CBDV) and Δ(9) -tetrahydrocannabivarin (THCV), for their ability to produce these behavioural effect characteristics of CB1 receptor inverse agonism in rats.. In experiment 1, we investigated the potential of THCV and CBDV to produce conditioned gaping (measure of nausea-induced behaviour) in the same manner as SR and AM251. In experiment 2, we investigated the potential of THCV and CBDV to enhance conditioned gaping produced by a toxin in the same manner as CB1 receptor inverse agonists.. SR (10 and 20 mg·kg(-1) ) and AM251 (10 mg·kg(-1) ) produced conditioned gaping; however, THCV (10 or 20 mg·kg(-1) ) and CBDV (10 or 200 mg·kg(-1) ) did not. At a subthreshold dose for producing nausea, SR (2.5 mg·kg(-1) ) enhanced lithium chloride (LiCl)-induced conditioned gaping, whereas Δ(9) -tetrahydrocannabinol (THC, 2.5 and 10 mg·kg(-1) ), THCV (2.5 or 10 mg·kg(-1) ) and CBDV (2.5 or 200 mg·kg(-1) ) did not; in fact, THC (2.5 and 10 mg·kg(-1) ), THCV (10 mg·kg(-1) ) and CBDV (200 mg·kg(-1) ) suppressed LiCl-induced conditioned gaping, suggesting anti-nausea potential.. The pattern of findings indicates that neither THCV nor CBDV produced a behavioural profile characteristic of CB1 receptor inverse agonists. As well, these compounds may have therapeutic potential in reducing nausea.

Topics: Animals; Behavior, Animal; Cannabinoid Receptor Agonists; Cannabinoids; Disease Models, Animal; Dronabinol; Drug Partial Agonism; Lithium Chloride; Male; Nausea; Phytochemicals; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant

Phytocannabinoids in Cannabis sativa have diverse pharmacological targets extending beyond cannabinoid receptors and several exert notable anticonvulsant effects. For the first time, we investigated the anticonvulsant profile of the phytocannabinoid cannabidivarin (CBDV) in vitro and in in vivo seizure models.. The effect of CBDV (1-100 μM) on epileptiform local field potentials (LFPs) induced in rat hippocampal brain slices by 4-aminopyridine (4-AP) application or Mg(2+) -free conditions was assessed by in vitro multi-electrode array recordings. Additionally, the anticonvulsant profile of CBDV (50-200 mg·kg(-1) ) in vivo was investigated in four rodent seizure models: maximal electroshock (mES) and audiogenic seizures in mice, and pentylenetetrazole (PTZ) and pilocarpine-induced seizures in rats. The effects of CBDV in combination with commonly used antiepileptic drugs on rat seizures were investigated. Finally, the motor side effect profile of CBDV was investigated using static beam and grip strength assays.. CBDV significantly attenuated status epilepticus-like epileptiform LFPs induced by 4-AP and Mg(2+) -free conditions. CBDV had significant anticonvulsant effects on the mES (≥100 mg·kg(-1) ), audiogenic (≥50 mg·kg(-1) ) and PTZ-induced seizures (≥100 mg·kg(-1) ). CBDV (200 mg·kg(-1) ) alone had no effect against pilocarpine-induced seizures, but significantly attenuated these seizures when administered with valproate or phenobarbital at this dose. CBDV had no effect on motor function.. These results indicate that CBDV is an effective anticonvulsant in a broad range of seizure models. Also it did not significantly affect normal motor function and, therefore, merits further investigation as a novel anti-epileptic in chronic epilepsy models.. This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8.

Topics: Animals; Anticonvulsants; Cannabinoids; Cannabis; Disease Models, Animal; Female; Hippocampus; In Vitro Techniques; Male; Mice; Mice, Inbred DBA; Mice, Inbred ICR; Motor Activity; Pentylenetetrazole; Phytotherapy; Pilocarpine; Rats; Rats, Inbred WKY; Seizures