Assessing the role of serotonergic receptors in cannabidiol's anticonvulsant efficacy

Pelz, Madeline; Schoolcraft, Kathleen D.; Larson, Chloe; Spring, Mitchell G.; López, Hassan H.

doi:10.1016/j.yebeh.2017.04.045

Cited by 27 publications

(20 citation statements)

References 39 publications

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“…Notwithstanding that, we found that acute CBD administration in the GASH/Sal significantly increased seizure latency and duration of the wild-running phase, whereas the duration of the convulsions was significantly reduced as compared to sham animals. Similar results were previously shown in other rodent models of epilepsy after CBD (100 mg/kg) intraperitoneal injections, reporting such effects on the duration of the seizure phases as a strong indication of anticonvulsant activity (Jones et al, 2012;Pelz et al, 2017). Indeed, we also observed these same effects in the GASH/Sal after acute treatment with VPA, but far more effectively and intensively than in the CBD-treated group.…”

Section: Discussionsupporting

confidence: 91%

“…Activation of the serotonin 5-HTR1A receptor hyperpolarizes the resting membrane potential and has an anticonvulsant effect in various experimental in vivo and in vitro seizure models (Salgado and Alkadhi, 1995;Gariboldi et al, 1996). Although CBD has been shown to be an agonist of the 5-HTR1A receptor (Russo et al, 2005), studies in the pentylenetetrazole model of generalized seizures reported that 5-HTR1A is not involved in CBD's anticonvulsant effect (Pelz et al, 2017). Consistently with this, our results showed normal mRNA expression levels of 5-HTR1A after chronic CBD treatment.…”

Section: Discussionmentioning

confidence: 99%

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Behavioral and Molecular Effects Induced by Cannabidiol and Valproate Administration in the GASH/Sal Model of Acute Audiogenic Seizures

Cabral-Pereira

Sánchez-Benito

Díaz-Rodríguez

et al. 2021

Front. Behav. Neurosci.

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Despite evidence that supports cannabidiol (CBD) as an anticonvulsant agent, there remains controversy over the antiseizure efficacy, possible adverse effects, and synergistic interactions with classic antiepileptics such as valproate (VPA). The genetic audiogenic seizure hamster from the University of Salamanca (GASH/Sal) is a reliable experimental model of generalized tonic–clonic seizures in response to intense sound stimulation. The present study examines the behavioral and molecular effects of acute and chronic intraperitoneal administrations of VPA (300 mg/kg) and CBD (100 mg/kg) on the GASH/Sal audiogenic seizures, as well as the coadministration of both drugs. The GASH/Sal animals were examined prior to and after the corresponding treatment at 45 min, 7 days, and 14 days for seizure severity and neuroethology, open-field behaviors, body weight variations, and various hematological and biochemical parameters. Furthermore, the brain tissue containing the inferior colliculus (so-called epileptogenic nucleus) was processed for reverse transcription–quantitative polymerase chain reaction analysis to determine the treatment effects on the gene expression of neuronal receptors associated with drug actions and ictogenesis. Our results indicated that single dose of VPA helps prevent the animals from getting convulsions, showing complete elimination of seizures, whereas 7 days of chronic VPA treatment had few effects in seizure behaviors. Acute CBD administration showed subtle attenuation of seizure behaviors, increasing seizure latency and decreasing the duration of the convulsion phase, but without entirely seizure abolition. Chronic CBD treatments had no significant effects on sound-induced seizures, although some animals slightly improved seizure severity. Acute and chronic CBD treatments have no significant adverse effects on body weight, hematological parameters, and liver function, although locomotor activity was reduced. The combination of VPA and CBD did not alter the therapeutic outcome of the VPA monotherapy, showing no apparent synergistic effects. As compared to sham animals, chronic treatments with CBD caused abnormal mRNA expression levels for Trpv1, Adora1, Slc29a1, and Cnr1 genes, whereas no differences in gene expression were found for Htr1a and Sigmar1. Our study shed light on the behavioral and molecular effects of CBD and VPA on the GASH/Sal model and constituted the basis to develop further studies on the pharmacological effects of CBD and its interactions with other anticonvulsants.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Behavioral and Molecular Effects Induced by Cannabidiol and Valproate Administration in the GASH/Sal Model of Acute Audiogenic Seizures

Cabral-Pereira

Sánchez-Benito

Díaz-Rodríguez

et al. 2021

Front. Behav. Neurosci.

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“…Contrary to what might be expected, pretreatment with WAY 100635 and MDL-100907 did not reduce the anticonvulsant effect of CBD. However, this study does not prove that CBD exerted its effects through the 5-HT 1A or 5-HT 2A receptors [90].…”

Section: -Ht Receptorscontrasting

confidence: 82%

Molecular Targets of Cannabidiol in Experimental Models of Neurological Disease

et al. 2020

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Cannabidiol (CBD) is a non-psychoactive phytocannabinoid known for its beneficial effects including antioxidant and anti-inflammatory properties. Moreover, CBD is a compound with antidepressant, anxiolytic, anticonvulsant and antipsychotic effects. Thanks to all these properties, the interest of the scientific community for it has grown. Indeed, CBD is a great candidate for the management of neurological diseases. The purpose of our review is to summarize the in vitro and in vivo studies published in the last 15 years that describe the biochemical and molecular mechanisms underlying the effects of CBD and its therapeutic application in neurological diseases. CBD exerts its neuroprotective effects through three G protein coupled-receptors (adenosine receptor subtype 2A, serotonin receptor subtype 1A and G protein-coupled receptor 55), one ligand-gated ion channel (transient receptor potential vanilloid channel-1) and one nuclear factor (peroxisome proliferator-activated receptor γ). Moreover, the therapeutical properties of CBD are also due to GABAergic modulation. In conclusion, CBD, through multi-target mechanisms, represents a valid therapeutic tool for the management of epilepsy, Alzheimer’s disease, multiple sclerosis and Parkinson’s disease.

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“…One recent study demonstrates that CBD's anticonvulsant properties were attenuated in TRPV1 knockout mice (Gray, Stott, Jones, Di Marzo, & Whalley, 2020). CBD also acts as allosteric modulator of 5HT 1A ; however, one specific study has ruled out 5HT 1A as a CBD target in seizure control (Pelz, Schoolcraft, Larson, Spring, & Lopez, 2017). CBD was also shown to act as a blocker of VGSCs (Hill et al, 2014), which represents a potential mode of anticonvulsive action in epilepsy.…”

Section: The Human Experiencementioning

confidence: 99%

Development of cannabidiol as a treatment for severe childhood epilepsies

Williams

Stephens

2020

British J Pharmacology

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In recent years, there has been a growing appreciation by regulatory authorities that cannabis-based medicines can play a useful role in disease therapy. Although often conflagrated by proponents of recreational use, the legislative rescheduling of cannabis-derived compounds, such as cannabidiol (CBD), has been associated with the steady increase in the pursuit of use of medicinal cannabis. One key driver in this interest has been the scientific demonstration of efficacy and safety of CBD in randomised, placebo-controlled clinical trials in children and young adults with difficult-to-treat epilepsies, which has encouraged increasing numbers of human trials of CBD for other indications and in other populations. The introduction of CBD as the medicine Epidiolex in the United States (in 2018) and as Epidyolex in the European Union (in 2019) as the first cannabis-derived therapeutic for the treatment of seizures was underpinned by preclinical research performed at the University of Reading. This work was awarded the British Pharmacological Society Sir James Black Award for Contributions to Drug Discovery 2019 and is discussed in the following review article.

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Assessing the role of serotonergic receptors in cannabidiol's anticonvulsant efficacy

Cited by 27 publications

References 39 publications

Behavioral and Molecular Effects Induced by Cannabidiol and Valproate Administration in the GASH/Sal Model of Acute Audiogenic Seizures

Behavioral and Molecular Effects Induced by Cannabidiol and Valproate Administration in the GASH/Sal Model of Acute Audiogenic Seizures

Molecular Targets of Cannabidiol in Experimental Models of Neurological Disease

Development of cannabidiol as a treatment for severe childhood epilepsies

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