Abstract
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.
Highlights
Epilepsy syndromes are considered neurological disorders characterized by an enduring predisposition to generate epileptic seizures that can be accompanied by a wide spectrum of behavioral and neuropsychiatric conditions (Kanner et al, 2012; Fisher et al, 2014)
The fact that classic anticonvulsant drugs such as valproate (VPA), phenobarbital, and lamotrigine were highly effective in suppressing sound-induced seizures in the GASH/Sal indicates that this animal model can be reliably used for preclinical screening of novel anticonvulsant agents (Barrera-Bailón et al, 2013, 2017)
We did not find a significant impairment of locomotor exploratory behaviors after chronic valproic acid (VPA) treatment, previous studies from BarreraBailón et al (2013) reported ataxic effects of VPA at doses of 300 mg/kg, which is in line with the reported side effects of VPA (Löscher and Hönack, 1995)
Summary
Epilepsy syndromes are considered neurological disorders characterized by an enduring predisposition to generate epileptic seizures that can be accompanied by a wide spectrum of behavioral and neuropsychiatric conditions (Kanner et al, 2012; Fisher et al, 2014). GASH/Sal animals, from 2 to 4 months of age at which susceptibility reached its maximum, undergoes generalized tonic–clonic seizures that are characterized by a short latency period after loud acoustic stimulation, followed by phases of wild running, convulsions, and stupor (Muñoz et al, 2017) Anticonvulsant drugs such as valproic acid (VPA), phenobarbital, and lamotrigine are highly effective in suppressing sound-induced seizures in the GASH/Sal (Barrera-Bailón et al, 2013, 2017), and GASH/Sal animals are suitable to examine the efficacy of antiepileptic agents (Werner and Coveñas, 2017). From a technical point of view, the present study is highly valuable as it combines a multitechnical approach to generate correlated results at behavioral and molecular levels that constituted the basis for further analysis of the CBD effects and its interactions with other anticonvulsant agents
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