caryophyllene and Epilepsies--Myoclonic

Cannabidiol (CBD) has been recently approved as an antiseizure agent in Dravet Syndrome (DS), a pediatric epileptic encephalopathy, but CBD could also be active against associated comorbidities. Such associated comorbidities were also attenuated by the sesquiterpene β-caryophyllene (BCP). Here, we have compared the efficacy of both compounds and further initiated the analysis of a possible additive effect between both compounds in relation with these comorbidities using two experimental approaches. The first experiment was aimed at comparing the benefits of CBD and BCP, including their combination in conditional knock-in Scn1a-A1783V mice, an experimental model of DS, treated since the postnatal day 10th to 24th. As expected, DS mice showed impairment in limb clasping, delay in the appearance of hindlimb grasp reflex and additional behavioural disturbances (e.g., hyperactivity, cognitive deterioration, social interaction deficits). This behavioural impairment was associated with marked astroglial and microglial reactivities in the prefrontal cortex and the hippocampal dentate gyrus. BCP and CBD administered alone were both able to partially attenuate the behavioural disturbances and the glial reactivities, with apparently greater efficacy against glial reactivities obtained with BCP, whereas superior effects in a few specific parameters were obtained when both compounds were combined. In the second experiment, we investigated this additive effect in cultured BV2 cells treated with BCP and/or CBD and stimulated with LPS. As expected, addition of LPS induced a marked increase in several inflammation-related markers (e.g., TLR4, COX-2, iNOS, catalase, TNF-α, IL-1β), as well as elevated Iba-1 immunostaining. Treatment with BCP or CBD attenuated these elevations, but, again and in general, superior results were obtained when both cannabinoids were combined. In conclusion, our results support the interest to continue investigating the combination of BCP and CBD to improve the therapeutic management of DS in relation with their disease-modifying properties.

Topics: Animals; Cannabidiol; Epilepsies, Myoclonic; Lipopolysaccharides; Mice; NAV1.1 Voltage-Gated Sodium Channel

Increasing evidence suggests that plant-derived extracts and their isolated components are useful for treatment of seizures and, hence, constitute a valuable source of new antiepileptic drugs with improved efficacy and better adverse effect profile. β-Caryophyllene is a natural bicyclic sesquiterpene that occurs in a wide range of plant species and displays a number of biological actions, including neuroprotective activity. In the present study, we tested the hypothesis that β-caryophyllene displays anticonvulsant effects. In addition, we investigated the effect of β-caryophyllene on behavioral parameters and on seizure-induced oxidative stress. Adult C57BL/6 mice received increasing doses of β-caryophyllene (0, 10, 30, or 100mg/kg). After 60 min, we measured the latencies to myoclonic and generalized seizures induced by pentylenetetrazole (PTZ, 60 mg/kg). We found that β-caryophyllene increased the latency to myoclonic jerks induced by PTZ. This result was confirmed by electroencephalographic analysis. In a separate set of experiments, we found that mice treated with an anticonvulsant dose of β-caryophyllene (100mg/kg) displayed an improved recognition index in the object recognition test. This effect was not accompanied by behavioral changes in the open-field, rotarod, or forced swim tests. Administration of an anticonvulsant dose of β-caryophyllene (100mg/kg) did not prevent PTZ-induced oxidative stress (i.e., increase in the levels of thiobarbituric acid-reactive substances or the decrease in nonprotein thiols content). Altogether, the present data suggest that β-caryophyllene displays anticonvulsant activity against seizures induced by PTZ in mice. Since no adverse effects were observed in the same dose range of the anticonvulsant effect, β-caryophyllene should be further evaluated in future development of new anticonvulsant drugs.

Topics: Animals; Anticonvulsants; Convulsants; Dose-Response Relationship, Drug; Electroencephalography; Epilepsies, Myoclonic; Mice; Mice, Inbred C57BL; Motor Activity; Oxidative Stress; Pentylenetetrazole; Polycyclic Sesquiterpenes; Postural Balance; Recognition, Psychology; Seizures; Sesquiterpenes; Swimming