Preclinical investigation of β-caryophyllene as a therapeutic agent in an experimental murine model of Dravet syndrome. (1st March 2022)

• Record Type: Journal Article
• Authors: Alonso, Cristina; Satta, Valentina; Díez-Gutiérrez, Paula; Fernández-Ruiz, Javier; Sagredo, Onintza
• Is Part Of: Neuropharmacology. Volume 205(2022)
• Publication Date: 2022-03-01
• Subjects: Dravet syndrome -- Infantile epileptic refractory syndromes -- Syn-Cre/Scn1aWT/A1783V mice -- Cannabinoids -- β-caryophyllene -- Seizuring activity -- Behavioural comorbidities -- Glial reactivity; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2021.108914
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Dravet Syndrome (DS) is caused by mutations in the Scn1a gene encoding the α1 subunit of the sodium channel Nav1.1, which results in febrile seizures that progress to severe tonic-clonic seizures and associated comorbidities. Treatment with cannabidiol has been approved for the management of seizures in DS patients, but it appears to be also active against associated comorbidities. In this new study, we have investigated β-caryophyllene (BCP), a cannabinoid with terpene structure that appears to also have a broad-spectrum profile, as a useful therapy against both seizuring activity and progression of associated comorbidities. This has been studied in heterozygous conditional knock-in mice carrying a missense mutation (A1783V) in Scn1a gene expressed exclusively in neurons of the Central Nervous System (Syn-Cre/Scn1a WT/A1783V ), using two experimental approaches. In the first approach, an acute treatment with BCP was effective against seizuring activity induced by pentylenetetrazole (PTZ) in wildtype (Scn1a WT/WT ) and also in Syn-Cre/Scn1a WT/A1783V mice, with these last animals having a greater susceptibility to PTZ. Such benefits were paralleled by a BCP-induced reduction in PTZ-induced reactive astrogliosis (labelled with GFAP) and microgliosis (labelled with Iba-1) in the prefrontal cortex and the hippocampal dentate gyrus, which were visible in both wildtype (Scn1a WT/WT ) and Syn-Cre/Scn1a WT/A1783V mice. In the second approach, both genotypes were treated repeatedly with BCP to investigate its effects on several DS comorbidities. Thus, BCP corrected important behavioural abnormalities of Syn-Cre/Scn1a WT/A1783V mice (e.g. delayed appearance of hindlimb grasp reflex, induction of clasping response, motor hyperactivity, altered social interaction and memory impairment), attenuated weight loss, and slightly delayed premature mortality. Again, these benefits were paralleled by a BCP-induced reduction in reactive astrogliosis and microgliosis in the prefrontal cortex and the hippocampal dentate gyrus typical of Syn-Cre/Scn1a WT/A1783V mice. In conclusion, BCP was active in Syn-Cre/Scn1a WT/A1783V mice against seizuring activity (acute treatment) and against several comorbidities (repeated treatment), in both cases in association with its capability to reduce glial reactivity in areas related to these behavioural abnormalities. This situates BCP in a promising position for further preclinical evaluation towards a close translation to DS patients. Highlights: BCP was active in Syn-Cre/Scn1a WT/A1783V mice against seizuring activity. BCP was also active and against long-term several comorbidities in these mice. Both effects are associated with a BCP-induced reduction in glial reactivity. BCP is an interesting compound for further preclinical evaluation in this disease.