Isabel Vieira de Assis Lima1, Hyorrana Priscila Pereira Pinto2, Paula Maria Quaglio Bellozi1, Maria Carolina Machado da Silva1, Luciano R Vilela1, Fabrício A Moreira1, Márcio Flávio Dutra Moraes3, Antônio Carlos Pinheiro de Oliveira4. 1. Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG, 31270-901, Brazil. 2. Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG, 31270-901, Brazil. 3. Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG, 31270-901, Brazil. mfdm@icb.ufmg.br. 4. Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG, 31270-901, Brazil. antoniooliveira@icb.ufmg.br.
Abstract
BACKGROUND: The phytocannabinoid cannabidiol (CBD) has previously shown to have anticonvulsant effects in preclinical and clinical studies. Recently, CBD has been approved to treat certain types of drug-resistant epileptic syndromes. However, the underlying mechanism of action remains unclear. The phosphatidylinositol 3-kinase (PI3K) signaling pathway has been proposed to modulate seizures and might be recruited by CBD. Thus, we tested the hypothesis that the anticonvulsant effect of CBD involves PI3K in a seizure model induced by pentylenetetrazole (PTZ). METHODS: We employed pharmacological and genetic approaches to inhibit PI3K and quantified its effects on seizure duration, latency, and number. RESULTS: PI3K genetic ablation increased the duration and number of seizures. CBD inhibited PTZ-induced seizures in mice. Genetic deletion of PI3K or pretreatment with the selective inhibitor LY294002 prevented CBD effects. CONCLUSION: Our data strengthen the hypothesis that the CBD anticonvulsant effect requires the PI3K signaling pathway.
BACKGROUND: The phytocannabinoid cannabidiol (CBD) has previously shown to have anticonvulsant effects in preclinical and clinical studies. Recently, CBD has been approved to treat certain types of drug-resistant epileptic syndromes. However, the underlying mechanism of action remains unclear. The phosphatidylinositol 3-kinase (PI3K) signaling pathway has been proposed to modulate seizures and might be recruited by CBD. Thus, we tested the hypothesis that the anticonvulsant effect of CBD involves PI3K in a seizure model induced by pentylenetetrazole (PTZ). METHODS: We employed pharmacological and genetic approaches to inhibit PI3K and quantified its effects on seizure duration, latency, and number. RESULTS: PI3K genetic ablation increased the duration and number of seizures. CBD inhibited PTZ-induced seizures in mice. Genetic deletion of PI3K or pretreatment with the selective inhibitor LY294002 prevented CBD effects. CONCLUSION: Our data strengthen the hypothesis that the CBD anticonvulsant effect requires the PI3K signaling pathway.
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