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Cannabidiol anticonvulsant effect is mediated by the PI3Kγ pathway.

Abstract：

:The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/Akt)/mechanistic target of rapamycin (mTOR) signaling pathway has been associated with several pathologies in the central nervous system (CNS), including epilepsy. There is evidence supporting the hypothesis that the PI3Kγ signaling pathway may mediate the powerful anticonvulsant properties associated with the cannabinoidergic system. This work aims to investigate if the anticonvulsant and neuroprotective effects of cannabidiol (CBD) are mediated by PI3Kγ. In vitro and in vivo experiments were performed on C57Bl/6 wild-type (WT) and PI3Kγ-/- mice. Behavioral seizures were induced by bilateral intra-hippocampal pilocarpine microinjection. Twenty-four hours after the first behavioral seizure, animals were perfused and their brains removed and processed, for histological analysis of neurodegeneration, microgliosis and astrocytosis. Primary cultures of hippocampal neurons were used for glutamate-induced cell death assay. CDB increased latency and reduced the severity of pilocarpine-induced behavioral seizures, as well as prevented postictal changes, such as neurodegeneration, microgliosis and astrocytosis, in WT animals, but not in PI3Kγ-/-. CBD in vivo effects were abolished by pharmacological inhibition of cannabinoid receptor or mTOR. In vitro, PI3Kγ inhibition or deficiency also changed CBD protection observed in glutamate-induced cell death assay. Thus, we suggest that the modulation of PI3K/mTOR signaling pathway is involved in the anticonvulsant and neuroprotective effects of CBD. These findings are important not only for the elucidation of the mechanisms of action of CBD, which are currently poorly understood, but also to allow the prediction of therapeutic and side effects, ensuring efficacy and safety in the treatment of patients with epilepsy.

journal_name

Neuropharmacology

journal_title

Neuropharmacology

authors

Lima IVA,Bellozi PMQ,Batista EM,Vilela LR,Brandão IL,Ribeiro FM,Moraes MFD,Moreira FA,de Oliveira ACP

doi

10.1016/j.neuropharm.2020.108156

subject

Has Abstract

pub_date

2020-10-01 00:00:00

pages

108156

eissn

0028-3908

issn

1873-7064

pii

S0028-3908(20)30224-0

journal_volume

176

pub_type

杂志文章

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Cannabidiol anticonvulsant effect is mediated by the PI3Kγ pathway.