Epilepsies and neuropsyquiatric comorbidities: characterization of the effects of the treatment with cannabidiol and HUF-101 in in vivo and in vitro experimental models

Abstract

In the current project we initially make an introduction to the history of the Wistar Audiogenic Rat (WAR) strain, developed by our group since the 1990s, and of the research with the epilepsies and neuropsyquiatric comorbidities involving this model. We introduce immediately after all the justification to search for novel antiepileptogenic and neuroprotection alternatives, because a significative part of the people with epilepsy (near 40%) are pharmacorresistant. In this context cannabidiol (CBD) and its fluorinated analogues (for example HUF-101) appear as important pharmacological alternatives. The hypotheses of this Project are: (1) CBD and its fluorinated analogue HUF-101 present neuroprotection, anticonvulsant and anxiolytic effects in experimental epilepsy models, such as: Status Epilepticus (SE) induced by intra-hipocampal microinjection of pilocarpine, model of Amygdala Rapid Kindling (ARK) and anticonvulsant and anxiolytic effect in models of generalized tonic-clonic (acute) and limbic (chronic) seizures in WARs, and their behavioral consequences, for example, increase of anxiety, respectively. (2) CBD displays different mechanisms of action, that can be mediated by non-conventional intra-cellular signaling pathways in neuronal models. (3) New systems of drug delivery (nanoparticles) can optimize the anticonvulsant and neuroprotection effect of CBD in the treatment of the epilepsies. In this context, the main goals of this project are (1) To evaluate the behavioral, electroencephalographic (EEGraphic) and histological effects of a unique dose of HUF-101, in different experimental models of epilepsies. (2). To evaluate the behavioral, cellular and molecular effects of CBD, after chronic administration, in acute and chronic audiogenic seizure models (WAR strain). (3) To investigate the effects of the chronic treatment with CBD on the main comorbidities associated to the epilepsies, initially with models of anxiety. (4) To elucidate de non-conventional signaling pathways activated by CBD and correlate them with the mechanisms of action in a neuronal cellular model and the epilepsies. (5) To develop, characterize and evaluate effects of the previous administration of CBD and HUF-101 in nanoparticles (CBDnp e HUFnp), in rats submitted to the model of SE induced by intra-hippocampal microinjection of pilocarpine, using behavioral, EEGraphic and histochemical tools. The preliminary results with in vivo and in vitro assays with CBD e HUF-101 are promising, both for the evaluation of their anti-convulsant, and their neuroprotection activities, as well as for the detection of the associated non-conventional cellular and molecular mechanisms of action. (AU)