Efeitos neuroprotetores de nanoemulsões de canabidiol e tetrahidrocanabinol em modelos de epilepsia induzida por PTZ: implicações mitocondriais e astrogliais

Abstract

Epilepsy is a prevalent neurological disorder in which mitochondrial dysfunction and glialactivation play a central role in its pathophysiology. The main phytocannabinoids of Cannabissativa, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), exhibit anticonvulsantproperties; however, their combined mechanisms of action, particularly regardingmitochondrial bioenergetics, oxidative stress, and astroglial modulation, remain poorlyelucidated. Therefore, this study investigated the effects of CBD and THC nanoemulsions,administered alone or in combination, in acute and chronic models of pentylenetetrazol(PTZ)-induced seizures. In the acute protocol, male Swiss mice received oral doses of CBD,THC, or their combinations in nanoemulsion form, and latency to the first generalized seizureand mortality were evaluated. In the chronic protocol, the development of epileptogenesis,cognitive performance, and neurochemical effects were assessed. Behavioral parameters in the chronic model included the novel object recognition test and the Y-maze test to analyzememory and cognitive function. Oxidative stress in the acute model was measured by lipidperoxidation markers (TBARS/MDA), nitrate/nitrite levels, and mitochondrial H₂O₂production. The expressions of GFAP, GAT-1, and Kir4.1 was evaluated by immunohistochemistry as markers of astrogliosis. Mitochondrial function was analyzed byoxygen consumption, respiratory control ratio, ADP/O ratio, and mitochondrial swelling in invitro and ex vivo preparations. The results demonstrated that the CBD/THC combinationsignificantly increased latency to seizures and death in the acute model, in addition to delaying the development of kindling in the chronic model. The nanoemulsions reduced oxidative and nitrosative stress levels and attenuated hippocampal astrogliosis. Significantmodulation of GAT-1 and Kir4.1 expression was observed in the treated groups, suggestingimproved synaptic homeostasis. In vitro and ex vivo assays showed enhanced mitochondrialbioenergetic efficiency. Overall, these findings indicate that the CBD/THC combination exertsa neuroprotective effect mediated by mitochondrial modulation, reduction of oxidative stress, and regulation of astroglial function, although dose-dependent cognitive effects and experimental limitations were observed.