Nanoemulsions of Cannabidiol, Δ9-Tetrahydrocannabinol, and Their Combination Similarly Exerted Anticonvulsant and Antioxidant Effects in Mice Treated with Pentylenetetrazole

<b>Background/Objectives:</b> The main biologically active molecules of <i>Cannabis sativa</i> L. are cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). Both exert anticonvulsant effects when evaluated as single drugs, but their possible interaction as components of <i>C. sativa</i> extracts has been scarcely studied. For this reason, we evaluated CBD and THC, combined or not, in two seizure models in mice, using an improved vehicle formula. <b>Methods:</b> Firstly, acute seizures were induced by intraperitoneal (i.p.) pentylenetetrazole (PTZ, 80 mg/kg), and mice received CBD or THC at 1, 3, 6, and 10 mg/kg, or a CBD/THC 1:1 combination at 1.5, 3, and 6 mg/kg, per os (p.o.), one hour before PTZ administration. Secondly, mice received p.o. CBD (10 mg/kg), CBD/THC (1.5, 3, and 6 mg/kg), valproic acid (50 mg/kg), or vehicle (nanoemulsions without CBD or THC), one hour before PTZ (30 mg/kg, i.p.) every other day for 21 days. Behavioral, biochemical, and immunohistochemical analyses were performed to assess the response to PTZ, oxidative stress, and astroglial activation. <b>Results:</b> In the acute model, CBD and THC at 3-10 mg/kg, and their combinations, significantly increased latency to generalized seizures and death, and improved survival rates. In the chronic model, similarly to valproic acid, CBD 10 mg/kg and CBD/THC at 1.5 and 3 mg/kg delayed kindling acquisition, while CBD/THC 6 mg/kg had no effect. CBD and CBD/THC treatments reduced oxidative and nitrosative stress and attenuated astrogliosis, as indicated by decreased glial fibrillary acidic protein and GABA transporter 1 expression and increased inwardly rectifying potassium channel 4.1 expression in hippocampal regions. However, no cannabinoid treatment prevented the impairment in novel object recognition and Y maze tests. <b>Conclusions:</b> These findings support the potential role of cannabinoids in counteracting seizures, possibly by reducing oxidative stress and astrogliosis. The study also highlights the importance of nanoemulsions as a delivery vehicle to enhance cannabinoid effectiveness while considering the risks associated with direct cannabinoid receptor activation.