Background/Objectives: Epilepsy is a complex neurological disorder with a strong link to oxidative stress, which contributes to seizure susceptibility and neuronal damage. This study aims to investigate the effects of curcumin (Cur), sodium valproate (VPA), and mitocurcumin (MitoCur), a mitochondria-targeted curcumin, on behavioral and oxidative stress parameters in a zebrafish model of pentylenetetrazole (PTZ)-induced seizures. Methods: Adult zebrafish were exposed to two concentrations (0.25 and 0.5 µM for Cur and MitoCur; 0.25 and 0.5 mM for VPA). Behavioral assessments, including locomotion, spatial exploration, and directional movement, were conducted using EthoVision XT tracking software. Oxidative stress markers, including superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GPx), and total antioxidant status (TAS), were analyzed in brain homogenates. Results: Behavioral analyses indicated dose-dependent effects, with higher doses generally reducing activity. MitoCur at 0.25 µM enhanced antioxidant defenses and reduced oxidative damage, while higher doses exhibited a pro-oxidant shift. VPA at 0.25 mM improved TAS without significantly altering MDA levels. Conclusions: These findings emphasize the importance of dose optimization in antioxidant-based epilepsy treatments and highlight the potential of MitoCur as a targeted therapeutic option.

Background/Objectives: Ongoing challenges in epilepsy therapy warrant research on alternative treatments that offer improved efficacy and reduced side effects. Designed to enhance mitochondrial targeting and increase bioavailability, mitocurcumin (MitoCur) was evaluated for the first time as an antiepileptic agent, with curcumin (Cur) and sodium valproate (VPA), a standard antiepileptic drug, included for comparison. This study investigated the effects on seizure onset, severity, and progression in a zebrafish model of pentylenetetrazole (PTZ)-induced seizures and measured the concentrations of the compounds in brain tissue. Methods: Zebrafish were pre-treated with MitoCur and Cur (both at 0.25 and 0.5 µM doses) and VPA (0.25 and 0.5 mM) and observed for four minutes to establish baseline locomotor behavior. Subsequently, the animals were exposed to a 5 mM PTZ solution for 10 min, during which seizure progression was observed and scored as follows: 1—increased swimming; 2—burst swimming, left and right movements; 3—circular movements; 4—clonic seizure-like behavior; 5—loss of body posture. The studied compounds were quantified in brain tissue through HPLC and LC-MS. Results: Compared to the control group, all treatments reduced the distance moved and the average velocity, without significant differences between compounds or doses. During PTZ exposure, seizure latencies revealed that all treatments effectively delayed seizure onset up to score 4, demonstrating efficacy in managing moderate seizure activity. Notably, MitoCur also provided significant protection against the most severe seizure score (score 5). Brain tissue uptake analysis indicated that MitoCur achieved higher concentrations in the brain compared to Cur, at both doses. Conclusions: These results highlight the potential of MitoCur as a candidate for seizure management.

Background/Objectives: Manganese–Curcumin–Triphenylphosphonium (Mn-C-TPP), a complex designed for mitochondrial targeting, was investigated with ascorbate to assess cytotoxicity and associated cellular responses. We hypothesized that Mn-C-TPP would amplify ascorbate-driven oxidative stress and produce synergistic cytotoxicity in susceptible cancer cell lines. Methods: An inverse, control-normalized SYTOX-derived response index (vehicle = 100; staurosporine = 0) was determined after 72 h in HCT116, A549, HepG2, and normal dermal human fibroblasts (NDHFs). H₂O₂-associated luminescence (ROS-Glo), caspase-3/7 activation, and mitochondrial membrane potential were assessed in selected cancer cell lines. Drug interactions were analyzed using SynergyFinder 3.0 (ZIP model). Results: Mn-C-TPP alone reduced the SYTOX-derived response index in HCT116 and HepG2, whereas A549 and NDHF showed smaller changes. Ascorbate enhanced cytotoxicity at selected combinations. In HCT116, 3 µM Mn-C-TPP plus 100 µM ascorbate decreased the SYTOX-derived response index toward the staurosporine reference. HepG2 responded markedly to 3–7 µM Mn-C-TPP with 100–300 µM ascorbate, whereas pronounced A549 responses occurred mainly at 15–30 µM Mn-C-TPP with 100–300 µM ascorbate. Mean ZIP scores were approximately 32, 54, 6, and 10 for HCT116, HepG2, A549, and NDHF, respectively. The NDHF response index remained close to the vehicle reference at lower combination doses but decreased at higher doses. Cellular assays showed increased H₂O₂-associated luminescence with Mn-C-TPP alone and higher mean signals with selected combinations than with ascorbate alone, together with caspase-3/7 activation and mitochondrial depolarization. Conclusions: These findings demonstrate cell-line- and concentration-dependent cytotoxicity and support further investigation of the proposed mitochondrial redox mechanism.

Background: Thiabendazole (TBZ), a benzimidazole with established antifungal and anthelmintic properties, has also been reported to exert antiangiogenic effects relevant to tissue remodeling and chronic inflammatory microenvironments. The present study examined how manganese coordination and cyclodextrin modify the dissolution behavior and endothelial activity of TBZ. Methods: Antiangiogenic potential was assessed through a human umbilical vein endothelial cells (HUVECs) scratch-wound migration assay. Dissolution profiles of TBZ, manganese–thiabendazole (MnTBZ), and MnTBZ/monochlorotriazynil-β-cyclodextrin (MCT-β-CD) formulation were evaluated under biorelevant pH conditions (1.2, 4.5, 6.8, 7.4) using the paddle method. Results: TBZ displayed a more rapid and extensive dissolution at pH 1.2, compared to MnTBZ. Partial dissociation at pH 4.5 modestly improved TBZ availability, while dissolution remained minimal at neutral pH. MCT-β-CD enhanced the solubility of MnTBZ at pH ≥ 6.8. In agreement with these profiles, TBZ exerted the strongest inhibition of endothelial migration, followed by MnTBZ/MCT-β-CD and MnTBZ. Conclusions: Manganese coordination and cyclodextrin formulation modulate both the dissolution behavior and endothelial migration-inhibitory activity of TBZ, suggesting that such formulation approaches may influence the delivery-related and functional properties of benzimidazole derivatives.