Ciubotaru Alin Dumitru, Leferman Carmen-Ecaterina, Ignat Bogdan-Emilian, Knieling Anton, Salaru Delia Lidia, Turliuc Dana Mihaela, Foia Liliana Georgeta, Dima Lorena, Minea Bogdan, Hritcu Luminita Diana, Cioroiu Bogdan Ionel, Stoica Laura, Ciureanu Ioan-Adrian, Ciobica Alin Stelian, Stoica Bogdan Alexandru, Ghiciuc Cristina Mihaela
Discipline of Pharmacology, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy Iasi, 16 Universitatii Street, 700115 Iasi, Romania.
Discipline of Biochemistry, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania.
Pharmaceuticals (Basel). 2024 Nov 29;17(12):1611. doi: 10.3390/ph17121611.
: 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. : 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. 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. These results highlight the potential of MitoCur as a candidate for seizure management.
癫痫治疗中持续存在的挑战促使人们开展对替代疗法的研究，这些替代疗法应具有更高的疗效和更低的副作用。为了增强线粒体靶向性并提高生物利用度，首次对米托姜黄素（MitoCur）作为抗癫痫药物进行了评估，并将姜黄素（Cur）和标准抗癫痫药物丙戊酸钠（VPA）纳入比较。本研究调查了其对戊四氮（PTZ）诱导的斑马鱼癫痫模型中癫痫发作的起始、严重程度和进展的影响，并测量了脑组织中这些化合物的浓度。斑马鱼用MitoCur和Cur（剂量均为0.25和0.5 μM）以及VPA（0.25和0.5 mM）进行预处理，并观察四分钟以建立基线运动行为。随后，将动物暴露于5 mM的PTZ溶液中10分钟，在此期间观察癫痫发作进展并评分如下：1 - 游泳增加；2 - 爆发性游泳、左右运动；3 - 圆周运动；4 - 阵挛性癫痫样行为；5 - 身体姿势丧失。通过HPLC和LC - MS对脑组织中的研究化合物进行定量。与对照组相比，所有处理均减少了移动距离和平均速度，各化合物或剂量之间无显著差异。在PTZ暴露期间，癫痫发作潜伏期表明，所有处理均有效延迟癫痫发作至评分4，表明在控制中度癫痫活动方面具有疗效。值得注意的是，MitoCur对最严重的癫痫发作评分（评分5）也提供了显著的保护作用。脑组织摄取分析表明，在两种剂量下，MitoCur在脑中达到的浓度均高于Cur。这些结果突出了MitoCur作为癫痫治疗候选药物的潜力。
