Ishola Ismail O, Ochieng Charles O, Olayemi Sunday O, Jimoh Memunat O, Lawal Saheed M
Department of Pharmacology, Therapeutics and Toxicology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, PMB 12003, Surulere, Lagos, Nigeria.
Department of Chemistry, Maseno University, Maseno, Kenya.
Pharmacol Biochem Behav. 2014 Dec;127:90-100. doi: 10.1016/j.pbb.2014.11.005. Epub 2014 Nov 6.
Vitex doniana Sweet (Verbanaceae) is used in traditional African medicine for the treatment of neurological disorders including depression. In our previous studies, three new phytoecdysteroids were isolated from methanol stem bark extract of V. doniana (VD) (11β-hydroxy-20-deoxyshidasterone, 21-hydroxyshidasterone, and 2,3-acetonide-24-hydroxyecdysone) along with known ecdysteroids. This study was designed to investigate antidepressant-like effect of VD and the isolated phytoecdysteroids in behavioral models of despair, forced-swim test (FST) and tail-suspension test (TST) in mice. VD (100 and 200mg/kg, p.o.) treatment reduced (P<0.05) the duration of immobility in both tests without affecting the locomotor activity and exploratory behavior as observed in the open field test. Similarly, 21-hydroxyshidasterone, 11β-hydroxy-20-deoxyshidasterone, ajugasterone and 24-hydroxyecdysone acute oral treatments significantly reduced immobility time with peak effect at 10mg/kg, which was similar to the effect of conventional antidepressants (imipramine and fluoxetine) in the FST. Conversely, pretreatment of mice with yohimbine (1mg/kg, i.p., α2-adrenoceptor antagonist), ketanserin (5mg/kg, i.p., 5-HT2A/2C receptor antagonist) or sulpiride (dopamine D2 receptor antagonist) prevented the antidepressant-like effect of 21-hydroxyshidasterone while the effects of 11β-hydroxy-20-deoxyshidasterone and 24-hydroxyecdysone were blocked by yohimbine or ketanserin in the FST. Moreover, the anti-immobility effect elicited by ajugasterone was prevented by prazosin (62.5μg/kg, i.p., α1-adrenoceptor antagonist) pretreatment. Our findings demonstrated that V. doniana and its phytoecdysteroids constituents elicited antidepressant-like effect in behavioral paradigm of despair. Furthermore, 21-hydroxyshidasterone produces its antidepressant-like effect through interaction with α2-adrenoceptor, 5-HT2A/2C receptor and dopamine D2-receptors but 11β-hydroxy-20-deoxyshidasterone and 24-hydroxyecdysone effects depend on interaction with α2-adrenoceptor and 5-HT2A/2C receptors while ajugasterone produces its action through interaction with post-synaptic α1-adrenoceptors. Thus, phytoecdysteroids could play a pivotal role in the treatment of major depression.
钝叶牡荆（马鞭草科）在非洲传统医学中用于治疗包括抑郁症在内的神经紊乱疾病。在我们之前的研究中，从钝叶牡荆（VD）的甲醇茎皮提取物中分离出了三种新的植物蜕皮甾酮（11β-羟基-20-脱氧蜕皮甾酮、21-羟基蜕皮甾酮和2,3-丙酮化物-24-羟基蜕皮激素）以及已知的蜕皮甾酮。本研究旨在通过小鼠绝望行为模型、强迫游泳试验（FST）和悬尾试验（TST），研究VD及分离出的植物蜕皮甾酮的抗抑郁样作用。VD（100和200mg/kg，口服）处理可缩短（P<0.05）两种试验中的不动时间，且不影响旷场试验中观察到的运动活性和探索行为。同样，21-羟基蜕皮甾酮、11β-羟基-20-脱氧蜕皮甾酮、筋骨草甾酮和24-羟基蜕皮激素的急性口服处理可显著缩短不动时间，在10mg/kg时达到峰值效应，这与传统抗抑郁药（丙咪嗪和氟西汀）在FST中的作用相似。相反，用育亨宾（1mg/kg，腹腔注射，α2-肾上腺素能受体拮抗剂）、酮色林（5mg/kg，腹腔注射，5-HT2A/2C受体拮抗剂）或舒必利（多巴胺D2受体拮抗剂）预处理小鼠，可阻断21-羟基蜕皮甾酮的抗抑郁样作用，而在FST中，育亨宾或酮色林可阻断11β-羟基-20-脱氧蜕皮甾酮和24-羟基蜕皮激素的作用。此外，哌唑嗪（62.5μg/kg，腹腔注射，α1-肾上腺素能受体拮抗剂）预处理可阻断筋骨草甾酮引起的抗不动作用。我们的研究结果表明，钝叶牡荆及其植物蜕皮甾酮成分在绝望行为范式中具有抗抑郁样作用。此外，21-羟基蜕皮甾酮通过与α2-肾上腺素能受体、5-HT2A/2C受体和多巴胺D2受体相互作用产生其抗抑郁样作用，但11β-羟基-20-脱氧蜕皮甾酮和24-羟基蜕皮激素的作用取决于与α2-肾上腺素能受体和5-HT2A/2C受体的相互作用，而筋骨草甾酮通过与突触后α1-肾上腺素能受体相互作用发挥作用。因此，植物蜕皮甾酮在重度抑郁症的治疗中可能起关键作用。
