Background

Depression causes significant debilitating symptoms and economic burden. Current management is challenged by slow onset of action and modest efficacies of antidepressants; thus, the search for newer antidepressants remains relevant. We evaluated the antidepressant effects of a kaurene diterpene, xylopic acid (XA), in zebrafish and mouse models.

Methods

The chronic unpredictable stress (CUS) protocol in zebrafish and the tail suspension test (TST), forced swim test (FST), lipopolysaccharide-induced depression-like behaviour test (LID) and repeated open space swimming test (OSST) in mice were used. We further examined the impact of depleting monoamines on XA’s antidepressant effects. The contribution of glutamatergic and nitrergic pathways on the antidepressant effect of XA in mice and XA’s effects on 5-HT receptors and monoamine oxidase (MAO) enzymes were also evaluated. Finally, XA’s influence on neuroprotection was evaluated by measuring BDNF and oxidative stress enzymes in whole brain. XA doses (1–10 μM) in zebrafish and (10, 30, 100 mg kg⁻¹) in mice exerted potent antidepressant-like potential in FST, TST, LID and showed fast-onset antidepressant-like property in the OSST.

Results

The antidepressant-like properties in mice were reversed by blocking synthesis/release of serotonin but not noradrenaline using p-chlorophenylalanine and α-methyl-p-tyrosine, respectively. This antidepressant-like effect was potentiated by d-cycloserine and Nω-Nitro-l-arginine methyl ester (l-NAME) but not by d-serine and L-arginine. XA also evoked partial agonist-like effects on 5-hydroxytrptamine receptors on the rat fundus but it did not have MAO inhibition effect. It also increased BDNF, glutathione and antioxidant enzymes.

Conclusion

Therefore, xylopic acid possesses antidepressant-like effects largely mediated by serotonergic and neuroprotective mechanisms.

中文翻译：

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木吡酸通过血清素能机制介导的抗抑郁样作用的证据

 背景

抑郁症会导致严重的衰弱症状和经济负担。目前的管理面临着抗抑郁药起效缓慢和疗效有限的挑战；因此，寻找新的抗抑郁药仍然具有现实意义。我们在斑马鱼和小鼠模型中评估了贝壳杉烯二萜、木吡酸 (XA) 的抗抑郁作用。

 方法

使用斑马鱼慢性不可预测应激（CUS）方案以及小鼠悬尾试验（TST）、强迫游泳试验（FST）、脂多糖诱导的抑郁样行为试验（LID）和重复开放空间游泳试验（OSST） 。我们进一步研究了消耗单胺对 XA 抗抑郁作用的影响。还评估了谷氨酸能和氮能途径对 XA 在小鼠中的抗抑郁作用的贡献以及 XA 对 5-HT 受体和单胺氧化酶 (MAO) 的影响。最后，通过测量全脑 BDNF 和氧化应激酶来评估 XA 对神经保护的影响。斑马鱼中的 XA 剂量（1-10 μM）和小鼠中的 XA 剂量（10, 30, 100 mg kg ^-1 ）在 FST、TST、LID 中发挥有效的抗抑郁样潜力，并在 OSST 中显示出快速起效的抗抑郁样特性。

 结果

通过分别使用对氯苯丙氨酸和α-甲基-对-酪氨酸阻断血清素而非去甲肾上腺素的合成/释放，可以逆转小鼠的抗抑郁样特性。这种抗抑郁样作用由d-环丝氨酸和 Nω-硝基-l-精氨酸甲酯 ( l -NAME) 增强，但d-丝氨酸和 L-精氨酸则不增强。 XA还对大鼠眼底的5-羟色胺受体产生部分激动剂样作用，但没有MAO抑制作用。它还增加了 BDNF、谷胱甘肽和抗氧化酶。

 结论

因此，木吡酸具有抗抑郁样作用，主要由血清素能和神经保护机制介导。