School of Pharmacy, Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei 230032, China.
Stomatologic Hospital and College, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei 230032, China.
ACS Chem Neurosci. 2024 Jun 5;15(11):2308-2321. doi: 10.1021/acschemneuro.4c00139. Epub 2024 May 15.
Considerable research efforts have been directed toward the symptom relief of Parkinson's disease (PD) by attenuating dopamine (DA) depletion. One common feature of these existing therapies is their unavailability of preventing the neurodegenerative process of dopaminergic neurons. (+)-Borneol, a natural highly lipid-soluble bicyclic monoterpene, has been reported to regulate the levels of monoamine neurotransmitters in the central nervous system and exhibit neuroprotective effects. However, the effect of (+)-borneol on the dopaminergic neuronal loss of methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice is not defined. Herein, we first report that 30 mg/kg (+)-borneol significantly attenuated the motor deficits of PD mice, which benefits from markedly increasing the level of DA and decreasing the metabolic rate of DA in the striatum of conscious and freely moving mouse detected by ultraperformance liquid chromatography tandem mass spectrometry online combined with in vivo brain microdialysis sampling. It is worth noting that the enhanced level of DA by (+)-borneol was enabled by the reduction in loss of tyrosine hydroxylase-immunoreactive dopaminergic neurons in the substantia nigra and striatum and promotion of reserpine- or nomifensine-induced DA release in PD mice. Interestingly, (+)-borneol evidently inhibited the decreased expression levels of DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) on the MPTP mouse model of PD. Moreover, (+)-borneol suppressed the neuroinflammation by inhibiting the production of IL-1β, IL-6, and TNF-α and attenuated oxidative stress by decreasing the level of MDA and increasing the activities of SOD and GSH-px in PD mice. These findings demonstrate that (+)-borneol protects DA neurons by inhibiting neuroinflammation and oxidative stress. Further research work for the neuroprotection mechanism of (+)-borneol will focus on reactive oxygen species-mediated apoptosis. Therefore, (+)-borneol is a potential therapeutic candidate for retarding the neurodegenerative process of PD.
大量的研究致力于通过减轻多巴胺（DA）耗竭来缓解帕金森病（PD）的症状。这些现有疗法的一个共同特点是无法阻止多巴胺能神经元的神经退行性过程。(+)-龙脑，一种天然的高亲脂性双环单萜，已被报道调节中枢神经系统中单胺神经递质的水平，并表现出神经保护作用。然而，(+)-龙脑对甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的 PD 小鼠多巴胺能神经元丢失的影响尚未确定。在此，我们首次报道 30mg/kg(+)-龙脑可显著改善 PD 小鼠的运动障碍，这得益于明显增加清醒和自由活动小鼠纹状体中 DA 的水平，并降低 DA 的代谢率，这是通过超高效液相色谱串联质谱在线与体内脑微透析采样相结合检测到的。值得注意的是，(+)-龙脑增强 DA 水平是通过减少黑质和纹状体中酪氨酸羟化酶免疫反应性多巴胺能神经元的丢失和促进 PD 小鼠利血平或诺米芬辛诱导的 DA 释放来实现的。有趣的是，(+)-龙脑明显抑制了 PD 小鼠模型上 DA 转运体（DAT）和囊泡单胺转运体 2（VMAT2）表达水平的降低。此外，(+)-龙脑通过抑制 IL-1β、IL-6 和 TNF-α 的产生，抑制神经炎症，并通过降低 MDA 水平和增加 SOD 和 GSH-px 的活性来减轻氧化应激，从而减轻 PD 小鼠的氧化应激。这些发现表明(+)-龙脑通过抑制神经炎症和氧化应激来保护 DA 神经元。进一步研究(+)-龙脑的神经保护机制将集中在活性氧介导的细胞凋亡上。因此，(+)-龙脑是一种有潜力的治疗候选药物，可以延缓 PD 的神经退行性过程。
