Department of Neurology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Research Center for Radiation Medicine, Chang Gung University, Taoyuan, Taiwan.
J Liposome Res. 2024 Dec;34(4):593-604. doi: 10.1080/08982104.2024.2346986. Epub 2024 May 23.
Anti-glutamatergic agents may have neuroprotective effects against excitotoxicity that is known to be involved in the pathogenesis of Parkinson's disease (PD). One of these agents is kynurenic acid (KYNA), a tryptophan metabolite, which is an endogenous N-methyl-D-aspartic acid (NMDA) receptor antagonist. However, its pharmacological properties of poor water solubility and limited blood-brain barrier (BBB) permeability rules out its systemic administration in disorders affecting the central nervous system. Our aim in the present study was to investigate the neuroprotective effects of KYNA-loaded micelles (KYNA-MICs) against PD and . Lipid-based micelles (MICs) in conjunction with KYNA drug delivery have the potential to enhance the penetration of therapeutic drugs into a diseased brain without BBB obstacles. KYNA-MICs were characterized by particle size (105.8 ± 12.1 nm), loading efficiency (78.3 ± 4.23%), and studies revealed that KYNA was successfully delivered by 5-fold increase in neurotoxin-induced PD brains. The results showed significant enhancement of KYNA delivery into brain. We also found that the KYNA-MICs exhibited several therapeutic effects. The KYNA-MICs reduced protein aggregation of an PD model, ameliorated motor functions, and prevented loss of the striatal neurons in a PD animal model. The beneficial effects of KYNA-MICs are probably explained by the anti-excitotoxic activity of the treatment's complex. As the KYNA-MICs did not induce any appreciable side-effects at the protective dose applied to a chronic PD mouse model, our results demonstrate that KYNA provides neuroprotection and attenuates PD pathology.
抗谷氨酸能药物可能对兴奋性毒性具有神经保护作用，已知兴奋性毒性与帕金森病（PD）的发病机制有关。其中一种药物是犬尿氨酸（KYNA），一种色氨酸代谢物，是内源性 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂。然而，其较差的水溶性和有限的血脑屏障（BBB）通透性药理学特性排除了其在影响中枢神经系统的疾病中的全身给药。我们在本研究中的目的是研究 KYNA 载药胶束（KYNA-MICs）对 PD 的神经保护作用。与 KYNA 药物递送相结合的基于脂质的胶束（MICs）有可能增强治疗药物穿透患病大脑而不受 BBB 障碍的影响。KYNA-MICs 的特征为粒径（105.8±12.1nm）、载药效率（78.3±4.23%）和。体内研究表明，KYNA-MICs 可使神经毒素诱导的 PD 脑内 KYNA 的递送增加 5 倍。结果表明 KYNA 向脑内的递送得到了显著增强。我们还发现 KYNA-MICs 表现出多种治疗作用。KYNA-MICs 减少了 PD 模型中的蛋白聚集，改善了运动功能，并防止了 PD 动物模型中纹状体神经元的丢失。KYNA-MICs 的有益作用可能归因于治疗复合物的抗兴奋毒性活性。由于 KYNA-MICs 在应用于慢性 PD 小鼠模型的保护剂量下没有引起任何明显的副作用，我们的结果表明 KYNA 提供了神经保护作用并减轻了 PD 病理。
