Khanal Shristi, Shin Eun-Joo, Yoo Chang Jae, Kim Jaekwang, Choi Dong-Young
College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea.
College of Pharmacy, Kangwon National University, Chuncheon, Gangwon, Republic of Korea.
Neuropharmacology. 2025 Mar 15;266:110278. doi: 10.1016/j.neuropharm.2024.110278. Epub 2024 Dec 24.
Neuroinflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Transformation of pro-interleukin (IL)-1β into a mature IL-1β via active inflammasome may be related to the progression of PD. Therefore, the modification of inflammasome activity may be a potential therapeutic strategy for PD. Inosine has been shown to exert anti-inflammatory effects in various disease models. In this study, we evaluated inosine's inhibitory effects on the microglial NLRP3 inflammasome, which may be related to the dopaminergic neuroprotective effects of inosine. Inosine suppresses lipopolysaccharides (LPS)-induced NLRP3 inflammasome activation in BV-2 microglial cells dose dependently. When SH-SY5Y cells were treated with conditioned medium from BV-2 cells treated with LPS and inosine, an NLRP3 inhibitor, or a caspase-1 inhibitor, the viability of SH-SY5Y cells was reduced indicating that LPS-induced microglial inflammasome activation could contribute to neuronal death. Inosine's modulatory effect on NLRP3 inflammasome activity appears to rely on the adenosine A and A receptors activation, as A or A receptor antagonists reversed the amelioration of NLRP3 activation by inosine. In addition, inosine treatment attenuated intracellular and mitochondrial ROS production mediated by LPS and this effect might be related to attenuation of NLRP3 inflammasome activity, as the antioxidant, N-acetyl cysteine ameliorated LPS-induced activation of the inflammasome. Finally, we assessed the inosine's neuroprotective effects via inflammasome activity modulation in mice receiving an intranigral injection of LPS. Immunohistochemical analysis revealed that LPS caused a significant loss of nigral dopaminergic neurons, which was mitigated by inosine treatment. LPS increased NLRP3 expression in IBA1-positive microglial cells, which was attenuated by inosine injection. These findings indicate that inosine can rescue neurons from LPS-induced injury by ameliorating NLRP3 inflammasome activity. Therefore, inosine could be applied as an intervention for neuroinflammatory diseases such as Parkinson's disease.
神经炎症在帕金森病（PD）的发病机制中起关键作用。通过活性炎性小体将前白细胞介素（IL）-1β转化为成熟的IL-1β可能与PD的进展有关。因此，调节炎性小体活性可能是PD的一种潜在治疗策略。已有研究表明，肌苷在各种疾病模型中具有抗炎作用。在本研究中，我们评估了肌苷对小胶质细胞NLRP3炎性小体的抑制作用，这可能与肌苷的多巴胺能神经保护作用有关。肌苷剂量依赖性地抑制脂多糖（LPS）诱导的BV-2小胶质细胞中NLRP3炎性小体的激活。当用LPS和肌苷、NLRP3抑制剂或半胱天冬酶-1抑制剂处理的BV-2细胞的条件培养基处理SH-SY5Y细胞时，SH-SY5Y细胞的活力降低，表明LPS诱导的小胶质细胞炎性小体激活可能导致神经元死亡。肌苷对NLRP3炎性小体活性的调节作用似乎依赖于腺苷A和A受体的激活，因为A或A受体拮抗剂可逆转肌苷对NLRP3激活的改善作用。此外，肌苷处理可减轻LPS介导的细胞内和线粒体活性氧的产生，这种作用可能与NLRP3炎性小体活性的减弱有关，因为抗氧化剂N-乙酰半胱氨酸可改善LPS诱导的炎性小体激活。最后，我们通过调节炎性小体活性评估了肌苷对接受黑质内注射LPS的小鼠的神经保护作用。免疫组织化学分析显示，LPS导致黑质多巴胺能神经元显著丢失，而肌苷处理可减轻这种丢失。LPS增加了IBA1阳性小胶质细胞中NLRP3的表达，而肌苷注射可使其减弱。这些发现表明，肌苷可通过改善NLRP3炎性小体活性来挽救神经元免受LPS诱导的损伤。因此，肌苷可作为帕金森病等神经炎症性疾病的一种干预措施。
