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激动剂和拮抗剂联合治疗神经炎症。

Combined Therapy of AAR Agonists and AAR Antagonists in Neuroinflammation.

机构信息

Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, 62032 Camerino, MC, Italy.

出版信息

Molecules. 2021 Feb 23;26(4):1188. doi: 10.3390/molecules26041188.

DOI:10.3390/molecules26041188
PMID:33672225
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7926490/
Abstract

Alzheimer's, Parkinson's, and multiple sclerosis are neurodegenerative diseases related by neuronal degeneration and death in specific areas of the central nervous system. These pathologies are associated with neuroinflammation, which is involved in disease progression, and halting this process represents a potential therapeutic strategy. Evidence suggests that microglia function is regulated by A and A adenosine receptors (AR), which are considered as neuroprotective and neurodegenerative receptors, respectively. The manuscript's aim is to elucidate the role of these receptors in neuroinflammation modulation through potent and selective AAR agonists (N-cyclopentyl-2'- or 3'-deoxyadenosine substituted or unsubstituted in 2 position) and AAR antagonists (9-ethyl-adenine substituted in 8 and/or in 2 position), synthesized in house, using N13 microglial cells. In addition, the combined therapy of AAR agonists and AAR antagonists to modulate neuroinflammation was evaluated. Results showed that AAR agonists were able, to varying degrees, to prevent the inflammatory effect induced by cytokine cocktail (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and interferon (IFN)-γ), while AAR antagonists showed a good ability to counteract neuroinflammation. Moreover, the effect achieved by combining the two most effective compounds ( and ) in doses previously found to be non-effective was greater than the treatment effect of each of the two compounds used separately at maximal dose.

摘要

阿尔茨海默病、帕金森病和多发性硬化症是神经退行性疾病，它们通过中枢神经系统特定区域的神经元变性和死亡联系在一起。这些病理学与神经炎症有关，神经炎症参与了疾病的进展，而阻止这一过程代表了一种潜在的治疗策略。有证据表明，小胶质细胞的功能受 A 和 A 腺苷受体 (AR) 的调节，这两种受体分别被认为是具有神经保护和神经退行性的受体。本文的目的是阐明这些受体在神经炎症调节中的作用，通过使用我们合成的强效和选择性的 AAR 激动剂（N-环戊基-2'-或 3'-脱氧腺苷取代或未取代 2 位）和 AAR 拮抗剂（8 位和/或 2 位取代的 9-乙基-腺嘌呤）来调节神经炎症。此外，还评估了 AAR 激动剂和 AAR 拮抗剂联合治疗来调节神经炎症的效果。结果表明，AAR 激动剂在不同程度上能够预防细胞因子鸡尾酒（肿瘤坏死因子 (TNF)-α、白细胞介素 (IL)-1β 和干扰素 (IFN)-γ）诱导的炎症效应，而 AAR 拮抗剂则具有很好的拮抗神经炎症的能力。此外，将两种最有效的化合物（和）以先前发现非有效剂量联合使用的效果大于以最大剂量单独使用两种化合物中任一种的治疗效果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/832e/7926490/9a8a702ebf76/molecules-26-01188-g012.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/832e/7926490/6e2a48fd0985/molecules-26-01188-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/832e/7926490/cb3685df75a7/molecules-26-01188-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/832e/7926490/9b410971b389/molecules-26-01188-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/832e/7926490/0fd9105d29da/molecules-26-01188-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/832e/7926490/20b7f6f4a69b/molecules-26-01188-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/832e/7926490/8395f2921719/molecules-26-01188-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/832e/7926490/b3901311c95d/molecules-26-01188-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/832e/7926490/9a8a702ebf76/molecules-26-01188-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/832e/7926490/766fedf0d103/molecules-26-01188-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/832e/7926490/231461389f2a/molecules-26-01188-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/832e/7926490/1fdfb3da53a1/molecules-26-01188-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/832e/7926490/2f8b63f40151/molecules-26-01188-g004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/832e/7926490/cb3685df75a7/molecules-26-01188-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/832e/7926490/9b410971b389/molecules-26-01188-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/832e/7926490/0fd9105d29da/molecules-26-01188-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/832e/7926490/20b7f6f4a69b/molecules-26-01188-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/832e/7926490/8395f2921719/molecules-26-01188-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/832e/7926490/b3901311c95d/molecules-26-01188-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/832e/7926490/9a8a702ebf76/molecules-26-01188-g012.jpg

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