National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy.
Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, Camerino, Italy.
J Neurochem. 2019 Apr;149(2):211-230. doi: 10.1111/jnc.14660. Epub 2019 Feb 11.
Cerebral ischemia is the second most common cause of death and a major cause of disability worldwide. Available therapies are based only on anticoagulants or recombinant tissue plasminogen activator. Extracellular adenosine increases during ischemia and acts as a neuroprotective endogenous agent mainly by activating adenosine A receptors (A Rs) which control calcium influx, glutamate release, membrane potential, and metabolism. Accordingly, in many experimental paradigms it has been already demonstrated that the stimulation of A R with full agonists is able to reduce ischemia-related structural and functional brain damage; unfortunately, cardiovascular side effects and desensitization of A R induced by these compounds have strongly limited their exploitation in stroke therapy so far. Among the newly emerging compounds, A R partial agonists could be almost free of side effects and equally effective. Therefore, we decided to evaluate the neuroprotective potential of two A R partial agonists, namely 2'-dCCPA and 3'-dCCPA, in in vitro and ex vivo experimental models of cerebral ischemia. Within the experimental paradigm of oxygen-glucose deprivation in vitro in human neuroblastoma (SH-SY5Y) cells both A R partial agonists increased cell viability. Considering the high level of expression of A Rs in the hippocampus and the susceptibility of CA1 region to hypoxia, we performed electrophysiological experiments in this subfield. The application of 7 min of oxygen-glucose deprivation constantly produces an irreversible synaptic failure in all the C57Bl/6 mice hippocampal slices evaluated; both tested compounds allowed a significant recovery of synaptic transmission. These findings demonstrate that A R and its partial agonists are still of interest for cerebral ischemia therapy. OPEN SCIENCE BADGES: This article has received a badge for Open Materials because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.
脑缺血是全球范围内仅次于死亡的第二大致死原因，也是导致残疾的主要原因。现有的治疗方法仅基于抗凝剂或重组组织纤溶酶原激活剂。细胞外腺苷在缺血期间增加，并作为一种神经保护内源性物质起作用，主要通过激活腺苷 A 受体（A Rs）来控制钙内流、谷氨酸释放、膜电位和代谢。因此，在许多实验模型中已经证明，用完全激动剂刺激 A R 能够减少与缺血相关的结构和功能脑损伤；不幸的是，这些化合物引起的心血管副作用和 A R 脱敏作用迄今为止极大地限制了它们在中风治疗中的应用。在新出现的化合物中，A R 部分激动剂几乎可以没有副作用，并且同样有效。因此，我们决定评估两种 A R 部分激动剂，即 2'-dCCPA 和 3'-dCCPA，在体外和离体脑缺血实验模型中的神经保护潜力。在体外人神经母细胞瘤（SH-SY5Y）细胞的氧葡萄糖剥夺实验中，两种 A R 部分激动剂均增加了细胞活力。考虑到 A Rs 在海马体中的高表达水平以及 CA1 区域对缺氧的敏感性，我们在该亚区进行了电生理实验。在所有评估的 C57Bl/6 小鼠海马切片中，7 分钟的氧葡萄糖剥夺应用始终会导致不可逆转的突触失活；两种测试化合物都允许突触传递得到显著恢复。这些发现表明 A R 及其部分激动剂仍然是脑缺血治疗的关注点。开放科学徽章：本文获得了开放材料徽章，因为它提供了重现手稿中研究的所有相关信息。本文的完整开放科学披露表格可以在文章末尾找到。有关开放实践徽章的更多信息可以在 https://cos.io/our-services/open-science-badges/ 找到。
