Lee Natasha Ting, Savvidou Ioanna, Selan Carly, Wright David K, Brkljaca Robert, Chia Joanne S J, Calvello Ilaria, Craenmehr Daphne D D, Larsson Pia, Tarlac Volga, Vuong Amy, Carmichael Irena, Wang Xiaowei, Peter Karlheinz, Robson Simon C, Nandurkar Harshal H, Sashindranath Maithili
Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, VIC, 3004, Australia.
Monash Biomedical Imaging, Monash University, Clayton, VIC, 3168, Australia.
J Neuroinflammation. 2025 Apr 21;22(1):115. doi: 10.1186/s12974-025-03394-7.
Global ischemic brain injury occurs after cardiac arrest or prolonged hypotensive episodes following surgery or trauma. It causes significant neurological deficits even after successful re-establishment of blood flow. It is the primary cause of death in 68% of inpatient and 23% of out-of-hospital cardiac arrest cases, but there are currently no treatments. Endothelial activation and dysfunction impairing small vessel blood flow is the cause of brain damage. Purinergic signaling is an endogenous molecular pathway, where CD39 and CD73 catabolize extracellular adenosine triphosphate (eATP) to adenosine. After ischemia, eATP is released, triggering thrombosis and inflammation. In contrast, adenosine is anti-thrombotic, protects against oxidative stress, and suppresses the immune response. Our group developed a bifunctional compound - anti-VCAM-CD39 that targets the dysregulated endothelium and promotes adenosine generation at the infarct site, localising the antithrombotic and anti-inflammatory effects of CD39. We investigated whether anti-VCAM-CD39 could improve outcome in a murine model of global ischaemia caused by dual carotid artery ligation (DCAL). Test drugs anti-VCAM-CD39 and controls were given 3 h after 30 min ischaemia. Assessments at 24 h included neurological function, infarct volume, perfusion, and albumin extravasation to assess blood-brain barrier (BBB) permeability. We showed that there was an overall improvement in neurological deficit in anti-VCAM-CD39-treated mice after DCAL. MRI revealed that these mice had significantly smaller infarcts and reduced apoptotic activity on the side of permanent occlusion, compared to saline treated mice. There was reduced albumin extravasation in treated mice after DCAL, suggesting anti-VCAM-CD39 conferred neuroprotection in the brain through preservation of BBB permeability. In vitro findings confirmed that anti-VCAM-CD39-mediated adenosine production protected against hypoxia-induced endothelial cell death. anti-VCAM-CD39 is a novel therapeutic that can promote neuroprotection, reduce tissue damage and inflammation after hypoxic brain injury in mice. These findings suggest that anti-VCAM-CD39 could be a new avenue of cardiac arrest therapy and could potentially be used in other cerebrovascular diseases where endothelial dysfunction is a constant underlying pathology.
全脑缺血性脑损伤发生在心脏骤停后，或手术或创伤后长时间的低血压发作之后。即使在成功恢复血流后，它也会导致严重的神经功能缺损。它是68%的住院患者和23%的院外心脏骤停病例的主要死因，但目前尚无治疗方法。内皮细胞激活和功能障碍损害小血管血流是脑损伤的原因。嘌呤能信号传导是一种内源性分子途径，其中CD39和CD73将细胞外三磷酸腺苷（eATP）分解为腺苷。缺血后，eATP释放，引发血栓形成和炎症。相比之下，腺苷具有抗血栓形成作用，可抵御氧化应激，并抑制免疫反应。我们的团队开发了一种双功能化合物——抗血管细胞黏附分子-1-CD39，它靶向失调的内皮细胞，并在梗死部位促进腺苷生成，使CD39的抗血栓形成和抗炎作用局部化。我们研究了抗血管细胞黏附分子-1-CD39是否能改善双侧颈动脉结扎（DCAL）所致全脑缺血小鼠模型的预后。在缺血30分钟后3小时给予试验药物抗血管细胞黏附分子-1-CD39和对照药物。24小时后的评估包括神经功能、梗死体积、灌注以及白蛋白外渗，以评估血脑屏障（BBB）通透性。我们发现，DCAL后，抗血管细胞黏附分子-1-CD39治疗的小鼠神经功能缺损总体有所改善。磁共振成像显示，与生理盐水治疗的小鼠相比，这些小鼠在永久性闭塞侧的梗死灶明显更小，凋亡活性降低。DCAL后，治疗小鼠的白蛋白外渗减少，表明抗血管细胞黏附分子-1-CD39通过维持血脑屏障通透性在脑内发挥神经保护作用。体外研究结果证实，抗血管细胞黏附分子-1-CD39介导的腺苷生成可保护内皮细胞免受缺氧诱导的死亡。抗血管细胞黏附分子-1-CD39是一种新型治疗药物，可促进神经保护，减少小鼠缺氧性脑损伤后的组织损伤和炎症。这些发现表明，抗血管细胞黏附分子-1-CD39可能是心脏骤停治疗的新途径，并可能潜在地用于其他以内皮功能障碍为持续潜在病理改变的脑血管疾病。
