MICA: Potential of P2X7 receptor antagonism to attenuate the adverse consequences of neurotrauma (PROTECT)

创伤性脑损伤（TBI）通常与福尔斯、道路交通和袭击有关，并且对社区具有巨大影响;它是生命的前四十年中死亡和残疾的主要原因，估计每年花费英国经济80亿英镑。目前的标准护理以神经外科干预和稳定为中心，但是死亡率相对较高，并且许多幸存者遭受终身残疾。尽管临床需求明显未得到满足，但临床上没有批准的药物可用于减少TBI对患者的影响。虽然药物很难减轻初始损伤的后果，但人们普遍认为，与初始创伤相关的死亡和垂死的脑组织会引起炎症，炎症会扩散到周围的脑组织，这些脑组织可能会受损，但并非不可逆。然而，炎症对邻近脑组织的额外压力扩大了脑损伤的体积。这种继发性非机械性脑损伤在最初的TBI事件后数小时至数天内开始，因此被认为是适合用药物进行潜在治疗的。在科学文献中，一种被称为P2 X7受体的药物靶点参与了对脑组织施加压力的生理过程，并可能导致脑细胞死亡-事实上，“死亡受体”一词已被用于P2 X7受体。P2 X7受体的初始激活引起脑细胞的兴奋，导致它们分泌增加炎症的化学物质，增加TBI后炎症环境对脑细胞的压力。随着P2 X7受体的更长时间的激活，受体改变形状，使得它在细胞膜中形成相对大的孔，这进一步压迫细胞并可导致细胞死亡。我们认为，用药物阻断P2 X7受体将阻止导致脑细胞应激的过程，从而有助于减少TBI后的继发性脑损伤。我们预测这将改善TBI患者的临床结局，使更多患者存活并减少残疾。幸运的是，通过与辉瑞制药公司的合作，我们将能够使用一种代号为CE-224，535的药物，这种药物具有选择性阻断P2 X7受体的能力。此外，迄今为止在健康志愿者和关节炎患者中使用CE-224，535的临床研究表明，口服给药后药物耐受性良好。我们的研究将采取逐步的方法。我们将首先使用接受神经外科手术的TBI患者的小块脑组织-该脑组织在标准神经外科技术期间远离大脑，因此其收集不会改变患者的结果。这些细胞的实验结果将能够预测CE-224，535需要进入TBI患者的大脑以阻断P2 X7受体的浓度，我们预测这将对患者有益。然后，我们将对TBI患者给予CE-224，535进行临床试验，临床试验的主要目的是评估CE-224，535具有良好的耐受性，并在大脑受损部位达到阻断P2 X7受体的浓度。我们还将监测药物对作为细胞损伤和炎症标志物的生物化学物质的任何影响，并监测患者的临床状况，并在28天后对患者进行随访。重要的是，即使由于研究的患者数量相对较少，患者的获益可能并不明显，但这些结果将更好地为直接评估CE-224，535（以及其他也阻断P2 X7受体的药物）使TBI患者获益的潜力的大型临床试验的设计提供信息。

Traumatic brain injury (TBI) is commonly associated with falls, road traffic and assaults and has a massive impact upon the community; it is the leading cause of death and disability in the first four decades of life, costing the UK economy an estimated £8 billion per year.Current standard care centers upon neurosurgical intervention and stabilization, yet mortality is relatively high and many that survive suffer life-time disability. Despite the obvious unmet clinical need, there are no approved drugs available in the clinic to reduce the impact of TBI on the patient. Whilst it would be difficult for a drug to reduce the consequences of the initial injury, it is well recognised that the dead and dying brain tissue associated with the initial trauma gives rise to inflammation that spreads to surrounding brain tissue that may be damaged but not irreversibly. However, the added stress of inflammation to this adjacent brain tissue expands the volume of brain damage. This secondary non-mechanical brain damage begins over hours to days after the initial TBI event and is hence considered amenable to potential treatment with drugs. It is well recognized in the scientific literature that a drug target called the P2X7 receptor is involved in the physiological processes that stress brain tissue and can lead to brain cell death - indeed the term 'death receptor' has been coined for the P2X7 receptor. Initial activation of the P2X7 receptor causes excitation of brain cells resulting in their secretion of chemicals that increase inflammation, adding to the stress upon brain cells from the inflammatory environment post-TBI. With more prolonged activation of the P2X7 receptor, the receptor changes shape such that it forms relatively large pores in the cell membrane, which further stresses the cells and can lead to cell death. We believe that blocking the P2X7 receptor with a drug will put a brake on the processes contributing to stressing the brain cells and so help reduce the secondary brain damage subsequent to TBI. We predict this will improve the clinical outcomes for patients following TBI allowing more patients to survive and reduce disability. It is fortunate that, through a collaboration with the pharmaceutical company Pfizer, we will be able to use a drug, code name CE-224,535, that is selective in its ability to block the P2X7 receptor. In addition, clinical studies to date using CE-224,535 in healthy volunteers and patients with arthritis have shown that the drug is well tolerated following oral administration.Our studies will take a step-wise approach. We will first use small pieces of brain tissue from TBI patients undergoing neurosurgery - this brain tissue comes away from the brain during standard neurosurgical techniques and hence its collection does not change the outcome for the patient. Results from experiments with these cells will enable a prediction concerning the concentrations of CE-224,535 that need to get into the brain of patients with TBI to block the P2X7 receptor, which we predict will be beneficial for the patient.We will then perform a clinical trial with CE-224,535 given to TBI patients with the primary purpose of the clinical trial to assess whether CE-224,535 is well tolerated and reaches concentrations in the injured part of the brain that will block the P2X7 receptor. We will also monitor any effect of the drug on biological chemicals that act as markers for cell damage and inflammation and monitor the clinical condition of the patient and follow up the patient after 28 days. Importantly, even if benefit for the patients is not overt possibly due to the relatively small number of patients studied, the outcomes will better inform the design of larger clinical trials that directly assess the potential of CE-224,535 (and other drugs that also block the P2X7 receptor) to benefit patients with TBI.