Prazosin Hydrochloride

▎药明康德内容团队编辑 遭遇创伤性脑损伤（traumatic brain injury，TBI）后，患者可能会出现致命的脑水肿。这类脑部肿胀会急剧增加死亡风险，并影响脑功能的恢复前景。在极端情况下，医生需要切除一部分颅骨以释放压力，但这样的手术风险极高，并且仅适用于小部分TBI患者。时至今日，脑水肿仍是院内死亡的常见病因，并且与长期的神经功能障碍相关。近日，一项发表于《自然》杂志的研究有望带来破局的方案。研究发现，一款基于已获批治疗高血压药物的鸡尾酒疗法，能够迅速缓解脑水肿，并且在动物模型中改善脑部损伤。这项最新研究由罗切斯特大学转化神经医学中心联合主任Maiken Nedergaard博士领导。2012年，Nedergaard实验室首次发现了大脑中的类淋巴系统，该系统能够清除大脑中的废物。此后，在先进的成像技术和AI驱动的流体力学模型的辅助下，研究人员能够更精准地预测、操纵中枢神经系统中脑脊液（CSF）的运动。在随后的10年内，人们对脑部类淋巴系统的理解不断深入。现在，最新研究又发现了该系统的又一项潜在作用：成为紧急情况下释放压力的“阀门”。“在身体其他部位，水肿有助于组织修复。但由于坚固的颅骨的存在，大脑膨胀能力有限，因此颅内压力增加，血液供应减少，使得废物碎片和毒性蛋白留在损伤部位而无法被冲刷走。由此，损伤恢复也变得更加复杂。”该研究的第一作者，罗切斯特大学转化神经医学中心助理教授Rashad Hussain说。图片来源：123RF研究团队从脑水肿的机制出发，找到了解决思路。脑水肿的主要诱因之一是去甲肾上腺素。出现TBI后，这种神经递质立即充斥着大脑。我们更熟悉的去甲肾上腺素功能是调控“逃跑或战斗”反应，但在TBI中，这种“肾上腺素能风暴”阻碍了脑脊液流入以及流出大脑的过程。研究指出，去甲肾上腺素限制了脑脊液从大脑引流，流入脑膜以及颈部淋巴结的过程，从而妨碍淋巴系统的功能。根据这一现象，研究团队推测，重新打开淋巴结的这些“门”或许可以将多余的脑脊液从大脑中冲走，从而缓解压力。为此，研究团队使用了一种由哌唑嗪、阿替美唑和普萘洛尔组成的鸡尾酒药物。这3种药物分别是α1-、α2和β-受体阻滞剂，其组合共同抑制了细胞摄取去甲肾上腺素所用的不同受体。Nedergaard实验室此前的研究已经表明，这种药物组合会提升类淋巴系统的效率，使其达到我们在睡觉时的活动水平，这正是系统操纵脑脊液流动、清除废物最有效的阶段。▲肾上腺素能抑制剂能抵消TBI对类淋巴流动的阻碍（图片来源：参考资料[2]）在这项的研究中，作者在TBI后不久给予小鼠上述鸡尾酒药物治疗，并且追踪了来自肿胀部位的脑脊液。脑脊液携带来自淋巴结损伤的碎片，通过淋巴管从脑部大量流出。结果，小鼠的脑水肿几乎立即消除，颅内压力恢复正常。同时，治疗使得小鼠的认知、行为和运动功能显著恢复。Nedergaard博士说：“这些发现表明，肾上腺素能风暴、由此产生的脑水肿和颅内压，以及留在脑内的碎片，都可以通过肾上腺素能抑制剂得到逆转，小鼠的恢复情况也得到改善。”▲肾上腺素能抑制剂作用机制示意图（图片来源：参考资料[2]）作者指出，已有几项临床研究证实了该药物组合的安全性，并观察到了神经系统获益，早期证据也表明这种方法可能有益于人类。阿替美唑可减少创伤后癫痫发作，哌唑嗪可有效治疗TBI相关的创伤后应激，而普萘洛尔作为β-受体阻滞剂可降低TBI患者的住院死亡率并改善功能预后。Nedergaard博士也表示，由于这些药物已经在临床上使用，因此有可能迅速进入临床研究以证实这些发现。参考资料：[1] Pulling the plug on brain injury: manipulating fluid flows could save lives, improve recovery post-TBI. Retrieved on Nov 16, 2023 from https://www.eurekalert.org/news-releases/1007861[2] Hussain, R., Tithof, J., Wang, W. et al. Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema. Nature (2023). https://doi.org/10.1038/s41586-023-06737-7本文来自药明康德内容微信团队，欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。更多推荐点个“在看”再走吧~

New research shows that a cocktail of drugs already approved to treat high blood pressure quickly reduces brain swelling and improves outcomes in animal models of brain injury.  Cerebral edema, the dangerous brain swelling that occurs after traumatic brain injury (TBI), can increase risk of death tenfold and significantly worsen prospects for recovery in brain function. In extreme cases, surgeons will remove a portion of the skull to relieve pressure, but this has significant risks and is not viable for the vast majority of TBI cases. Physicians have very few tools at their disposal that are effective in treating cerebral edema, which is one of the leading causes of in-hospital deaths, and is associated with long-term neurological disability. New research appearing today in the journal Nature could change all that, showing that a cocktail of drugs already approved to treat high blood pressure quickly reduces brain swelling and improves outcomes in animal models of brain injury. "Our research shows that cerebral edema is the consequence of impaired fluid flow through the glymphatic system and its associated lymphatic drainage," said Maiken Nedergaard, MD, DMSc, co-director of the University of Rochester Center for Translational Neuromedicine and senior author of the study. "This impairment is under adrenergic control, and can therefore be rescued pharmacologically by broadly inhibiting adrenergic receptors. Because these drugs are already being used clinically and have observed neurological benefits, there is the potential to move quickly to clinical studies to confirm these findings." Manipulating fluid flows in the brain to release post-TBI brain pressure The glymphatic system was first described by Nedergaard's lab in 2012 as the brain's unique waste removal process. Since then, a growing understanding of the mechanics of the system-aided by advanced imaging technologies and AI-driven models of fluid dynamics -- has allowed researchers to better predict and manipulate the movement of cerebrospinal fluid (CSF) in the central nervous system. This research has opened new possibilities to treat Alzheimer's and other neurological disorders and more effectively deliver and distribute drugs in the central and peripheral nervous system, including the inner ear. The new study points to the potential to repurpose the glymphatic system to act as an emergency pressure release valve. Cerebral edema is a common consequence of moderate and severe cases of TBI. "In other parts of the body, edema helps with tissue repair, but because of the skull, the brain has limited capacity for expansion. As a result, pressure increases, blood supply decreases, and debris and toxic proteins are trapped at the injury site, compounding the damage and impairing recovery," said Rashad Hussain, PhD, an assistant professor in the Center for Translational Neuromedicine and first author of the study. One of the main triggers of cerebral edema is noradrenaline, a neurotransmitter that floods the brain immediately after TBI. Noradrenaline is typically associated with the flight-or-fight response, but in TBI this "adrenergic storm" impairs the flow of CSF in and out of the brain. The researchers describe how noradrenaline interferes with the function of the glymphatic system. Specifically, it restricts the movement of fluid through the section of the system's plumbing where CSF drains from the brain and flows into the meningeal and cervical lymph nodes in the neck. This observation led the team to speculate whether reopening these gates to the lymph nodes could flush excess CSF from the brain, thereby relieving pressure. Blood pressure medications suppress adrenaline "storm" and restart fluid flow To accomplish this, the team used a cocktail of drugs, including prazosin, atipamezole, and propranolol. This combination of alpha- and beta-blockers collectively suppress the different receptors used by cells to take up noradrenaline. Previous research in Nedergaard's lab has shown that this combination of drugs ramps up the glymphatic system, replicating the level of activity experienced when we sleep, which is when the system is most efficient in manipulating CSF flow to remove waste. In the new study, the same drug cocktail was administered to mice soon after TBI. Using fluorescent microspheres, the researchers traced CSF originating from the site of the swelling as it exited in bulk from the brain via lymphatic vessel, carrying with it debris from the injury to the lymph nodes. The result was an almost immediate elimination of cerebral edema and a sustained return to normal intracranial pressure in the animals. The treatment resulted significant recovery of cognitive, behavioral, and motor function. "These findings show that the adrenergic storm, the resulting edema and intracranial pressure, and retention of neural debris, can all be reversed by broad adrenergic inhibition, with subsequent improvement in recovery in injured mice," said Nedergaard. The authors point to several clinical studies that demonstrate the safety profiles and observed neurological benefits of these drugs, early indications that this approach could also benefit humans. Atipamezole reduces post-traumatic seizures, prazosin is effective in treating the post-traumatic stress associated with TBI, and beta-blockers reduce in-hospital mortality and improve functional outcome of TBI patients. Additionally, Nedergaard and her colleagues at the University of Copenhagen have shown that individuals who take beta-blockers for hypertension are at lower risk for Alzheimer's. Additional co-authors in the study include: Jeffrey Tifhof, Wei Wang, Arokoruba Cheetham-West, Wei Song, Weiguo Peng, Qian Sun, Sisi Peng, and Doug Kelley with the University of Rochester; Bjorn Sigurdsson and Pia Weikop with the University of Copenhagen; Virginia Pla, Hajime Hirase and Steve Goldman with both with the Universities of Rochester and Copenhagen; Daeyun Kim with the University of Minnesota; Jorge Castorena-Gonzalez with the Tulane University; and Michael Davis with the University of Missouri. The research was supported with funding from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the National Institute of Neurological Disorders and Stroke, the Burroughs Wellcome Fund, the Joint Programme -- Neurodegenerative Disease Research, the Novo Nordisk Foundation, the Lundbeck Foundation, and the US Army Research Office.