Centre of Perinatal Medicine and Health, Institute of Clinical Sciences, Department of Obstetrics and Gynecology & Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.
EGA Institute for Women's Health, University College London, UK.
Brain. 2018 Oct 1;141(10):2925-2942. doi: 10.1093/brain/awy220.
Hypoxic-ischaemic encephalopathy remains a global health burden. Despite medical advances and treatment with therapeutic hypothermia, over 50% of cooled infants are not protected and still develop lifelong neurodisabilities, including cerebral palsy. Furthermore, hypothermia is not used in preterm cases or low resource settings. Alternatives or adjunct therapies are urgently needed. Exendin-4 is a drug used to treat type 2 diabetes mellitus that has also demonstrated neuroprotective properties, and is currently being tested in clinical trials for Alzheimer's and Parkinson's diseases. Therefore, we hypothesized a neuroprotective effect for exendin-4 in neonatal neurodisorders, particularly in the treatment of neonatal hypoxic-ischaemic encephalopathy. Initially, we confirmed that the glucagon like peptide 1 receptor (GLP1R) was expressed in the human neonatal brain and in murine neurons at postnatal Day 7 (human equivalent late preterm) and postnatal Day 10 (term). Using a well characterized mouse model of neonatal hypoxic-ischaemic brain injury, we investigated the potential neuroprotective effect of exendin-4 in both postnatal Day 7 and 10 mice. An optimal exendin-4 treatment dosing regimen was identified, where four high doses (0.5 µg/g) starting at 0 h, then at 12 h, 24 h and 36 h after postnatal Day 7 hypoxic-ischaemic insult resulted in significant brain neuroprotection. Furthermore, neuroprotection was sustained even when treatment using exendin-4 was delayed by 2 h post hypoxic-ischaemic brain injury. This protective effect was observed in various histopathological markers: tissue infarction, cell death, astrogliosis, microglial and endothelial activation. Blood glucose levels were not altered by high dose exendin-4 administration when compared to controls. Exendin-4 administration did not result in adverse organ histopathology (haematoxylin and eosin) or inflammation (CD68). Despite initial reduced weight gain, animals restored weight gain following end of treatment. Overall high dose exendin-4 administration was well tolerated. To mimic the clinical scenario, postnatal Day 10 mice underwent exendin-4 and therapeutic hypothermia treatment, either alone or in combination, and brain tissue loss was assessed after 1 week. Exendin-4 treatment resulted in significant neuroprotection alone, and enhanced the cerebroprotective effect of therapeutic hypothermia. In summary, the safety and tolerance of high dose exendin-4 administrations, combined with its neuroprotective effect alone or in conjunction with clinically relevant hypothermia make the repurposing of exendin-4 for the treatment of neonatal hypoxic-ischaemic encephalopathy particularly promising.
缺氧缺血性脑病仍然是全球健康负担。尽管医学进步和采用治疗性低温治疗，但仍有超过 50%的冷却婴儿未得到保护，仍会发展出终身神经残疾，包括脑瘫。此外，早产儿或资源匮乏的情况下不使用低温治疗。急需替代或辅助治疗方法。Exendin-4 是一种用于治疗 2 型糖尿病的药物，也具有神经保护作用，目前正在临床试验中用于治疗阿尔茨海默病和帕金森病。因此，我们假设 Exendin-4 对新生儿神经疾病具有神经保护作用，特别是在治疗新生儿缺氧缺血性脑病方面。最初，我们证实胰高血糖素样肽 1 受体 (GLP1R) 在人类新生儿大脑和出生后第 7 天（人类相当于晚期早产儿）和第 10 天（足月）的鼠神经元中表达。使用一种经过充分表征的新生鼠缺氧缺血性脑损伤模型，我们研究了 Exendin-4 在出生后第 7 天和 10 天的小鼠中的潜在神经保护作用。确定了最佳的 Exendin-4 治疗剂量方案，即 4 次高剂量（0.5 µg/g），从出生后第 7 天缺氧缺血性损伤后 0 小时开始，然后在 12 小时、24 小时和 36 小时给予，导致显著的脑神经保护作用。即使在缺氧缺血性脑损伤后 2 小时延迟使用 Exendin-4 治疗，神经保护作用也能持续。这种保护作用在各种组织病理学标志物中都得到了观察：组织梗死、细胞死亡、星形胶质细胞增生、小胶质细胞和内皮细胞激活。与对照组相比，高剂量 Exendin-4 给药不会改变血糖水平。Exendin-4 给药不会导致不良的器官组织病理学（苏木精和伊红）或炎症（CD68）。尽管最初体重增加减少，但动物在治疗结束后恢复了体重增加。总体而言，高剂量 Exendin-4 给药耐受性良好。为了模拟临床情况，对出生后第 10 天的小鼠单独或联合进行 Exendin-4 和治疗性低温治疗，并在 1 周后评估脑组织损失。Exendin-4 治疗单独即可显著保护神经，并增强治疗性低温的脑保护作用。总之，高剂量 Exendin-4 给药的安全性和耐受性，以及其单独或与临床相关低温联合使用的神经保护作用，使得 Exendin-4 用于治疗新生儿缺氧缺血性脑病具有特别大的前景。
