Toker Daniel, Chiang Jeffrey N, Vespa Paul M, Schnakers Caroline, Monti Martin M
Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA.
Neurocrit Care. 2025 Feb 4. doi: 10.1007/s12028-025-02217-0.
Despite advancements in the neuroscience of consciousness, no new medications for disorders of consciousness (DOC) have been discovered in more than a decade. Repurposing existing US Food and Drug Administration (FDA)-approved drugs for DOC is crucial for improving clinical management and patient outcomes.
To identify potential new treatments among existing FDA-approved drugs, we used a deep learning-based drug screening model to predict the efficacy of drugs as awakening agents based on their three-dimensional molecular structure. A retrospective cohort study from March 2012 to October 2024 tested the model's predictions, focusing on changes in Glasgow Coma Scale (GCS) scores in 4047 patients in a coma from traumatic, vascular, or anoxic brain injury.
Our deep learning drug screens identified saxagliptin, a dipeptidyl peptidase-4 inhibitor, as a promising awakening drug for both acute and prolonged DOC. The retrospective clinical analysis showed that saxagliptin was associated with the highest recovery rate from acute coma among diabetes medications. After matching patients by age, sex, initial GCS score, coma etiology, and glycemic status, brain-injured patients with diabetes on incretin-based therapies, including dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 analogues, recovered from coma at significantly higher rates compared to both brain-injured patients with diabetes on non-incretin-based diabetes medications (95% confidence interval of 1.8-14.1% higher recovery rate, P = 0.0331) and brain-injured patients without diabetes (95% confidence interval of 2-21% higher recovery rate, P = 0.0272). Post matching, brain-injured patients with diabetes on incretin-based therapies also recovered at a significantly higher rate than patients treated with amantadine (95% confidence interval for the difference 2.4-25.1.0%, P = 0.0364). A review of preclinical studies identified several pathways through which saxagliptin and other incretin-based medications may aid awakening from both acute and chronic DOC: restoring monoaminergic and GABAergic neurotransmission, reducing brain inflammation and oxidative damage, clearing hyperphosphorylated tau and amyloid-β, normalizing thalamocortical glucose metabolism, increasing neural plasticity, and mitigating excitotoxic brain damage.
Our findings suggest incretin-based medications in general, and saxagliptin in particular, as potential novel therapeutic agents for DOC. Further prospective clinical trials are needed to confirm their efficacy and safety in DOC.
尽管意识神经科学取得了进展，但十多年来尚未发现用于意识障碍（DOC）的新药物。将美国食品药品监督管理局（FDA）已批准的现有药物重新用于治疗DOC对于改善临床管理和患者预后至关重要。
为了在现有FDA批准的药物中识别潜在的新治疗方法，我们使用了一种基于深度学习的药物筛选模型，根据药物的三维分子结构预测其作为苏醒剂的疗效。一项从2012年3月至2024年10月的回顾性队列研究对该模型的预测进行了测试，重点关注4047名因创伤性、血管性或缺氧性脑损伤而昏迷的患者格拉斯哥昏迷量表（GCS）评分的变化。
我们的深度学习药物筛选确定了二肽基肽酶-4抑制剂沙格列汀是一种有望用于急性和长期DOC的苏醒药物。回顾性临床分析表明，在糖尿病药物中，沙格列汀与急性昏迷的最高恢复率相关。在按年龄、性别、初始GCS评分、昏迷病因和血糖状态匹配患者后，接受基于肠促胰岛素疗法（包括二肽基肽酶-4抑制剂和胰高血糖素样肽-1类似物）的糖尿病脑损伤患者与接受非肠促胰岛素类糖尿病药物治疗的糖尿病脑损伤患者相比，昏迷恢复率显著更高（恢复率高1.8-14.1%，95%置信区间，P = 0.0331），也高于非糖尿病脑损伤患者（恢复率高2-21%，95%置信区间，P = 0.0272）。匹配后，接受基于肠促胰岛素疗法的糖尿病脑损伤患者的恢复率也显著高于接受金刚烷胺治疗的患者（差异的95%置信区间为2.4-25.1%，P = 0.0364）。对临床前研究的回顾确定了沙格列汀和其他基于肠促胰岛素的药物可能有助于从急性和慢性DOC中苏醒的几种途径：恢复单胺能和GABA能神经传递、减少脑部炎症和氧化损伤、清除过度磷酸化的tau蛋白和淀粉样β蛋白、使丘脑皮质葡萄糖代谢正常化、增加神经可塑性以及减轻兴奋性毒性脑损伤。
我们的研究结果表明，一般而言基于肠促胰岛素的药物，特别是沙格列汀，是DOC的潜在新型治疗药物。需要进一步的前瞻性临床试验来证实它们在DOC中的疗效和安全性。
