Abulseoud Osama A, Alasmari Fawaz, Hussein Abdelaziz M, Sari Youssef
Department of Psychiatry and Psychology, Alex School of Medicine at Mayo Clinic, Phoenix, AZ, United States.
Department of Pharmacology and Experimental Therapeutics, University of Toledo, Toledo, OH, United States.
Front Neurosci. 2022 Jul 5;16:841036. doi: 10.3389/fnins.2022.841036. eCollection 2022.
Dysregulation of glutamate homeostasis is a well-established core feature of neuropsychiatric disorders. Extracellular glutamate concentration is regulated by glutamate transporter 1 (GLT-1). The discovery of a beta-lactam antibiotic, ceftriaxone (CEF), as a safe compound with unique ability to upregulate GLT-1 sparked the interest in testing its efficacy as a novel therapeutic agent in animal models of neuropsychiatric disorders with hyperglutamatergic states. Indeed, more than 100 preclinical studies have shown the efficacy of CEF in attenuating the behavioral manifestations of various hyperglutamatergic brain disorders such as ischemic stroke, amyotrophic lateral sclerosis (ALS), seizure, Huntington's disease, and various aspects of drug use disorders. However, despite rich and promising preclinical data, only one large-scale clinical trial testing the efficacy of CEF in patients with ALS is reported. Unfortunately, in that study, there was no significant difference in survival between placebo- and CEF-treated patients. In this review, we discussed the translational potential of preclinical efficacy of CEF based on four different parameters: (1) initiation of CEF treatment in relation to induction of the hyperglutamatergic state, (2) onset of response in preclinical models in relation to onset of GLT-1 upregulation, (3) mechanisms of action of CEF on GLT-1 expression and function, and (4) non-GLT-1-mediated mechanisms for CEF. Our detailed review of the literature brings new insights into underlying molecular mechanisms correlating the preclinical efficacy of CEF. We concluded here that CEF may be clinically effective in selected cases in acute and transient hyperglutamatergic states such as early drug withdrawal conditions.
谷氨酸稳态失调是神经精神疾病公认的核心特征。细胞外谷氨酸浓度由谷氨酸转运体1（GLT-1）调节。β-内酰胺抗生素头孢曲松（CEF）被发现是一种安全的化合物，具有上调GLT-1的独特能力，这引发了人们对在具有高谷氨酸能状态的神经精神疾病动物模型中测试其作为新型治疗剂疗效的兴趣。事实上，100多项临床前研究表明，CEF在减轻各种高谷氨酸能脑病的行为表现方面具有疗效，如缺血性中风、肌萎缩侧索硬化症（ALS）、癫痫、亨廷顿舞蹈症以及药物使用障碍的各个方面。然而，尽管有丰富且有前景的临床前数据，但仅报道了一项测试CEF对ALS患者疗效的大规模临床试验。不幸的是，在该研究中，安慰剂治疗组和CEF治疗组患者的生存率没有显著差异。在这篇综述中，我们基于四个不同参数讨论了CEF临床前疗效的转化潜力：（1）CEF治疗的起始与高谷氨酸能状态的诱导的关系；（2）临床前模型中的反应起始与GLT-1上调起始的关系；（3）CEF对GLT-1表达和功能的作用机制；（4）CEF的非GLT-1介导机制。我们对文献的详细综述为与CEF临床前疗效相关的潜在分子机制带来了新的见解。我们在此得出结论，CEF在急性和短暂性高谷氨酸能状态（如早期戒毒情况）的特定病例中可能具有临床疗效。
