Ceftriaxone as a Novel Therapeutic Agent for Hyperglutamatergic States: Bridging the Gap Between Preclinical Results and Clinical Translation

Abstract

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.

Synthesis and Structure–Activity Relationships for Glutamate Transporter Allosteric Modulators

“…Overall, 40 (NA-014) appears to be highly selective at EAAT2, and our experiments strongly suggest that it acts as a positive allosteric modulator (PAM). Allosteric modulation holds potential to provide a rapid approach to maintaining the highly precise temporal and spatial aspects of glutamatergic synaptic transmission, in contrast to EAAT expression enhancers, , and a range of neurological and neuropsychiatric disorders could benefit from this approach. Collectively, these results encourage us to progress to in vivo studies.…”

Editorial for the Special Issue: “Feature Papers in Drug Toxicity”

“…It is well known that beta-lactams (e.g. ceftriaxone) have been effective in attenuating the effects of abused drugs, including opioids and alcohol, and these are suggested to be mediated through the upregulation of GLT-1 and xCT expression in the target brain reward regions [ 2 ]. Regulation of glutamate homeostasis is critical in drug dependence.…”

Glutamate transporters in health and disease

“…Other compounds that protect neurons from glutamate-induced excitotoxic death, such as LDN-OSU0212320, decrease infarct volume in mice when administered 24 hours prior to photothrombotic ischemia; however, only in male mice, suggesting that this treatment may not be effective in the female population and further emphasizing the importance of sex differences in targeted treatments [107,108]. A significant drawback associated with β-lactam antibiotics in enhancing EAAT2 expression is the extended time required for drug onset (≥24 hours) [169]. Therefore, in the context of clinical ischemic injury, more fast-acting compounds need to be developed.…”