32.6K
views
50
authors
7
articles
Editors
6
Impact
Loading...

Antidepressant fluoxetine can affect cerebral glucose metabolism in clinic, but the underlying molecular mechanism remains poorly understood. Here, we examined the effect of fluoxetine on brain regional glucose metabolism in a rat model of depression induced by repeated corticosterone injection, and explored the molecular mechanism. Fluoxetine was found to recover the decrease of 18F-fluorodeoxyglucose (18F-FDG) signal in prefrontal cortex (PFC), and increased 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose (2-NBDG, a fluorescent glucose analog) uptake in an astrocyte-specific manner in ex vivo cultured PFC slices from corticosterone-induced depressive rats, which were consistent with its improvement of animal depressive behaviors. Furthermore, fluoxetine restricted nuclear translocation of glucocorticoid receptor (GR) to suppress the transcription of thioredoxin interacting protein (TXNIP). Subsequently, it promoted glucose transporter 1 (GLUT1)-mediated glucose uptake and glycolysis of PFC astrocytes through suppressing TXNIP expression under corticosterone-induced depressive state. More importantly, fluoxetine could improve glucose metabolism of corticosterone-stimulated astrocytes via TXNIP-GLUT1 pathway. These results demonstrated that fluoxetine increased astrocytic glucose uptake and glycolysis in corticosterone-induced depression via restricting GR-TXNIP-GLUT1 pathway. The modulation of astrocytic glucose metabolism by fluoxetine was suggested as a novel mechanism of its antidepressant action.

6,027 views
12 citations

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.

5,341 views
20 citations
Recommended Research Topics
Frontiers Logo

Frontiers in Pharmacology

Novel Therapeutic Approaches for the Treatment of Ocular Disease, Volume I
Edited by Kyriaki Thermos, Stephanie C Joachim, Deniz Hos, Giovanni Casini
47.3K
views
12
articles
Frontiers Logo

Frontiers in Pharmacology

Neurodegeneration, Cell signaling and Neuroreparative Strategies
Edited by Ana Rita Vaz, Valle Palomo, Ana Falcão
47.8K
views
11
articles
Frontiers Logo

Frontiers in Pharmacology

Pharmacological Approaches towards the Resolution of Neuroinflammation and Neurodegeneration
Edited by Erika Gyengesi, Gerald Muench, Monokesh K Sen, Huazheng Liang
34.1K
views
43
authors
5
articles
Frontiers Logo

Frontiers in Pharmacology

Novel Therapeutic Approaches for the Treatment of Ocular Disease, Volume II
Edited by Kyriaki Thermos, Stephanie C Joachim, Giovanni Casini, Massimo Dal Monte
18.3K
views
58
authors
7
articles
Frontiers Logo

Frontiers in Pharmacology

Neurodegeneration, Cell signaling and Neuroreparative Strategies, Volume II
Edited by Valle Palomo, Ana Falcão, Ana Rita Vaz
21.9K
views
47
authors
7
articles