Calcium-Dependent Interplay of Lithium and Tricyclic Antidepressants, Amitriptyline and Desipramine, on N-methyl-D-aspartate Receptors

Abstract

The facilitated activity of N-methyl-D-aspartate receptors (NMDARs) in the central and peripheral nervous systems promotes neuropathic pain. Amitriptyline (ATL) and desipramine (DES) are tricyclic antidepressants (TCAs) whose anti-NMDAR properties contribute to their analgetic effects. At therapeutic concentrations <1 µM, these medicines inhibit NMDARs by enhancing their calcium-dependent desensitization (CDD). Li+, which suppresses the sodium–calcium exchanger (NCX) and enhances NMDAR CDD, also exhibits analgesia. Here, the effects of different [Li+]s on TCA inhibition of currents through native NMDARs in rat cortical neurons recorded by the patch-clamp technique were investigated. We demonstrated that the therapeutic [Li+]s of 0.5–1 mM cause an increase in ATL and DES IC50s of ~10 folds and ~4 folds, respectively, for the Ca2+-dependent NMDAR inhibition. The Ca2+-resistant component of NMDAR inhibition by TCAs, the open-channel block, was not affected by Li+. In agreement, clomipramine providing exclusively the NMDAR open-channel block is not sensitive to Li+. This Ca2+-dependent interplay between Li+, ATL, and DES could be determined by their competition for the same molecular target. Thus, submillimolar [Li+]s may weaken ATL and DES effects during combined therapy. The data suggest that Li+, ATL, and DES can enhance NMDAR CDD through NCX inhibition. This ability implies a drug–drug or ion–drug interaction when these medicines are used together therapeutically.

Structure and Neuroprotector Properties of a Complex Compound of Lithium with Comenic Acid

“…There is evidence that lithium, by inactivating the Src kinase, inhibits the phosphorylation of NR2B, a subunit of the NMDA receptor, which leads to its inactivation [ 29 , 30 ] and inhibits NMDA receptor expression in rats [ 31 ]. In addition, it has been shown that Li + inhibits the sodium–calcium exchanger, increasing intracellular Ca 2+ levels, and enhances calcium-dependent desensitization of the NMDA receptor [ 32 , 33 ]. In the study [ 24 ], it was found that short-term (1 h) treatment of cultures with lithium did not affect glutamate-induced Ca 2+ entry into neurons, while long-term treatment (7 days) significantly reduced glutamate-induced Ca 2+ entry into neurons.…”

PCLLA-nanoHA Bone Substitute Promotes M2 Macrophage Polarization and Improves Alveolar Bone Repair in Diabetic Environments

“…This enhanced effect of PCLLA-nanoHA may be attributed to its increased degradability, leading to the release and exposure of HA components, such as calcium and phosphate ions [39,40], which are known to activate downstream signaling pathways, including the JAK-STAT, PI3K-Akt pathways, and mitochondrial pathways [41,42]. However, further investigation is needed to elucidate the specific mechanisms by which ions directly regulate macrophages function and how leptin protein responds to ions, ultimately influencing macrophages fate.…”