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Antidepressants are used to treat depression and some anxiety disorders, including use in pregnant patients. The pharmacological actions of these drugs generally determine the uptake and metabolism of a series of neurotransmitters, such as serotonin, norepinephrine, or dopamine, along with an increase in BDNF expression. However, many aspects of antidepressant action remain unknown, particularly whether antidepressants interfere with normal neurodevelopment when taken by pregnant women. In order to reveal cellular and molecular implications crucial to the functioning of pathways related to antidepressant effects, we performed an investigation on neuronally differentiating human SH-SY5Y cells. To our knowledge, this is the first time human SH-SY5Y cells in cultures of purely neuronal cells induced by controlled differentiation with retinoic acid are followed by short-term 48-h exposure to 0.1-10 μM escitalopram or venlafaxine. Treatment with antidepressants (1 μM) did not affect the electrophysiological properties of SH-SY5Y cells. However, the percentage of mature neurons exhibiting voltage-gated sodium currents was substantially higher in cultures pre-treated with either antidepressant. After exposure to escitalopram or venlafaxine, we observed a concentration-dependent increase in activity-dependent BDNF promoter IV activation. The assessment of neurite metrics showed significant down-regulation of neurite outgrowth upon exposure to venlafaxine. Identified changes may represent links to molecular processes of importance to depression and be involved in neurodevelopmental alterations observed in postpartum children exposed to antidepressants antenatally., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We investigated the effect of ginkgolide B (GB), a component of the extract from the leaves of the Ginkgo biloba tree, on recombinant glycine receptors (GlyRs) expressed in Xenopus oocytes by using voltage-clamp recording. GB (0.01-10 microM) inhibited glycine-induced currents of homo-oligomeric alpha1, alpha2 and alpha 3 GlyRs, with the highest potency being found at the alpha1 GlyR (IC(50) value=0.61+/-0.1 microM). Coexpression of the alpha subunits with the beta subunit resulted in a shift of the IC(50) value of GB to nanomolar values, indicating selectivity of GB for beta subunit containing GlyRs. We also analyzed the mechanism of GB inhibition and the effect of point mutations introduced into the alpha1 subunit. Our results are consistent with a channel blocking effect, since (i) GB inhibited glycine currents non-competitively, and (ii) a point mutation in the pore forming M2 domain reduced GB potency. In conclusion, GB is a potent blocker of beta subunit containing GlyR channels and hence can be used to discriminate homo- from hetero-oligomeric GlyRs. As hetero-oligomeric GlyRs are known to be synaptically localized, GB represents a channel blocker that may be employed to separate extrasynaptic from synaptic glycine currents.

Platelet-activating factor (PAF), a biologically active lipid (1-O-alkyl-2-acetyl-sn-glycero-3-phosphoholine), is identified in different regions of brain, including hippocampus. Specific PAF-activated receptors (PAFRs) are expressed in corresponding brain areas. PAF has been proposed to be a retrograde messenger of long-term potentiation (LTP): the antagonist of PAFRs, ginkgolide B (or BN52021) prevents induction of LTP. Recently it has been found that ginkgolide B is also an efficient blocker of the glycine receptor (GlyR) operated chloride channels (IC(50)=270+/-10 nM in hippocampal pyramidal neurons). The question is as follows: is the alteration of LTP by BN52021 due to the PAF antagonism or to the inhibition of glycine-gated chloride channels? We have studied the effects of ginkgolides B and J on LTP induced in the CA1 area of rat hippocampus. Ginkgolide J which is the weakest blocker of PAFR (IC(50)=54 microM, as compared to IC(50)=2.5 microM for ginkgolide B) inhibits GlyR-operated channels with IC(50)=2.0 microM. This assures a convenient concentration window which allows to inhibit GlyR-operated channels without affecting PAFRs. An amount of 5 microM of ginkgolide J did not prevent the induction of LTP, while ginkgolide B (5 microM) completely inhibited this phenomenon. The effect of ginkgolide B on LTP did not alter considerably if GlyRs were blocked by strychnine (2 microM). Strychnine itself had no significant effect on the induction of LTP. Both ginkgolides and strychnine significantly facilitated short-term potentiation (STP). Our data support a hypothesis according to which ginkgolides affect LTP by inhibiting PAFRs.

We have found that the platelet activating factor antagonist (BN52021) is an effective blocker of the glycine (Gly) receptor-mediated responses in the hippocampal pyramidal neurons of rat. Using the whole-cell voltage clamp and concentration clamp recording techniques, we investigated the mechanism underlying the inhibitory action of this terpenoid on the glycine-induced chloride current. BN52021 selectively and reversibly inhibits glycine current in a non-competitive and voltage-dependent fashion. The antagonistic effect of this substance is more pronounced at positive membrane potentials. At holding potential -70mV and in the presence of 200 microM glycine IC50 value for the blocking action of BN52021 was 270+/-10nM. Repetitive applications of BN52021 reveal the use-dependence of its blocking action. When co-applied with strychnine (STR), a competitive glycine receptor antagonist, BN52021 does not alter the IC50 value for strychnine. The inhibitory effect of BN52021 on gamma-aminobutyric acid (GABA) current is at least 25 times less potent than the effect on glycine current. This substance fails to affect AMPA and NMDA responses. It may be concluded that BN52021 inhibits glycine-gated Cl- channels by interacting with the pore region and does not compete for the strychnine-binding centre.