Insights into the Potential Impact of Quetiapine on the Microglial Trajectory and Inflammatory Response in Organotypic Cortical Cultures Derived from Rat Offspring

Abstract

Atypical antipsychotics currently constitute the first-line medication for schizophrenia, with quetiapine being one of the most commonly prescribed representatives of the group. Along with its specific affinity for multiple receptors, this compound exerts other biological characteristics, among which anti-inflammatory effects are strongly suggested. Simultaneously, published data indicated that inflammation and microglial activation could be diminished by stimulation of the CD200 receptor (CD200R), which takes place by binding to its ligand (CD200) or soluble CD200 fusion protein (CD200Fc). Therefore, in the present study, we sought to evaluate whether quetiapine could affect certain aspects of microglial activity, including the CD200-CD200R and CX3CL1-CX3CR1 axes, which are involved in the regulation of neuron–microglia interactions, as well as the expression of selected markers of the pro- and anti-inflammatory profile of microglia (Cd40, Il-1β, Il-6, Cebpb, Cd206, Arg1, Il-10 and Tgf-β). Concurrently, we examined the impact of quetiapine and CD200Fc on the IL-6 and IL-10 protein levels. The abovementioned aspects were investigated in organotypic cortical cultures (OCCs) prepared from the offspring of control rats (control OCCs) or those subjected to maternal immune activation (MIA OCCs), which is a widely implemented approach to explore schizophrenia-like disturbances in animals. The experiments were performed under basal conditions and after additional exposure to the bacterial endotoxin lipopolysaccharide (LPS), according to the “two-hit” hypothesis of schizophrenia. The results of our research revealed differences between control and MIA OCCs under basal conditions and in response to treatment with LPS in terms of lactate dehydrogenase and nitric oxide release as well as Cd200r, Il-1β, Il-6 and Cd206 expression. The additional stimulation with the bacterial endotoxin resulted in a notable change in the mRNA levels of pro- and anti-inflammatory microglial markers in both types of OCCs. Quetiapine diminished the influence of LPS on Il-1β, Il-6, Cebpb and Arg1 expression in control OCCs as well as on IL-6 and IL-10 levels in MIA OCCs. Moreover, CD200Fc reduced the impact of the bacterial endotoxin on IL-6 production in MIA OCCs. Thus, our results demonstrated that quetiapine, as well as the stimulation of CD200R by CD200Fc, beneficially affected LPS-induced neuroimmunological changes, including microglia-related activation.

Prenatal Immune Challenge Differentiates the Effect of Aripiprazole and Risperidone on CD200–CD200R and CX3CL1–CX3CR1 Dyads and Microglial Polarization: A Study in Organotypic Cortical Cultures

“…As previously reported [58], exposure to the bacterial endotoxin significantly reduced the mRNA levels of Cx3cr1 in both control (p = 0.0058) and MIA (p = 0.0106) OCCs. qRT-PCR analyses revealed that the addition of aripiprazole at a dose of 100 µM to control OCCs resulted in upregulated expression of both Cx3cr1 (p = 0.0054) and Cx3cl1 (p = 0.0229).…”

“…Thirty minutes following the last medium change, control and MIA OCCs were stimulated with either aripiprazole or risperidone for 2 h and later additionally exposed to LPS for 24 h [ 57 , 58 , 59 ]. Control groups in both types of OCCs were subjected to the appropriate vehicle in the analogous volume and regimen.…”

“…As the research described in this article was a part of the project evaluating the effects of different antipsychotics (quetiapine, aripiprazole and risperidone) on OCCs under varied conditions, some results (precisely, for the groups: control OCCs + vehicle, control OCCs + LPS, MIA OCCs + vehicle and MIA OCCs + LPS) of qRT-PCR analyses have already been published in the article regarding quetiapine [ 58 ]. However, those data are also shown herein due to their importance in presenting the impact of aripiprazole and risperidone on the gene expression of the studied parameters.…”

“…Statistical analysis was performed using planned comparisons via one-way ANOVA (contrast analysis). * p < 0.05 vs. control OCCs + vehicle, # p < 0.05 vs. control OCCs + LPS, ˆp < 0.05 vs. MIA OCCs + vehicle, $ p < 0.05 vs. MIA OCCs + LPS [58]. In the next set of experiments, we measured the impact of aripiprazole (100 µM) and risperidone (5 µM) treatment on the protein levels of proinflammatory IL-6 and antiinflammatory IL-10 under basal and LPS-induced conditions in MIA OCCs (Figure 1).…”

“…Statistical analysis was performed using factorial ANOVA with Duncan's post hoc test or planned comparisons via one-way ANOVA (contrast analysis). * p < 0.05 vs. control OCCs + vehicle, # p < 0.05 vs. control OCCs + LPS, ˆp < 0.05 vs. MIA OCCs + vehicle [58]. The microglial response to insults to the homeostasis of the CNS generates the release of multiple pro-and anti-inflammatory factors as well as the expression of various CD antigens [65].…”