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    • Several evidences showed that seizures increase

    2021-01-18

    Several evidences showed that seizures increase brain extracellular glutamate, which binds to N-methyl-d-aspartate (NMDA) receptor, then up-regulated cyclooxygenase-2 (COX-2) expression in brain capillaries to increase BBB P-gp expression [11,13,29,30]. A recent study demonstrated a different signaling pathway that glutamate signaled through NMDA receptors on brain capillary endothelial cells to activate eEF-2 K/eEF-2 and in turn increased P-gp expression [12]. Our finding is distinct from recently published studies. We have found a novel signaling pathway that glutamate activated PXR and NF-κB p65 expression in mouse brain capillary endothelial cells, which may bind site of mdr1 gene [31], and thus increased P-gp expression. It also increased CYP3A expression by PXR binding to the CYP3A promoter [32]. In primary cultures of endothelial cells obtained from epileptic brain tissues, PXR expression significantly increased and resulted in some submits of CYP overexpression [18]. Additionally, CBZ is a potential PXR activators and substrate of P-gp. CBZ has shown to induce ABCC2 and CYP3A4 in the intestinal tract and liver, which interferes with its XL184 and decreases its oral bioavailability [16,33]. Experiments confirmed ABCC2 expression induced by CBZ was PXR dependent. CBZ was PXR agonist and PXR residue Gln285 to be important for CBZ-PXR interaction [34]. Previous studies have shown that central nervous system inflammation and peripheral inflammation related to alter the expression and activity of BBB P-gp in both humans and animals studies [35]. Our group also has indicated that inflammatory factors contributed to seizure-induced brain P-gp overexpression via the activation of NF-κB signals [21]. PXR and NF-κB can modulate the P-gp expression, but there was a mechanism of mutual inhibitory between NF-κB and PXR signaling pathways [36]. In the present study, our finding demonstrated that CBZ or glutamate induced the P-gp and CYP3A expression regulated by PXR or NF-κB p65, which was consistent with previous studies. Furthermore, PXR or NF-κB p65 may be responsible for the regulation of P-gp and CYP3A expression in CBZ media, pretreated by l-glutamate for 30 min. Conversely, P-gp and CYP3A expression was decreased by knock down of PXR or NF-κB p65 gene, and they may negatively feedback on each other due to mutual inhibitory between them. At the same time, we also have confirmed that the overexpression of P-gp is capable of effective efflux function. This can be partially explained that the mechanism underlying the development of DRE using CBZ treatment. Although we have demonstrated that P-gp and CYP3A were regulated by PXR or NF-κB p65 following by exposure in l-glutamate, CBZ or both. The precise molecular regulatory mechanism was not elucidated. Glutamate binds to the NMDA receptor to activate COX-2, then may be triggered NF-κB p65 expression [37], but the signaling pathway of up-regulated PXR was unknown. Moreover, one of novel possible specific mechanisms of DRE was validated in vitro. Although the recent study from our group has shown that P-gp up-regulation was attributed to increase PXR expression, but not NF-κB in the chronic phase of epilepsy [38], further studies remain to be performed in vivo experimental animals or human specimen.
    Conclusion In conclusion, PXR or NF-κB p65 was strongly up-regulated after stimulation with l-glutamate, CBZ or both in bEnd.3 cells, which resulted in P-gp and CYP3A overexpression (Fig. 7), and the P-gp expression may be dominated by PXR, CYP3A expression was mainly regulated by NF-κB p65. Development of inhibitor to PXR or NF-κB p65 may provide a new approach for DRE patients.
    Conflict of interest
    Acknowledgment This study was supported by two grants from the National Natural Science Foundation of China (Grant No.: 81400981, 81171222).
    Introduction Androgens play critical roles in several stages of development and maintenance of the prostate through activation of the androgen receptor (AR). Testosterone is a principal androgen that circulates in the bloodstream largely bound to sex hormone-binding globulin (SHBG) and diffuses into a target organ as a free form of testosterone [1], [2]. In the prostate, testosterone is converted by steroid 5α-reductase 2 (SRD5A2) into dihydrotestosterone (DHT), having higher affinity than testosterone to the AR, and activates the AR. The activated AR translocates from the cytoplasm to the nucleus, dimerizes, binds to the androgen response element (ARE) in the genome sequences of target genes, and regulates their transcription.