Luteolin is an important phytoestrogen with antidepressant effects found in many foods. We aimed to clarify the underlying antidepressant mechanisms of luteolin on PMAT associated with the monoamine hypothesis. We found rPmat had high expression in the limbic system, significant differences in mRNA expression between the pregnant and non-pregnant rats and an upward trend in mice with chronic unpredictable mild stress (CUMS). The results in the stably transfected cell models demonstrated that luteolin was the inhibitor of monoamine transporters. Further studies in C6 cells and primary hippocampal neurons revealed luteolin significantly downgraded PMAT mainly through the oestrogen β receptor (ERβ) and upgraded brain-derived neurotrophic factor (BDNF) expression. These results for PMAT have also been demonstrated in ovariectomized depressed rats. In conclusion, luteolin could directly and indirectly inhibit serotonin reuptake, resulting in an increase in monoamine neurotransmitters in the synaptic cleft. These findings manifest the antidepressant mechanisms of luteolin through PMAT.
Doxorubicin (DOX) has been widely used to treat various tumors; however, DOX-induced cardiotoxicity limits its utilization. Since high accumulation of DOX in cardiomyocytes/mitochondria is the key reason, we aimed to clarify the mechanisms of DOX uptake and explore whether selectively inhibiting DOX uptake transporters would attenuate DOX accumulation and cardiotoxicity. Our results demonstrated that OCTN1/OCTN2/PMAT (organic cation/carnitine transporter 1/2 or plasma membrane monoamine transporter), especially OCTN2, played crucial roles in DOX uptake in cardiomyocytes, while OCTN2 and OCTN1 contributed to DOX transmembrane transport in mitochondria. Metformin (1–100 μM) concentration-dependently reduced DOX (5 μM for accumulation, 500 nM for cytotoxicity) concentration and toxicity in cardiomyocytes/mitochondria via inhibition of OCTN1-, OCTN2- and PMAT-mediated DOX uptake but did not affect its efflux. Furthermore, metformin ( iv : 250 and 500 mg/kg or ig : 50, 100 and 200 mg/kg) could dose-dependently reduce DOX (8 mg/kg) accumulation in mouse myocardium and attenuated its cardiotoxicity. In addition, metformin (1–100 μM) did not impair DOX efficacy in breast cancer or leukemia cells. In conclusion, our study clarified the role of multiple transporters, especially OCTN2, in DOX uptake in cardiomyocytes/mitochondria; metformin alleviated DOX-induced cardiotoxicity without compromising its antitumor efficacy by selective inhibition of multiple transporters mediated DOX accumulation in myocardium/mitochondria.
1. Jatrorrhizine is an active ingredient found in various traditional Chinese medicinal plants. Based on our previous finding that jatrorrhizine was a potent inhibitor of OCT2 and OCT3, the aim of the present study was to explore whether jatrorrhizine has an antidepressant-like action action via inhibition of uptake-2 transporters.2. In vitro uptake tests showed that jatrorrhizine strongly inhibited PMAT-mediated MPP+ uptake with an IC50 value of 1.05 μM and reduced 5-HT and NE uptake mediated by hOCT2, hOCT3 and hPMAT with IC50 values of 0.1–1 μM (for OCT2 and OCT3) and 1–10 μM (for PMAT).3. In mouse synaptosomes, jatrorrhizine suppressed 5-HT and NE uptake in a concentration dependently manner, where the role of uptake-2 inhibition is significant.4. The antidepressant-like action of jatrorrhizine was evaluated by mouse tail suspension test (TST). The TST showed that one week of jatrorrhizine (5, 10 and 20 mg/kg, i.p.) or venlafaxine (20 mg/kg, i.g.) can significantly reduce the duration of immobility when compared with vehicle control group.5. The concentration of jatrorrhizine shows a dose-dependent increase in brain tissues.6. Our study suggested that jatrorrhizine might be used as an antidepressant agent via inhibition of uptake-2 transporters.
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