Lipid emulsion inhibits the cardiac toxicity caused by chloroquine via inhibition of reactive oxygen species production

Abstract

Background: Lipid emulsion (LE) is effective in treating intractable cardiac depression induced by the toxicity of highly lipid-soluble drugs including local anesthetics. However, the effect of LE on chloroquine-evoked cardiac toxicity remains unclear. This study aimed to examine the effect of Lipofundin MCT/LCT, an LE, on the cardiotoxicity caused by chloroquine in H9c2 rat cardiomyoblasts and elucidate the underlying cellular mechanism. Methods: The effects of chloroquine (1 × 10 -4 M), LE, and the reactive oxygen species (ROS) scavengers mitotempo and N-acetyl-L-cysteine (NAC), alone or combined, on cell viability and migration, apoptosis, ROS production, calcium levels, mitochondrial membrane potential, and adenosine triphosphate (ATP) were examined. Additionally, the effects of LE on the activities of catalase (CAT), malondialdehyde (MDA), and superoxide dismutase (SOD) induced by chloroquine were assessed. Results: Pretreatment with LE, mitotempo, or NAC reversed the reduction in cell migration and viability, mitochondrial membrane potential, and ATP levels evoked by chloroquine, and inhibited the increase in cleaved caspase-3, ROS, and calcium concentration induced by chloroquine. LE inhibited the increase in Bax expression, TUNEL-positive cells, MDA activity, and late apoptosis, and reversed the reduction in SOD and CAT activity induced by chloroquine. Chloroquine did not significantly affect cleaved caspase-8 expression, and LE did not significantly affect chloroquine concentration.Conclusion: Collectively, these results suggest that LE with 50% long-chain and 50% mediumchain fatty acids inhibits the cardiotoxicity and late apoptosis induced by chloroquine toxicity via the intrinsic mitochondrial apoptotic pathway, which is associated with direct inhibition of ROS production.

Mechanisms underlying lipid emulsion resuscitation for drug toxicity: a narrative review

“…In contrast, Lipofundin MCT/LCT with 50% long-chain and 50% medium-chain triglycerides, extracts more bupivacaine from human serum than Intralipid [ 25 ]. Furthermore, Lipofundin MCT/LCT has been found to reverse vasodilation induced by toxic doses of bupivacaine in isolated rat aorta as well as reverse the decreased cell viability caused by toxic doses of chloroquine more than Intralipid [ 27 , 53 ]. Lipofundin MCT/LCT also inhibits NO-mediated vasodilation by acetylcholine more than Intralipid, suggesting that the medium-chain triglycerides contained in Lipofundin MCT/LCT may have a significant effect on the inhibition of NO-mediated vasodilation [ 59 ].…”

“…However, LE attenuated cardiotoxicity caused by bupivacaine, which is mediated by fatty acid oxidation and inhibition of mitochondrial permeability transition pore (MPTP) opening [51]. Furthermore, toxic doses of the anti-malarial drug chloroquine, β-blocker propranolol, and chemotherapeutic agent doxorubicin produces cardiotoxicity, which is mediated by mitochondrial dysfunction or decreased ATP production via the generation of reactive oxygen species (ROS) [52][53][54]. However, LE inhibited cardiotoxicity caused by these drugs, which is mediated by mitigation of mitochondrial dysfunction via attenuation of ROS production [52][53][54].…”

“…Furthermore, toxic doses of the anti-malarial drug chloroquine, β-blocker propranolol, and chemotherapeutic agent doxorubicin produces cardiotoxicity, which is mediated by mitochondrial dysfunction or decreased ATP production via the generation of reactive oxygen species (ROS) [52][53][54]. However, LE inhibited cardiotoxicity caused by these drugs, which is mediated by mitigation of mitochondrial dysfunction via attenuation of ROS production [52][53][54]. Taken together, these reports suggest that LE attenuates cardiac toxicity evoked by toxic doses of bupivacaine, propranolol, chloroquine, doxorubicin, which is probably mediated by the inhibition of mitochondrial dysfunction via inhibition of ROS production, fatty acid supply, and ATP production.…”

Chloroquine inhibits vasodilation induced by ATP-sensitive potassium channels in isolated rat aorta

“…Second, to examine the role of ROS and K ATP channel inhibitors in the chloroquine-mediated inhibition of levcromakalim-induced vasodilation, we investigated the effects of the ROS scavenger N-acetyl-ʟ-cysteine (NAC, 5×10 −3 M) and K ATP channel inhibitor glibenclamide (5×10 −6 M) on chloroquine (6×10 −5 M)-mediated inhibition of vasodilation induced by levcromakalim in the isolated endotheliumdenuded rat aorta (Baik et al 2016;Lee et al 2022). The isolated rat aorta was treated with chloroquine alone for 20 min, NAC, and glibenclamide alone for 35 min, or it was pretreated with NAC or glibenclamide for 15 min, followed by chloroquine for 20 min.…”

“…ROS generation by chloroquine was measured using 2ʹ,7ʹdichlorofluorescin diacetate (H 2 DCFDA) in VSMCs, as described previously (Lee et al 2022). Cells seeded on a cover glass (at a density of 2×10 5 cells/well in a 6-well culture plate) were incubated at 37°C in a CO 2 incubator overnight and starved overnight with a serum-free medium.…”