Epicatechin regulation of mitochondrial structure and function is opioid receptor dependent

Abstract

Scope The flavanol (-)-epicatechin (Epi), a component of cacao, has cardiac protective benefits in humans. Our previous study demonstrated Epi has δ-opioid receptor (DOR) binding activity and promotes cardiac protection. Here we examined the effects of 10 days of Epi treatment on: cardiac mitochondrial respiration, ROS production, calcium swelling, and mitochondrial membrane fluidity. Methods & Results Mice were randomized into four groups: (1) Control (Saline), (2) Naltrindole (Nalt; DOR antagonist), (3) Epi, and (4) Epi+Nalt and received 1 mg kg−1 Epi or water via oral gavage. Nalt groups received 5 mg kg−1 ip per day for 10 days. Significant increases in mitochondrial respiration and enhanced free radical production during state 3 respiration were observed with Epi. Additionally, we observed significant increases in rigidity of mitochondrial membranes and resistance to calcium induced mitochondrial swelling with Epi treatment. Blocking the DOR with Nalt resulted in decreases in all of the observed parameters by Epi treatment. Conclusion These findings indicate that Epi induces an integrated response that includes metabolic and structural changes in cardiac mitochondria resulting in greater functional capacity via DOR. Mitochondrial targeted effects of epicatechin may explain the physiologic benefit observed on cardiac protection and support epicatechin’s potential clinical application as a cardiac protective mimetic.

Molecular Mechanisms and Therapeutic Effects of (−)-Epicatechin and Other Polyphenols in Cancer, Inflammation, Diabetes, and Neurodegeneration

“…However, the interesting finding was that (−)-epicatechin-dextran activation was significantly higher than nonconjugated (−)-epicatechin, suggesting the existence of an (−)-epicatechin cell membrane receptor. Panneerselvam et al concluded that (−)-epicatechin is interacting with cell membrane δ -opioid receptors, promoting cardiac protection [ 101 , 102 ]. In one study, the authors used mice that were treated with either control saline, 1 mg/kg (−)-epicatechin, or 5 mg/kg naltrindole, a δ -opioid receptor antagonist, by daily intraperitoneal injection for 10 days [ 102 ].…”

“…Panneerselvam et al concluded that (−)-epicatechin is interacting with cell membrane δ -opioid receptors, promoting cardiac protection [ 101 , 102 ]. In one study, the authors used mice that were treated with either control saline, 1 mg/kg (−)-epicatechin, or 5 mg/kg naltrindole, a δ -opioid receptor antagonist, by daily intraperitoneal injection for 10 days [ 102 ]. They observed that mitochondria isolated from the hearts of mice treated only with (−)-epicatechin had higher state 3 respiration rates.…”

Development of Therapeutics That Induce Mitochondrial Biogenesis for the Treatment of Acute and Chronic Degenerative Diseases

“…95 The epicatechin epigallocatechin-3-gallate ( 3 ), 96 promotes cAMP-dependent signaling to increase SIRT1 and PGC-1α. 97 Although there are limited data regarding the structural basis for 2 activation of cAMP-dependent signaling, Akt-dependent signaling is mediated by the 3″-, 3′-, and 4′-hydroxyl groups.…”

Mitochondria in the middle: exercise preconditioning protection of striated muscle

“…Recently, epicatechin was shown to have δ‐opioid receptor binding activity and to improve mitochondrial state 3 respiration, thus stimulating preconditioning (Panneerselvam et al . ).…”