Rottlerin
Systematic (IUPAC) name | |
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(E)-1-[6-[(3-acetyl-2,4,6-trihydroxy-5-methylphenyl)methyl]-5,7-dihydroxy-2,2-dimethylchromen-8-yl]-3-phenylprop-2-en-1-one
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Identifiers | |
PubChem | CID: 5281847 |
ChemSpider | 4445144 |
ChEBI | CHEBI:8899 |
Synonyms | Mallotoxin |
Chemical data | |
Formula | C30H28O8 |
Molecular mass | 516.53852 g/mol |
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Rottlerin (mallotoxin) is a polyphenol natural product isolated from the asian tree Mallotus philippensis. Rottlerin displays a complex spectrum of pharmacology.[1]
Contents
Effects
Uncoupler of oxidative phosphorylation
Rottlerin has been shown to be an uncoupler of mitochondrial oxidative phosphorylation.[2][3][4]
Potassium channel opener
Rottlerin is a potent large conductance potassium channel (BKCa++) opener.[5] BKCa++ is found in the inner mitochondrial membrane of cardiomyocytes.[6] Opening these channels is beneficial for post-ischemic changes in vasodilation.[7] Other BKCa++ channel openers are reported to limit the mitochondrial calcium overload due to ischemia.[8][9] Rottlerin is also capable of reducing oxygen radical formation.[1]
Other BKCa++ channel openers (NS1619, NS11021 and DiCl-DHAA) have been reported to have cardio-protective effects after ischemic-reperfusion injury.[9][10][11] There were reductions in mitochondrial Ca++ overload, mitochondrial depolarization, increased cell viability and improved function in the whole heart.[9][10][11]
Role in cardioplegia reperfusion
Clements et al.[5] reported that rottlerin improves the recovery of isolated rat hearts perfused with buffer after cold cardioplegic arrest. A majority of patients recover but some develop a cardiac low-output syndrome attributable in part to depressed left ventricular or atrial contractility, which increases chance of death.[5]
Contractility and vascular effects
Rottlerin increases in isolated heart contractility independent of its vascular effects, as well as enhanced perfusion through vasomotor activity.[5] The activation of BKCa++ channels by rottlerin relaxes coronary smooth muscle and improves myocardial perfusion after cardioplegia.[5]
Myocardial stunning is associated with oxidant radical damage and calcium overload.[5] Contractile abnormalities can occur through oxidant-dependent damage and also through calcium overload in the mitochondria resulting in mitochondrial damage.[12][13][14] BKCa++ channels reside in the inner mitochondrial membrane[6] and their activation is proposed to increase K+ accumulation in mitochondria.[8][9] This limits Ca2+ influx into mitochondria, reducing mitochondrial depolarization and permeability transition pore opening.[8][9] This may result in less mitochondrial damage and therefore greater contractility since there is a decrease in apoptosis compared to no stimulation of BKCa++ channels.[5]
Akt activation
Rottlerin also enhances the cardioplegia-induced phosphorylation of Akt on the activation residue Thr308.[5] Akt activation modulates mitochondrial depolarization and the permeability transition pore.[15][16] Clements et al[5] found that Akt functions downstream of the BKCa++ channels and its activation is considered beneficial after ischemic-reperfusion injury. It is unclear what the specific role of Akt may play in modulating of myocardial function after rottlerin treatment of cardioplegia.[5] More research needs to be done to examine if Akt is necessary to improve cardiac function when rottlerin is administered.[5]
Antioxidant properties
The antioxidant properties of rottlerin have been demonstrated but it is unclear whether the effects are because of BKCa++ channel opening or an additional mechanism of rottlerin.[1][5][17] There was no oxygen dependent damage found by rottlerin in the study conducted by Clements et al.[5]
Ineffective PKCδ selective inhibitor
Rottlerin has been reported to be a PKCδ inhibitor.[18] PKCδ has been implicated in depressing cardiac function and cell death after ischemia-reperfusion injury as well as promoting vascular smooth muscle contraction and decreasing perfusion.[5] However, the role of rottlerin as a specific PKCδ inhibitor has been questioned. There have been several studies using rottlerin as a PKCδ selective inhibitor based on in vitro studies, but some studies showed it did not block PKCδ activity and did block other kinase and non-kinase proteins in vitro.[1][19][20] Rottlerin also uncouples mitochondria at high doses and results in depolarization of the mitochondrial membrane potential.[1] It was found to reduce ATP levels, activate 5'-AMP-activated protein kinase and affect mitochondrial production of reactive oxygen species (ROS).[1][6][21] It is difficult to say that rottlerin is a selective inhibitor of PKCδ since there are biological and biochemical processes that are PKCδ –independent that may affect outcomes.[1][5][6][21] A proposed mechanism of why rottlerin was found to inhibit PKCδ is that it decreased ATP levels and can block PKCδ tyrosine phosphorylation and activation.[1]
Sources
The Kamala tree, also known as Mallotus philippensis, grows in Southeast Asia.[18] The fruit of this tree is covered with a red powder called kamala, and is used locally to make dye for textiles, syrup and used as an old remedy for tape-worm, because it has a laxative effect.[22] Other uses include afflictions with the skin, eye diseases, bronchitis, abdominal disease, and spleen enlargement but scientific evidence is not present.[23]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 Clements RT, Cordeiro B, Feng J, Bianchi C, Sellke FW. "Rottlerin increases cardiac contractile performance and coronary perfusion through BKCa++ channel activation after cold cardioplegic arrest in isolated hearts. Circulation 2011 Sep 13; 124(11 Suppl):S55-61
- ↑ 6.0 6.1 6.2 6.3 Zakharov SI, Morrow JP, Liu G, Yang L, Marx SO. Activation of the BK (SLO1) potassium channel by mallotoxin" J Biol Chem 2005;280: 30882–30887
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ 8.0 8.1 8.2 Kang SH, Park WS, Kim N, Youm JB, Warda M, Ko JH, Ko EA, Han J. "Mitochondrial Ca2+-activated K+ channels more efficiently reduce mitochondrial Ca2+ overload in rat ventricular myocytes" Am J Physiol Heart Circ Physiol 2007;293:H307–H313
- ↑ 9.0 9.1 9.2 9.3 9.4 Lua error in package.lua at line 80: module 'strict' not found.
- ↑ 10.0 10.1 Lua error in package.lua at line 80: module 'strict' not found.
- ↑ 11.0 11.1 Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Heinen A, Aldakkak M, Stowe DF, Rhodes SS, Riess ML, Varadarajan SG, Camara AK. "Reverse electron flow-induced ROS production is attenuated by activation of mitochondrial Ca2 -sensitive K channels" Am J Physiol Heart Circ Physiol 2007;293:H1400–H1407.
- ↑ 18.0 18.1 Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ 21.0 21.1 Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
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