Rottlerin (mallotoxin) is apolyphenol natural product isolated from the Asian treeMallotus philippensis. Rottlerin displays a complex spectrum of pharmacology.[1]
Rottlerin is a potent large conductancepotassium channel (BKCa++) opener.[5] BKCa++ is found in the inner mitochondrial membrane ofcardiomyocytes.[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]
Mallotoxin is also a hERG potassium channel activator.[12]
Clementset 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]
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.[13][14][15] BKCa++ channels reside in the inner mitochondrial membrane[6] and their activation is proposed to increase K+ accumulation in mitochondria.[8][9] This limitsCa2+ 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]
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.[16][17] 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]
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][18] There was no oxygen dependent damage found by rottlerin in the study conducted by Clementset al.[5]
Rottlerin has been reported to be aPKCδ inhibitor.[19] 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 proteinsin vitro.[1][20][21] 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][22] 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][22] 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]
TheKamala tree, also known asMallotus philippensis, grows in Southeast Asia.[19] 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.[23] Other uses include afflictions with the skin, eye diseases, bronchitis, abdominal disease, and spleen enlargement but scientific evidence is not present.[24]
^abcdefghSoltoff SP (September 2007). "Rottlerin: an inappropriate and ineffective inhibitor of PKCdelta".Trends in Pharmacological Sciences.28 (9):453–458.doi:10.1016/j.tips.2007.07.003.PMID17692392.
^Tillman DM, Izeradjene K, Szucs KS, Douglas L, Houghton JA (August 2003). "Rottlerin sensitizes colon carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis via uncoupling of the mitochondria independent of protein kinase C".Cancer Research.63 (16):5118–5125.PMID12941843.
^Han JG, Yang Q, Yao XQ, Kwan YW, Shen B, He GW (October 2009). "Role of large-conductance calcium-activated potassium channels of coronary arteries in heart preservation".The Journal of Heart and Lung Transplantation.28 (10):1094–1101.doi:10.1016/j.healun.2009.06.011.PMID19782293.
^abcKang SH, Park WS, Kim N, Youm JB, Warda M, Ko JH, et al. (July 2007). "Mitochondrial Ca2+-activated K+ channels more efficiently reduce mitochondrial Ca2+ overload in rat ventricular myocytes".American Journal of Physiology. Heart and Circulatory Physiology.293 (1):H307–H313.doi:10.1152/ajpheart.00789.2006.PMID17351070.
^abcdeSato T, Saito T, Saegusa N, Nakaya H (January 2005). "Mitochondrial Ca2+-activated K+ channels in cardiac myocytes: a mechanism of the cardioprotective effect and modulation by protein kinase A".Circulation.111 (2):198–203.doi:10.1161/01.cir.0000151099.15706.b1.PMID15623543.S2CID9912508.
^abBentzen BH, Osadchii O, Jespersen T, Hansen RS, Olesen SP, Grunnet M (March 2009). "Activation of big conductance Ca(2+)-activated K (+) channels (BK) protects the heart against ischemia-reperfusion injury".Pflügers Archiv.457 (5):979–988.doi:10.1007/s00424-008-0583-5.PMID18762970.S2CID25090971.
^Zeng H, Lozinskaya IM, Lin Z, Willette RN, Brooks DP, Xu X (November 2006). "Mallotoxin is a novel human ether-a-go-go-related gene (hERG) potassium channel activator".The Journal of Pharmacology and Experimental Therapeutics.319 (2):957–962.doi:10.1124/jpet.106.110593.PMID16928897.S2CID21096055.
^Kloner RA, Jennings RB (December 2001). "Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 2".Circulation.104 (25):3158–3167.doi:10.1161/hc5001.100039.PMID11748117.S2CID52874593.
^Heinen A, Aldakkak M, Stowe DF, Rhodes SS, Riess ML, Varadarajan SG, Camara AK (September 2007). "Reverse electron flow-induced ROS production is attenuated by activation of mitochondrial Ca2+-sensitive K+ channels".American Journal of Physiology. Heart and Circulatory Physiology.293 (3):H1400–H1407.doi:10.1152/ajpheart.00198.2007.PMID17513497.S2CID20330939.
^abGschwendt M, Müller HJ, Kielbassa K, Zang R, Kittstein W, Rincke G, Marks F (February 1994). "Rottlerin, a novel protein kinase inhibitor".Biochemical and Biophysical Research Communications.199 (1):93–98.Bibcode:1994BBRC..199...93G.doi:10.1006/bbrc.1994.1199.PMID8123051.
^abTapia JA, Jensen RT, García-Marín LJ (January 2006). "Rottlerin inhibits stimulated enzymatic secretion and several intracellular signaling transduction pathways in pancreatic acinar cells by a non-PKC-delta-dependent mechanism".Biochimica et Biophysica Acta (BBA) - Molecular Cell Research.1763 (1):25–38.doi:10.1016/j.bbamcr.2005.10.007.PMID16364465.
^Rao VS, Seshadri TR (1947). "Kamala dye as an anthelmintic".Proceedings of the Indian Academy of Sciences.26 (3) 178:178–181.doi:10.1007/BF03170871.S2CID81455004.
^Mitra R, Kapoor LD (November 1976). "Kamala--the national flower of India--its ancient history and uses in Indian medicine".Indian Journal of History of Science.11 (2):125–132.PMID11610202.
