What’s Aicar and its Medical use?

What's Aicar?

CAS Number: 3031-94-5

Chemical formula: C9H15N4O8P

Molecular Weight: 338.211

Appearance: Sterile filtered white lyophilized (freeze-dried) powder

AA Sequence: 5-Aminoimidazole-4-carboxamide ribonucleotide

Aicar, also named AICA ribonucleotide. Its Sequence is 5-Aminoimidazole-4-carboxamide ribonucleotide. Aicar, also known as ZMP, is an intermediate in the generation of inosine monophosphate. Aicar is an analog of adenosine monophosphate (AMP). And it is capable of stimulating AMP-dependent protein kinase (AMPK) activity. Doctors have already used Aicar clinically to treat and protect against cardiac ischemic injury. In the 1980s, doctors have already used the drug as a method to preserve blood flow to the heart during surgery.

Currently, it was shown that Aicar as a potential treatment for diabetes by increasing the metabolic activity of tissues by changing the physical composition of muscle. AICAR (commonly under the name Acadesine) is an analog of adenosine. It enters cardiac cells to inhibit adenosine kinase and adenosine deaminase. It enhances the rate of nucleotide re-synthesis increasing adenosine generation from adenosine monophosphate only during conditions of myocardial ischemia. In cardiac myocytes, AICA-riboside is phosphorylated to AICA-ribotide (ZMP) to activate AMPK without changing the levels of the nucleotides. ZMP is able to enter the de novo synthesis pathway for adenosine synthesis to inhibit adenosine deaminase causing an increase in ATP levels and adenosine levels.

Medical use

It has been shown that a brief period of coronary arterial occlusion followed by reperfusion prior to prolonged ischemia is known as preconditioning. It has been shown that this is protective. Preconditioning preceded myocardial infarction, may delay cell death and allow for greater salvage of myocardium through reperfusion therapy.

AICAR has been shown to precondition the heart shortly before or during ischemia.

AICAR triggers a preconditioned anti-inflammatory state by increasing NO production from endothelial nitric oxide synthase.

When AICAR is given 24 hours prior to reperfusion, it prevents post ischemic leukocyte-endothelial cell adhesive interactions with increased NO production.

AICAR-dependent preconditioning is also mediated by an ATP-sensitive potassium channel and hemeoxygenase-dependent mechanism. It increases AMPK-dependent recruitment of ATP-sensitive K channels to the sarcolemma causing the action potential duration to shorten, and preventing calcium overload during reperfusion.

The decrease in calcium overload prevents inflammation activation by ROS.

AICAR also increases AMPK-dependent glucose uptake through translocation of GLUT-4 which is beneficial for the heart during post-ischemic reperfusion.

The increase in glucose during AICAR preconditioning lengthens the period for preconditioning up to 2 hours in rabbits and 40 minutes in humans undergoing coronary ligation.

As a result, AICAR reduces the frequency and size of myocardial infarcts up to 25% in humans allowing improved blood flow to the heart. As well, the treatment has been shown to decrease the risk of an early death and improve recovery after surgery from an ischemic injury.

References

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  2. Galinanes M, Bullough D, Mullane KM, Hearse DJ. Sustained protection by acadesine against ischemia- and reperfusion-induced injury. Studies in the transplanted rat heart.Circulation 86:589–597 (1992) Zarembo, Alan. “‘Exercise pill’ could take the work out of workouts.” Los Angeles Times [Los Angeles] 01 08 2008, n. pag. Web. 21 Jan. 2012. <http://articles.latimes.com/2008/aug/01/science/sci-couchpill1>.
  3. Kristiansen, S.B. et al. 5-Aminoimidazole-4-carboxamide-1- β – d -ribofuranoside Increases Myocardial Glucose Uptake during Reperfusion and Induces Late Pre-conditioning : Potential Role of AMP-Activated Protein Kinase. Pharmacology Toxicology 10-16 (2009).doi:10.1111/j.1742-7843.2009.00402.x
  4. Zhang, L., Frederich, M., He, H., & Balschi, J. a. Relationship between 5-aminoimidazole-4-carboxamide-ribotide and AMP-activated protein kinase activity in the perfused mouse heart. American journal of physiology. Heart and circulatory physiology, 290(3), .H1235-43. (2006)doi:10.1152/ajpheart.00906.2005
  5. Longnus SL, Wambolt RB, Parsons HL, Brownsey RW, Allard MF 5-Aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR) stimulates myocardial glycogenolysis by allosteric mechanisms. Am J Physiol Regul Integr Comp Physiol 284:R936–R944 (2003)
  6. Murry, C.E., Jennings, R.B. & Reimer, K.A.. Preconditioning with ischaemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74, 1124–1136. (1986)
  7. Mullane K Acadesine: the prototype adenosine regulating for reducing myocardial ischaemic injury. Cardiovasc Res 27:43–47(1993)
  8. Gaskin, F. Spencer. “MECHANISMS OF ADENOSINE MONOPHOSPHATE-ACTIVATED PROTEIN KINASE-INDUCED PRECONDITIONING IN ISCHEMIA/REPERFUSION.” Department of Medical Pharmacology and Physiology. (2007)
  9. Spencer Gaskin, Kazuhiro Kamada, Mozow Yusof, William Durante, Garrett Gross, and Ronald J. Korthuis. AICAR Preconditioning Prevents Postischemic Leukocyte Rolling and Adhesion: Role of KATP Channels and Heme Oxygenase Microcirculation 16:2, 167-176 (2009)
  10. Sukhodub, A., Jovanovic, S., Du, Q., Budas, G., Clelland, A.K., Shen, M., Sakamoto, K., Tian, R. & Jovanovic, A. AMP-activated protein kinase mediates preconditioning in cardiomyocytes by regulating activity and trafficking of sarcolemmal ATP-sensitive K(+) channels. J Cell Physiol 210, 224–236. (2007).
  11. Tsuchida, A., Yang, X.M., Burckhartt, B., Mullane, K.M., Cohen, M.V. & Downey, J.M. Acadesine extends the window of protection afforded by ischaemic preconditioning. Cardiovasc Res 28, 379–383. (1994).
  12. Iii, R.R.R. et al. Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR. Society (2012).
  13. Burckhartt, B., Yang, X.M., Tsuchida, A., Mullane, K.M., Downey, J.M. & Cohen, M.V. Acadesine extends the window of protection afforded by ischaemic preconditioning in conscious rabbits. Cardiovasc Res 29, 653–657. (1995).
  14. Mangano DT. Effects of acadesine on myocardial infarction, stroke, and death following surgery. A meta-analysis Pflugers Arch – Eur J Physiol (2006) 453:147–156 155 of the 5 international randomized trials. The Multicenter Study of Perioperative Ischemia (McSPI) Research Group. JAMA 277:325–332(1997)
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