AICAR (5-aminoimidazole-4-carboxamide (AICA) riboside), also called acadesine or AICA ribonucleotide, is an synthetic nucleotide analog that acts as an adenosine monophosphate activated protein kinase (AMPK) agonist and adenosine regulator. AICAR has been used clinically during heart surgery to prevent ischemic injury caused when blood rushes back to the heart; it may also be helpful in diabetes and metabolic syndrome, and has also been shown to enhance athletic performance. Through AMPK, AICAR exerts diverse actions throughout the body including stimulation of liver fatty acid oxidation (FAO), ketogenesis, beta-cell modulation of insulin secretion, stimulation of glucose uptake, and decreased apoptosis through reducing reactive oxidative species (ROS) within cells. Acadesine was studied for its anti-ischemic properties in coronary artery bypass grafts (CABG) by Pericor and Schering-Plough.
AICAR is sometimes referred to as an exercise mimetic, meaning for sedentary or unhealthy individuals it mimics or enhances the health benefits of exercise; in athletes, it may improve exercise performance, and has been banned by the World Anti-Doping Agency.
Narkar et al (Salk Institute, 2008) discovered that AICAR enhanced the performance of mice in endurance-type exercise by converting fast-twitch muscle fibers to the more energy-efficient, fat-burning, slow-twitch type. They also found that AICAR and GW1516, when given to "sedentary" mice, activated 40% of the genes that were turned on when mice were given GW1516 and made to exercise. Media publicity touting "exercise pills" and "exercise in a pill" followed.
Pold et al (2005) demonstrate a proof of concept suggesting the manner in which AICAR/acadesine could help patients with diabetes:
Five-week-old, pre-diabetic ZDF rats underwent daily treadmill running or AICAR treatment over an 8-week period and were compared with an untreated group. In contrast to the untreated, both the exercised and AICAR-treated rats did not develop hyperglycemia during the intervention period. Whole-body insulin sensitivity, as assessed by a hyperinsulinemic-euglycemic clamp at the end of the intervention period, was markedly increased in the exercised and AICAR-treated animals compared with the untreated ZDF rats (P < 0.01). In addition, pancreatic beta-cell morphology was almost normal in the exercised and AICAR-treated animals, indicating that chronic AMPK activation in vivo might preserve beta-cell function. …[This] suggest[s] that activation of AMPK may represent a therapeutic approach to improve insulin action and prevent a decrease in beta-cell function associated with type 2 diabetes.
With AMPK expressed in numerous tissue types, AICAR has a number of other potential experimental/clinical and research chemical uses. Bai et al found that "data demonstrate that AICAR-initiated AMPK activation may represent a promising alternative to our current approaches to suppressing intestinal inflammation in IBD."
AICAR may potentially treat certain cancers; Guo et al (2009) published "results suggest[ing] a mechanism by which AICAR inhibits the proliferation of EGFRvIII expressing glioblastomas and point toward a potential therapeutic strategy for targeting EGFR-activated cancers."
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Lemieux K, Konrad D, Klip A, Marette A. "The AMP-activated protein kinase activator AICAR does not induce GLUT4 translocation to transverse tubules but stimulates glucose uptake and p38 mitogen-activated protein kinases alpha and beta in skeletal muscle". Faseb J. 17 (12): 1658–65. 2003.
Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H, Kang H, Shaw RJ, Evans RM. "AMPK and PPARdelta agonists are exercise mimetics". Cell 134 (3): 405–15. 2008.
WADA 2009 Prohibited List: WADA PROHIBITED LIST PDF (PDF Document).
Kim JE, Kim YW, Lee IK, Kim JY, Kang YJ, Park SY. "AMP-activated protein kinase activation by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) inhibits palmitate-induced endothelial cell apoptosis through reactive oxygen species suppression". J. Pharmacol. Sci. 106 (3): 394–403. 2008.
Pold R, Jensen LS, Jessen N, Buhl ES, Schmitz O, Flyvbjerg A, Fujii N, Goodyear LJ, Gotfredsen CF, Brand CL, Lund S. Long-term AICAR administration and exercise prevents diabetes in ZDF rats. Diabetes. 2005 Apr;54(4):928-34.
Bai A, Yong M, Ma Y, Ma A, Weiss C, Guan Q, Bernstein C, Peng Z. Novel Anti-Inflammatory Action of 5-Aminoimidazole-4-carboxamide ribonucleoside with protective effect in DSS-induced acute and chronic colitis. J Pharmacol Exp Ther. 2010 Mar 17.
Guo D, Hildebrandt IJ, Prins RM, Soto H, Mazzotta MM, Dang J, Czernin J, Shyy JY, Watson AD, Phelps M, Radu CG, Cloughesy TF, Mischel PS. The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis.Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12932-7.