AICAR

AICAR, also called acadesine or AICA riboside, is a nucleoside rather than a peptide: an imidazole carboxamide base joined to ribose, with a theoretical mass of 258.2 Da. This listing is a sealed vial holding 50 mg of the compound as dry powder. Research on AICAR centres on what cells make of it, the AMP mimic ZMP, which switches on AMP-activated protein kinase (AMPK), and runs from perfused rat muscle and mice to leukaemia cells and heart surgery trials.

A nucleoside, not a peptide

AICAR contains no amino acids and no peptide bonds. The lot certificate identifies it as 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, C9H14N4O5: a ribose sugar attached to an imidazole ring of the kind cells build as an intermediate on the way to purines. It is stored much like a freeze-dried peptide, cold, dry and dark, but its chemistry belongs with the nucleosides.

The name causes its own confusion. Read strictly, AICAR stands for the ribonucleotide, the phosphorylated form that biochemists call ZMP, while the compound in the vial is the unphosphorylated riboside that cells convert into it. The AICAR (acadesine) guide explains how the acronym drifted. With a theoretical mass of 258.2 Da, 50 mg works out to about 194 µmol, a little less once the residual water reported on the certificate is allowed for. The same compound is sold already dissolved as the AICAR preloaded pen.

What the research covers

From AICAR to ZMP to AMPK

AMPK is a kinase made of a catalytic alpha subunit and two further subunits, beta and gamma, and it is switched on by high AMP and low ATP¹. Hardie and Carling described it in 1997 as a fuel gauge for the cell: on sensing low energy it turns off ATP-consuming pathways such as fatty acid and sterol synthesis and turns on ATP-producing ones such as fatty acid oxidation¹. A 1995 study in rat hepatocytes proposed AICAR as a way to activate the kinase in intact cells². The hepatocytes accumulated the monophosphate, ZMP, which reproduced both activating effects of AMP on AMPK, and unlike earlier methods the treatment left cellular ATP, ADP and AMP unchanged². Activation was followed by inactivation of HMG-CoA reductase and an almost complete halt to fatty acid and sterol synthesis, and in isolated fat cells AICAR opposed lipolysis set off by isoprenaline².

Muscle and endurance in rodents

Merrill and colleagues perfused rat hindlimbs with AICAR in 1997³. AMPK in the muscle was activated, acetyl-CoA carboxylase was inactivated and malonyl-CoA fell, and fatty acid oxidation rose 2.8-fold with a significant increase in glucose uptake, while oxygen uptake did not change³. The paper that made AICAR known outside biochemistry came eleven years later. Narkar and colleagues reported that in sedentary mice, AICAR on its own induced metabolic genes and raised treadmill running endurance by 44%⁴. The same study found that a PPAR-delta agonist combined with exercise training increased oxidative muscle fibres and endurance⁴. PPAR-delta agonists such as GW501516 are covered in the Cardarine (GW501516) guide.

Leukaemia cells and heart surgery

In cells from 70 patients with B-cell chronic lymphocytic leukaemia, acadesine induced apoptosis in every sample, through a caspase-dependent route that appeared not to depend on p53⁵. Blocking nucleoside transport or adenosine kinase prevented both the apoptosis and the phosphorylation of AMPK, so the compound had to enter the cell and be converted to ZMP to act⁵. Normal B lymphocytes were as sensitive as the leukaemic cells, while T cells were only slightly affected⁵. Acadesine was first developed as a drug for heart surgery. RED-CABG, a randomized, double-blind, placebo-controlled trial run at 300 sites in 7 countries, tested it in intermediate- to high-risk patients having on-pump coronary bypass surgery, with death, stroke or severe left ventricular dysfunction within 28 days as the main outcome⁶. The AICAR guide reports that the trial enrolled 3,080 patients and failed, and that acadesine has never been approved for any indication.

What is not established

Corton's 1995 paper put a question mark after the word specific in its title², and the question has not gone away: the guide reviews knockout studies in which some effects of AICAR persisted without AMPK. Most of the findings above come from perfused tissue, isolated cells and mice. The human record consists of hospital trials in surgery and leukaemia, none of which led to an approval, and no human endurance or performance study of AICAR has been published. None of the studies used SCALE Performance material.

Frequently asked questions

References

1. Hardie DG, Carling D. The AMP-activated protein kinase--fuel gauge of the mammalian cell?. Eur J Biochem. 1997;246(2):259-73. DOI · PubMed
2. Corton JM, Gillespie JG, Hawley SA, et al. 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells?. Eur J Biochem. 1995;229(2):558-65. DOI · PubMed
3. Merrill GF, Kurth EJ, Hardie DG, et al. AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol. 1997;273(6):E1107-12. DOI · PubMed
4. Narkar VA, Downes M, Yu RT, et al. AMPK and PPARdelta agonists are exercise mimetics. Cell. 2008;134(3):405-15. DOI · PubMed
5. Campàs C, Lopez JM, Santidrián AF, et al. Acadesine activates AMPK and induces apoptosis in B-cell chronic lymphocytic leukemia cells but not in T lymphocytes. Blood. 2003;101(9):3674-80. DOI · PubMed
6. Newman MF, Ferguson TB, White JA, et al. Effect of adenosine-regulating agent acadesine on morbidity and mortality associated with coronary artery bypass grafting: the RED-CABG randomized controlled trial. JAMA. 2012;308(2):157-64. DOI · PubMed