AICAR

AICAR (5-aminoimidazole-4-carboxamide ribonucleoside) is a nucleoside analog: an imidazole carboxamide base joined to ribose. It is also called AICA riboside. As a drug candidate, it is called acadesine. Cells convert it to ZMP, an AMP mimic. ZMP activates AMP-activated protein kinase (AMPK), the cell's energy sensor (Corton et al., 1995). ZMP is also a natural intermediate of purine synthesis. AICAR became one of the most used AMPK activators.

Yet many of its effects do not depend on AMPK (Višnjić et al., 2021). As acadesine, it reached cardiac surgery and leukemia trials.

That page lists no formula, weight or CAS number. Those values, the aliases and the structure come from PubChem CID 17513 (acadesine). PubChem notes that "AICAR" also names the phosphorylated ribotide. PubChem's name lookup for AICAR returns that molecule (CID 65110, C₉H₁₅N₄O₈P, 338.21 g/mol). It is ZMP, not the compound in the vial.

Published work on AICAR falls into six areas. Each one below lists its model. Most of the work is in cells and animals.

From AICAR to ZMP to AMPK

In rat hepatocytes, AICAR built up as its monophosphate, ZMP. ZMP mimicked both activating effects of AMP on AMPK. AICAR left the cells' ATP, ADP and AMP unchanged. It almost stopped fatty acid and sterol synthesis (Corton et al., 1995). The riboside enters cells through adenosine transporters. Adenosine kinase then phosphorylates it.

ZMP is 40 to 50 times less potent than AMP at AMPK. It builds up to high levels in the cytoplasm (Višnjić et al., 2021). A study in primary B-cell chronic lymphocytic leukemia (B-CLL) cells blocked nucleoside transport or adenosine kinase. Either block stopped both AMPK phosphorylation and AICAR-induced apoptosis (Campàs et al., 2003). Models: rat liver cells and human leukemia cells.

Effects that do not need AMPK

In rat hepatocytes, AICAR cut oxygen consumption in a concentration-dependent way. It still did so in hepatocytes from mice lacking both AMPK catalytic subunits. In isolated mitochondria, ZMP directly inhibited respiratory-chain complex I (Guigas et al., 2007). A systematic review adds other effects that do not need AMPK.

It notes actions of millimolar ZMP on enzymes such as fructose-1,6-bisphosphatase. It also notes an S-phase arrest in leukemia cell lines that does not need AMPK. It urges caution in reading AICAR-only studies as evidence about AMPK (Višnjić et al., 2021). Models: rat and knockout mouse hepatocytes, mitochondria and cell lines.

Cell, tissue and rodent metabolic studies

In isolated rat adipocytes, AICAR activated AMPK and blunted isoprenaline-stimulated lipolysis. In perfused rat hindlimbs, 2 mM AICAR for 45 minutes activated AMPK and inactivated ACC.

In a third study, rats were given AICAR at 1 mg/g body weight daily for 4 weeks. Their white quadriceps and soleus had higher citrate synthase, succinate dehydrogenase and malate dehydrogenase activity. All three muscles studied had more hexokinase. Quadriceps also had more GLUT-4 (Winder et al., 2000). Models: rat adipocytes, perfused rat muscle and rats.

The 2008 mouse study

This study came from Narkar and colleagues at the Salk Institute. They tested whether drugs acting on AMPK or PPARδ could mimic training-induced changes in mouse muscle. They used sedentary 8-week-old C57BL/6J mice. AICAR at 500 mg/kg/day for 4 weeks raised AMPK and ACC phosphorylation in quadriceps. It also up-regulated 32 genes linked to oxidative metabolism.

On a treadmill test, the AICAR group ran about 23% longer and 44% farther than vehicle controls. In primary muscle cells, AICAR raised oxidative marker genes only when PPARδ was present (Narkar et al., 2008). These are mouse and cell data only. Models: C57BL/6J mice and primary mouse muscle cells.