AICAr, a Widely Used AMPK Activator with Important AMPK-Independent Effects: A Systematic Review PMC

AICAR (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside) is a substance produced naturally by the body that stimulates AMP activated protein kinase (AMPK), a protein that regulates metabolism in a variety of ways. AMPK acts as an energy regulator and is activated during exercise or other circumstances that use up cellular energy. In 1995, Dianabol Elbrus Pharmaceuticals order 5-amino-4-imidazolecarboxamide (AICA) ribonucleoside or riboside was first proposed to be used as the activator of AMP-kinase (AMPK) in intact cells or, in other words, to play the same role that phorbol esters had in dissecting signaling pathways regulated by protein kinase C [1]. The study by Corton et al. was based on previous work showing that administration of the AICA riboside to intact cells causes AICA ribonucleotide or ribotide to accumulate inside the cell [2], and a study by Sullivan et al. [3] demonstrated that AICA ribotide mimicked the effect of AMP on allosteric activation of rat liver AMPK. Since then, the compound that has been widely used as an AMPK-agonist was an exogenous dephosphorylated AICA riboside that should be properly abbreviated AICAr. However, in more than 1700 articles that can be retrieved from PubMed on AMPK and AICA riboside, AICAr is often abbreviated as AICAR, although the AICAR acronym should be reserved for AICA ribotide or the phosphorylated form that is a physiological, endogenous precursor in de novo purine synthesis [4].

Table 7

• The animals treated with AICAR from week 7 alone (group 5) or in combination with Methotrexate (group 6) did not improve the glucose tolerance.
• Thus, under in vitro conditions, it has been demonstrated that AICAR exposure in rat hepatoma cells and isolated hepatocytes leads to a downregulation of gluconeogenetic enzymes and suppressed gluconeogenesis, respectively (29,30).
• Researchers are actively exploring the potential benefits of AICAR administration, including fat burning, inflammation reduction, and endurance optimization.
• The initial body weight of the animals in all groups at the beginning of the study did not differ.
• The evidence shows that the growth-inhibitory response to the AMPK activator, MT 63–78, is not affected by the status of the upstream AMPK-activating kinase LKB1.

AICAR, introduced from the first day of the study, reduced the content of lipid inclusions in the cytoplasm. Methotrexate administration had no effect on the therapeutic activity of AICAR in the study. The aim of the study was to investigate the effect of AMP-activated protein kinase activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) on the consequences of metabolic syndrome and type 2 diabetes induced by the consumption of a high-fat diet (HFD) in male C57Bl/6 mice. Additionally, the animals from group 6 were administered Methotrexate (MTX) at a dose of 1 mg/kg in parallel with AICAR, which slows down the metabolism of AICAR. The animals were recorded with signs of metabolic syndrome and type 2 diabetes mellitus by recording their body weights, glucose and insulin levels, and the calculating HOMA-IRs. At the end of the study, at the end of the 13th week, during necropsy, the internal organs were assessed, the masses of the organs were recorded, and special attention was paid to visceral fat, assessing its amount and the mass of the fat surrounding epididymis.

Drug mechanisms: Enzyme activators offer potential treatment strategy

AICAR has been used medically to help with restriction of blood supply to tissues, called ischemia. Interestingly, in the 1980’s it was sometimes used during surgery to help preserve blood flow to the heart. These days, AICAR shows to be promising in diabetes treatment because of its ability to increase metabolic activity of tissues by changing the composition of muscles in the body. There are many circumstances that activate AMPK naturally, including hypoxia (low oxygen levels during exercise or at elevation), hypoglycemia (low blood sugar with exercise or fasting), the use of cellular energy during muscle contraction, and anything that disrupts energy creation within cells.

New insights into activation and function of the AMPK

However, given the unique functions and/or subcellular (or tissue)-specific distribution of the distinct AMPK complex,3, 4, 5 referencing screening to the α1β1γ1 complex may present a limited range of the physiology of AMPK. As shown in Figure 3, AICA ribotide (AICAR) or ZMP is a normal cellular intermediate in de novo purine synthesis. AICAR or ZMP is increased in Lesch-Nyhan syndrome, one of the most common disorders of purine and pyrimidine metabolism. The Lesch-Nyhan results from a deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), so that the activity of the salvage pathway is diminished and the de novo pathway of purine nucleotide synthesis accelerated, leading to an accumulation of ZMP or AICAR [96]. Yeast is a good experimental system to study the effects of AICAr that are AMPK-independent as the yeast AMPK orthologue SNF1 is activated by ADP rather than AMP, and genes strongly regulated by Snf1p are not identical to AICAr-regulated transcription.

Economically, it makes most sense to run AICAR during the 4 weeks leading up to your competition. In terms of doping, GW is easily detectable for up to 40 days in urine tests, as it is not a naturally occuring substance in the body. Meanwhile, AICAR is a naturally occuring substance in the body, so this makes it more difficult to test for. To combat this, a baseline value was established, which determines if someone is using AICAR to dope with.

Joohun Ha and colleagues at Kyung Hee University, Seoul, have reviewed the research into agents designed to activate AMPK to assess their feasibility as drugs. The researchers suggest that AMPK activators are potentially useful for the treatment of conditions such as obesity, type 2 diabetes and cancer. Combining different AMPK activators in different clinical contexts might provide optimal treatment. They conclude that more research is needed to determine the precise mechanisms of action of AMPK activators and thereby optimize treatment strategies. Ubiquitous expression of AMPKα1-, β1- and γ1-subunits in many tissues makes the α1β1γ1 complex a reference for AMPK assays to identify AMPK activators.

AICAR (alternatively, acadesine) is a naturally occurring substance that regulates adenosine—a nucleoside that occurs in all cells of the body. It also activates AMP-activated protein kinase (AMPK), a protein that regulates metabolism and energy homeostasis [1, 2]. AICAr-induced apoptosis and concurrent activation of AMPK were described in childhood acute lymphoblastic leukemia (ALL) cell lines [110], as well as in B cells isolated from patients with mantle cell lymphoma and splenic marginal zone lymphoma [7]. In chronic myelogenous leukemia (CML) cell lines [12] and primary samples [111], AICAr had antiproliferative effects, but AMPK knock-down by shRNA failed to prevent the effect of AICAr, indicating an AMPK-independent mechanism [12]. In azacytidine (Aza)-resistant myelodysplastic syndrome and acute myeloid leukemia (MS/AML) cell lines and primary samples, 2 mM AICAr blocked proliferation, and these initial findings led to a phase I/II clinical trial using AICAr in 12 patients with Aza-refractory MDS/AML patients. Despite a very good response in one out of four patients, the trial was stopped because the highest dose of AICAr caused serious renal side effects in patients with severe comorbidities [10].