Introduction

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. The AMPK-stimulating AICAR can also be synthesized in a lab and is being evaluated in preclinical research and human clinical trials as a therapeutic agent to treat certain human metabolic disorders[1].

Benefits

In studies, AMPK agonist AICAR improved memory function and neurogenesis when administered for one week but not upon longer treatment. In muscle, effects of AICAR and exercise overlap, while in the brain, cell proliferation, neurotrophin levels and expression of neural plasticity-relevant genes are only transiently increased by AICAR. Indeed, fourteen days of AICAR resulted in increased expression of apoptotic genes, inflammatory cytokine levels, and differentially regulated oxidative stress markers.

Uses

The therapeutic potential of AICAR is due to the fact that the pathological processes that cause disturbances in the action of AMPK can cause such dangerous conditions as hypertension, ischemia, cancer, Alzheimer’s disease, obesity, and diabetes. AICAR has anti-ischemic properties. Thus, in the work of Leung et al., it was shown that AICAR limits the severity of myocardial ischemia after bypass surgery, as evidenced by the shorter duration of ischemia in patients receiving high doses of AICAR. AICAR receives orphan drug designation for adult chronic lymphocytic leukemia (B-Cell) in the European Union.

In 2007, it was found that the activation of AMP-activated protein kinase (AMPK) in muscle by AICAR, as with exercise, increases glucose uptake. The course application of AICAR induces a metabolic shift in cardiomyocytes exposed to free fatty acids, characterized by improved glucose transport and the redirection of fatty acids to neutral storage. Such metabolic changes in vivo may protect the heart of patients with type 2 diabetes from ischemia-reperfusion injury.

AICAR was found to be able to inhibit the synthesis of fatty acids and cholesterol in liver cells, enhance fatty acid oxidation, and inhibit gluconeogenesis. In skeletal muscle cells, AICAR has been found to activate glycogen phosphorylase and increase glycogenolysis, stimulate fatty acid oxidation and glucose uptake, and inhibit protein synthesis. All of these studies have confirmed the role of AMPK as the central metabolic site of the cell, which is activated whenever the AMP/ATP ratio is high and acts to increase catabolic and inhibit anabolic processes. The effects of AICAR that were previously studied indicate the possibility of its use in treating type 2 diabetes. AICAR induces hypoglycemia in vivo. In addition, AICAR may help reduce peripheral insulin resistance. In various animal models of insulin resistance, the administration of AICAR has been shown to improve metabolic disturbances and enhance insulin sensitivity in peripheral tissues. AICAR systemic administration in humans has beneficial effects by reducing hepatic glucose production and increasing skeletal muscle glucose uptake[2].

AICAR also has great potential in the treatment of metabolic syndrome associated with obesity. AICAR reduces inflammation in human adipose tissue explants and in mice fed a high-fat diet, promotes weight loss, and also reduces inflammation in adipocytes while reducing damage to the liver and kidneys, as well as reducing resistance to glucose, which may indicate that it helps to reduce the complications caused by obesity. AICAR reduces glucose levels, as shown in genetically modified mice with diabetes and obesity. To lower the relatively high AMPK activation threshold, as well as increase the relatively low bioavailability, limiting the effectiveness of AICAR in the treatment of type 2 diabetes, it was decided to administer AICAR in combination with the antitumor drug Methotrexate, which can increase the activation of AMPK stimulated by AICAR in skeletal muscles, to one of the groups of animals. It has previously been shown that Methotrexate significantly lowered the threshold for AICAR-stimulated AMPK activation and potentiated glucose uptake and lipid oxidation in skeletal muscle.

References

[1] Davide Guerrieri, Henriette van Praag. “Exercise-mimetic AICAR transiently benefits brain function.” Oncotarget 6 21 (2015): 18293–313.

[2] Elena A Tukhovskaya. “AICAR Improves Outcomes of Metabolic Syndrome and Type 2 Diabetes Induced by High-Fat Diet in C57Bl/6 Male Mice.” International Journal of Molecular Sciences 23 24 (2022).