AICAR

AICAR Chemical definition

AICAR (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside; or often also called as AICA ribonucleotide) is an synthetic analog of adenosine monophosphate (AMP), that stimulates AMP-dependent protein kinase (AMPK) activity. AICAR has chemical formula C₉H₁₅N₄O₈P and molar mass 338.213 g·mol⁻¹. The AMPK-stimulating AICAR is synthesized in a lab and is being evaluated in preclinical research and human clinical trials as a therapeutic agent to treat certain metabolic disorders in humans.

Adenosine monophosphate and AMP activated protein kinase

Nucleotides are molecules consisting of a nucleoside and a phosphate group, they are the basic building blocks of DNA and RNA, and also play a central role in metabolism at a fundamental, cellular level. Nucleotide Adenosine monophosphate (AMP; or also known as 5′-adenylic acid) is a substance produced naturally by the body, that consists of a phosphate group, the sugar ribose, and the nucleobase adenine; it is an ester of phosphoric acid and the nucleoside adenosine. Adenosine monophosphate plays an important role in many cellular metabolic processes, being interconverted to ADP and/or ATP. AMP is also a component in the synthesis of RNA.

AMP activated protein kinase (AMPK; 5′ adenosine monophosphate-activated protein kinase) is an enzyme and 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. It plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. AMPK is expressed in a number of tissues, including the liver, brain, and skeletal muscle. In response to binding AMP and ADP, the net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, inhibition of adipocyte lipolysis, and modulation of insulin secretion by pancreatic beta-cells.

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. The effects of activating AMPK are extremely complex since it is involved in so many different metabolic pathways of the body.

AICAR History

AICAR was first used in the 1980s as a method to preserve blood flow to the heart during surgery. Currently, AICAR has also been shown as a potential treatment for diabetes by increasing the metabolic activity of tissues by changing the physical composition of muscle.

AICAR as protection and treatment of Myocardial ischemia

AICAR has been used clinically to treat and protect against cardiac ischemic injury.

What is Myocardial ischemia? Myocardial ischemia (also called cardiac ischemia) occurs when blood flow to your heart is reduced, preventing the heart muscle from receiving enough oxygen. The reduced blood flow is usually the result of a partial or complete blockage of your heart’s arteries (coronary arteries). Myocardial ischemia reduces the heart muscle’s ability to pump blood. A sudden, severe blockage of one of the heart’s artery can lead to a heart attack. Myocardial ischemia might also cause serious abnormal heart rhythms. Treatment for myocardial ischemia involves improving blood flow to the heart muscle. Treatment may include medications, a procedure to open blocked arteries (angioplasty) or bypass surgery.

AICAR, research and medical use

A brief period of coronary arterial occlusion followed by reperfusion prior to prolonged ischemia is known as preconditioning. It has been shown that this is protective. Preconditioning preceded myocardial infarction, may delay cell death and allow for greater salvage of myocardium through reperfusion therapy.

AICAR has been shown to precondition the heart shortly before or during ischemia. AICAR triggers a preconditioned anti-inflammatory state by increasing NO production from endothelial nitric oxide synthase. When AICAR is given 24 hours prior to reperfusion, it prevents post ischemic leukocyte-endothelial cell adhesive interactions with increased NO production. AICAR-dependent preconditioning is also mediated by an ATP-sensitive potassium channel and hemeoxygenase-dependent mechanism. It increases AMPK-dependent recruitment of ATP-sensitive K channels to the sarcolemma causing the action potential duration to shorten, and preventing calcium overload during reperfusion. The decrease in calcium overload prevents inflammation activation by ROS. AICAR also increases AMPK-dependent glucose uptake through translocation of GLUT-4 which is beneficial for the heart during post-ischemic reperfusion. The increase in glucose during AICAR preconditioning lengthens the period for preconditioning up to 2 hours in rabbits and 40 minutes in humans undergoing coronary ligation.

As a result, AICAR reduces the frequency and size of myocardial infarcts up to 25% in humans allowing improved blood flow to the heart. As well, the treatment with AICAR has been shown to decrease the risk of an early death and improve recovery after surgery from an ischemic injury.

AICAR effect on performance

AMP activated protein kinase (AMPK) once activated by AICAR, works to make energy more available. For example, it increases the usage of fat for energy and causes cells to make more mitochondria (the cells’ powerhouses or energy creators). AMP activated protein kinase basically ensures that the various tissues in the body don’t run out of energy. Despite the strong stimulation of metabolic processes in the body, AICAR is able to enormously increase performance, up to an incredible 40-50% compared to conventional endurance performance: Ronald M. Evans and colleagues, from Howard Hughes Medical Center and Salk Institute conducted a series of experiments with AICAR in 2000, and in these studies, they found that mice receiving AICAR could run 44% further, even without training.

AICAR as a performance-enhancing drug & Doping

In 2009, the French Anti-Doping Agency, suspected that AICAR had been used in the 2009 Tour de France for its supposed performance enhancing properties. As of January 2011, AICAR was officially a banned substance in the World Anti Doping Code, and the standard levels in elite athletes have been determined, to interpret test results. AICAR is still experimental compound that is not yet approved for therapeutic use in humans and should not be used by any athletes.

Scientifically investigated possible benefits of AICAR

• • AICAR has been used clinically to treat and protect against cardiac ischemic injury
  • AICAR may reduce the frequency and size of myocardial infarcts up to 25% in humans
  • Pharmacological activation of AMPK by AICAR lessens tissue cardiac injury and protects mitochondrial structure in cardiomyocytes (cardiac muscle cells)
  • AICAR has strong ability to treat metabolic disorders and diseases in humans (incl. diabetes)
  • AICAR is able to enormously increase performance, up to an incredible 40-50% compared to conventional endurance performance

AICAR possible side-effects

• • Too much activation of AMPK, or activating it in the wrong tissue, can cause serious side effects, including neurodegeneration, or preventing cells from dividing
  • The accumulation of naturally-occurring AICAR (adenosine monophosphate – AMP) in the body is also associated with metabolic disorders in humans
  • AICAR is still not adequately researched and other side effects and risks associated with its use are possible

AICAR FAQ

What is AICAR?

AICAR is an synthetic analog of adenosine monophosphate, a substance produced naturally by the body. Adenosine monophosphate plays an important role in many cellular metabolic processes, being interconverted to ADP and/or ATP, it is also a component in the synthesis of RNA.

What does AICAR do?

AICAR stimulates AMP-dependent protein kinase (AMPK) activity, what leads to stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, inhibition of adipocyte lipolysis, and modulation of insulin secretion by pancreatic beta-cells. 

Can AICAR increase performance and endurance?

AICAR through activation of AMP-activated protein kinase (AMPK) is able to enormously increase performance, up to an incredible 40-50% compared to conventional endurance performance.

What is AICAR used for?

AICAR has been used clinically to treat and protect against cardiac ischemic injury. The drug was first used in the 1980s as a method to preserve blood flow to the heart during surgery. Currently, AICAR has also been shown as a potential treatment for diabetes by increasing the metabolic activity of tissues by changing the physical composition of muscle.

Is AICAR safe?

AICAR has been clinicaly tested in humans for a variety of conditions. “It was found to be a quite safe drug, at least at the doses we were using,” said chemist Paul Laikind, who began testing it in the 1980s as a means of preserving blood flow to the heart during surgery. But AICAR is still experimental compound, that requires further review and other side effects and risks associated with its use are possible.

How does Aicar activates AMPK?

AICAR is an adenosine monophosphate (AMP) analog taken up into cells by adenosine transporters and phosphorylated by adenosine kinase. Similarly to cellular AMP, AICAR binds to site 3 on the AMPKγ subunit.

What is AMPK enzyme?

AMP activated protein kinase (AMPK) is an enzyme and 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. It plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low.

How do you activate AMPK naturally?

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. The effects of activating AMPK are extremely complex since it is involved in so many different metabolic pathways of the body.

Does exercise activate AMPK?

AMPK is activated by low energy status (increased AMP/ADP: ATP) such as during exercise, and regulates metabolic process and energy homeostasis by switching off ATP consuming pathways (fatty acid and cholesterol synthesis) and switching on ATP generating processes (glucose uptake and fatty acid oxidation).

Does AMPK help you lose weight?

Boosting AMPK activity results in a healthier metabolic status, which can lead to less fat production.

How do you activate AMPK levels?

AMP-activated protein kinase, or AMPK, is known as a master regulator of metabolism. Cells activate AMPK when they are running low on energy, and AMPK is activated in tissues throughout the body following exercise or during calorie restriction.

What is the difference between AICAR and GW1516?

While AICAR is analogue of naturally produced substance in the body Adenosine monophosphate (AMP) and a PPAR-delta AMPK axis agonist, GW-1516 is fully synthetically designed substance and a PPAR-delta agonist.

Is AICAR an officially banned substance in Sport?

Since January 2011, AICAR has been an officially banned substance under the World Anti-Doping Code and standard levels have been set for top athletes to interpret test results.

AICAR dosage

In scientific and clinical studies, the dose of AICAR is often reported as 10-20 mg / kg body weight per day with minimal side effects. Extremely high doses and overdoses of AICAR may be dangerous as they may affect blood flow to the heart.