AICAR

What is AICAR?

AICAR, or 5-Aminoimidazole-4-carboxamide ribonucleotide, is a naturally occurring intermediate in the synthesis of inosine monophosphate (IMP), a precursor to purines (components of DNA and RNA). In a pharmacological context, AICAR (also known by its nucleoside form, acadesine) is an analog of adenosine monophosphate (AMP). Its primary function is to mimic AMP and activate an important cellular enzyme called AMP-activated protein kinase (AMPK).

AMPK is often referred to as a "master regulator" of cellular energy homeostasis. It acts as an energy sensor within cells, monitoring the ratio of AMP to ATP (adenosine triphosphate, the cell's main energy currency). When cellular energy levels are low (indicated by a high AMP/ATP ratio), AMPK is activated.

The activation of AMPK by AICAR leads to a cascade of effects that regulate energy metabolism. Specifically, it promotes catabolic pathways that generate ATP (like glucose and fatty acid oxidation) and inhibits anabolic pathways that consume energy (like protein and lipid synthesis).

In a medical context, AICAR was first used in the 1980s to protect the heart during surgery by increasing blood flow. It is also being investigated for its potential to treat a range of metabolic disorders, including diabetes and obesity, by improving insulin sensitivity and increasing metabolic activity in tissues.

Side Effects and Benefits

Benefits:

• Metabolic Regulation: AICAR's primary benefit is its ability to activate AMPK, which can improve insulin sensitivity, increase glucose uptake, and promote fatty acid oxidation. This makes it a subject of research for metabolic disorders like diabetes and obesity.

• Cardiovascular Health: It has been shown to have cardioprotective effects, improving endothelial function and reducing inflammation and oxidative stress. This makes it a potential agent for treating conditions like myocardial ischemia and atherosclerosis.

• Exercise-Mimetic Effects: Chronic AICAR treatment has been shown to induce changes in muscle composition that are similar to those caused by endurance exercise. It can promote the transformation of muscle fiber types from fast-twitch (glycolytic) to slow-twitch (oxidative), leading to increased stamina and endurance in animal studies.

• Cognitive Function: Some animal studies suggest that AICAR may improve cognition and motor coordination, potentially by increasing the expression of mitochondrial and neural plasticity genes in the brain.

Potential Side Effects and Risks:

• Cardiac Hypertrophy: Chronic, systemic activation of AMPK, particularly through certain isoforms, has been associated with an undesirable increase in heart muscle size (cardiac hypertrophy).

• Increased Appetite: In some animal models, activating AMPK in the hypothalamus (the brain's energy-sensing center) has been reported to increase feeding behavior and body weight gain, which could counteract its other metabolic benefits.

• Immune System Modulation: While AMPK activation can have anti-inflammatory effects, its role is complex and context-dependent. There is some evidence that it could potentially impair immune cell function or lead to unwanted immunosuppression.

Pros and Cons

Pros:

• Potential Therapeutic Agent: AICAR shows promise for treating significant health conditions such as obesity, diabetes, and cardiovascular diseases by directly targeting cellular energy pathways.

• "Exercise-in-a-Bottle" Concept: The ability of AICAR to mimic the physiological effects of endurance exercise on a cellular level is a major pro, as it could be beneficial for individuals who are unable to exercise due to injury or other physical limitations.

Cons:

• Limited Human Data: The majority of the research on AICAR's benefits and side effects has been conducted on animals. Its effects, safety, and optimal use in humans are not well-established.

• Undesirable Side Effects: The potential for adverse effects like cardiac hypertrophy and increased appetite raises serious safety concerns, particularly with long-term or uncontrolled use.

• Doping Risk: Due to its performance-enhancing properties (mimicking the effects of exercise), AICAR is a prohibited substance in sports.

Dosage and Frequency

Information on human dosage and frequency is not readily available in the provided search results, as its clinical use is still under development. The search results mention specific dosages in animal studies, such as:

• Rats: 250 mg/kg, administered three times per week (M, W, F) for an extended period, or 500 mg/kg daily for four weeks.

• Intravenous Infusion: A clinical study on acadesine (the nucleoside form of AICAR) used a dose of 42 mg/kg delivered as an IV infusion over approximately 7 hours.

These dosages are for research purposes and are not a recommendation for human use.

Half-life and Detection Time

• Half-life: The provided search results do not specify a precise half-life for AICAR. However, they indicate that when AICAR enters red blood cells, it is converted into a phosphorylated form (AICAR-ribotide). This form is "conserved within the erythrocyte and its concentration remains elevated for up to 10 days upon administration."

• Detection Time: Due to its endogenous nature, detecting AICAR abuse is challenging. Standard urine tests may show elevated levels for several hours after administration. However, a more reliable method for detecting illicit use is by measuring the concentration of AICAR-ribotide in red blood cells. Because this phosphorylated form remains stable for a longer period, it can serve as a "long-term marker" for illicit use, with concentrations remaining elevated for up to 10 days. The World Anti-Doping Agency (WADA) has developed a method using carbon isotope ratio mass spectrometry to distinguish between endogenous and exogenous AICAR.

Sterogenic, Progestronic, and Prolactin Effects

The provided search results do not contain information on any sterogenic, progestronic, or prolactin effects of AICAR. The search results on prolactin discuss its role in mammary gland development and lactation and its relationship with progesterone and estrogen. There is no mention of AICAR influencing these hormonal pathways.

Anabolic Androgenic Ratio

The anabolic-androgenic ratio is a measure used to compare the muscle-building (anabolic) effects of a substance to its masculinizing (androgenic) effects. This ratio is specifically relevant to anabolic-androgenic steroids (AAS).

AICAR is not an anabolic-androgenic steroid. It does not act on androgen receptors or have a steroid structure. Its mechanism of action is completely different, focusing on cellular energy metabolism through AMPK. Therefore, the concept of an anabolic-androgenic ratio does not apply to AICAR. The search results that list this ratio are for other substances like testosterone and various steroids, not for AICAR.