Cells Free Full-Text AICAr, a Widely Used AMPK Activator with Important AMPK-Independent Effects: A Systematic Review

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Cells Free Full-Text AICAr, a Widely Used AMPK Activator with Important AMPK-Independent Effects: A Systematic Review

(-)Epicatechin consumption in elderly sarcopenia patients (25 mg for 7 days) improved the ratio of plasma follistatin/myostatin levels, as well as increased hand strength [133]. In addition, vasodilation and blood pressure were shown to be affected by oral consumption in human subjects in a dose-dependent manner. This effect was linked to NO levels as inhibition of NO synthase reduces (-)epicatechin’s vascular effects [134]. Although resveratrol intake reflects exercise-like effects in improving mitochondrial function and insulin sensitivity in obesity, and has neuro-protective functions in neurodegenerative models, it is still necessary to elucidate the mechanisms of action and to determine the adequate intake dosages. The compound 5-Aminoimidazole-4-carboxamide ribonucleotide (also known as AICAR or AICA-ribotide) is the analog of AMP and intermediate metabolite of the purine synthesis pathway. AICAR is an endogenous substance, and is the active agent of the drug 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside.

We performed Western blot to test the nuclear translocation of Nrf2 and the protein expression of NLRP3 https://www.lezichron-olam.com/oxymetholone-effects-3/ as well as its downstream proteins caspase-1 and cleaved IL-1β in hepatic tissues of sodium taurocholate-induced SAP rats after treatment with AICAR. The nuclear translocation of Nrf2 was increased following sodium taurocholate treatment, whereas AICAR supplementation further promoted the nuclear accumulation of Nrf2 (Figures 4A,C). Moreover, sodium taurocholate treatment significantly increased the hepatic expression of NLRP3, caspase-1 and cleaved-IL-1β, while AICAR supplementation reversed this phenomenon (Figures 4B,C). These findings suggest that AICAR markedly alters the nuclear accumulation of Nrf2 and inhibits NLRP3 inflammasome activation in sodium taurocholate-induced PALI rats by activating AMPK phosphorylation.

Resveratrol

This review will focus on the identified targets relevant to energy metabolism in muscle, such as the 5’ adenosine monophosphate-activated protein kinase (AMPK) – sirtuin (SIRT1) – Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) pathway, and the molecules affecting it. When tested in parallel with an exercise regimen, resveratrol attenuated exercise-induced oxidative stress damage in young and old rodents. In 3 and 27 month old C57Bl/6J mice, after 10 days of resveratrol-supplemented diet, the compound vastly reduced oxidative stress damage to muscle fibers [110]. A resveratrol-enriched diet (146 mg/kg/day), via activation of the SIRT1/AMPK pathway, increased running endurance in rats trained on treadmills for 12 weeks [111]. Similarly, a resveratrol-enriched diet paired with regular exercise improved endurance in aged mice [112]. Interestingly, young C57Bl/6J and KKay male mice fed with a 400 mg/kg resveratrol-enriched diet showed almost twice the running endurance of their controls, both in the standard and high-fat diet paradigm [102].

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]. The cell cycle analyses of AICAr-arrested cells in some studies revealed an increase in the proportion of cells in the G0/G1 phase, as would be expected from the mechanism of cell cycle arrest in response to AMPK activation and mTORC1 inhibition [23]. However, in embryonic stem cells, AICAr increased the cell population at both G1 and non-cycling S phases [85].

Western Blot Analysis

To better understand the molecular mechanisms, numerous studies focus on the systemic metabolic networks of transcriptional activators and interconnected enzymes involving AMPK, SIRT1, and PGC-1α. However, the possibility of minimal or even detrimental effects on brain function of candidate compounds targeting these peripheral pathways must also be considered. Indeed, differences between effects of exercise-mimetics on central versus peripheral systems could be another factor limiting the viability of a pharmacological alternative to exercise (Fig. 2, Table 1).

Indeed, studies in both animal models and humans reported a promising link between (-)epicatechin consumption and cognition. Daily oral administration of up to 30 mg/kg epicatechin to female C57Bl/6J mice improved spatial memory, increased dentate granule cell spine density, enhanced hippocampal vascularization and expression of genes important for synaptic plasticity [135]. Furthermore, three months of (-)epicatechin consumption in C57Bl/6J male mice reduced anxiety in the open field and elevated plus maze tests, possibly via hippocampal and cortical monoaminergic (monoamine oxidase) and neurotrophic (BDNF) systems [139]. As a central metabolic regulator that reacts to an increase in AMP/ATP ratio, AMPK restricts growth and proliferation in response to energetic or nutritional stress.

Single doses of at least 30mg/kg have been reported to improve muscle glucose uptake and cardiac function [3]. Researchers are actively exploring the potential benefits of AICAR administration, including fat burning, inflammation reduction, and endurance optimization. Resveratrol is a highly lipophilic molecule, but despite its easy adsorption, it is known for its scarce bioavailability. However, the molecular properties of resveratrol allow it to both cross the cellular membrane and interact with membrane receptors. Therefore, resveratrol could activate pathways at the extracellular, cytoplasmatic or nuclear level [97].

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]. The nomenclature is additionally complicated because the other name used for the endogenous substance or AICAR is ZMP [5].

  • AICAR, as an AMPK activator and biologically active compound, may cause some mild side effects when used.
  • PPARδ is a nuclear hormone receptor which acts as a transcriptional regulator of more than 100 genes and in doing so plays a crucial role in a variety of biological processes, from energy regulation to development and differentiation [26].
  • We should further determine the role of AICAR in PALI in humanoid large animals and in clinical studies.
  • It promises numerous benefits, such as improving metabolism, enhancing muscle function, and increasing endurance.

In human aortic endothelial cells, AICAr stimulated AMPK activity and nitric oxide (NO) production, and the effects were proved to be AMPK-dependent since the effects were inhibited by the expression of a dominant-negative (DN) AMPK mutant [60]. Similar AMPK-dependent effects on NO production were observed in response to hypoxia [61], and studies performed in the knockout of the upstream kinase LKB1 confirmed the important role of AMPK in angiogenesis [62]. The central goal of this study was to investigate the pharmacological activation of AMPK by AICAR as a therapeutic strategy for the treatment of PALI. Our findings demonstrated that AICAR activates AMPK, which leads to Nrf2-mediated antioxidant stress and inhibition of NLRP3-related inflammation, and thus improving PALI.

An active lifestyle has also been shown to enhance mood and cognition, and may delay the onset of neurodegenerative diseases. The beneficial effects of exercise on the body and brain are likely not replaced by one single pill. The complex underlying molecular mechanisms and modes of action provide multiple opportunities for pharmacological strategies for the various diseases.