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

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

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.

We performed Western blot to test the nuclear translocation of Nrf2 and the protein expression of NLRP3 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.

  • Exercise is an effective tool to counteract a wide variety of metabolic problems, age-related loss of function and physiological issues.
  • This peptide can help increase the amount of small, rapidly oxidizing muscle fibers, which are more efficient in aerobic activity.
  • Metformin is a compound that belongs to the biguanidine class, commonly used in clinical treatment as an anti-diabetic drug.
  • Notably, AICAR supplementation further augmented the hepatic expression levels of HO-1 and NQO-1 after sodium taurocholate treatment in rats (Figures 3A–E).
  • Notably, the levels of these two markers indicated that liver injury in Nrf2 KO mice was higher than that in WT mice (Figure 7E).

AICAr, Adenosine, and Ischemic Heart

This study indicated that AMPK exerted an essential role in the pathological processes of PALI and presented the first evidence that pharmacological activation of AMPK by AICAR ameliorates PALI, suggesting that AICAR may be a promising therapeutic agent for the treatment of PALI. The dentate gyrus of the hippocampus is crucial for cognition and its functional decline is strongly linked to age-related memory loss [140]. Even more so, epicatechin has shown promising neuroprotective effects in preventing the onset of neurodegenerative diseases [142], in mouse models of Parkinson’s [143] and Alzheimer’s disease [144].

AICAR Prevents SAP-Induced Hepatic Inflammation in a Sodium Taurocholate-Induced SAP Rat Model

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.

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].

The hypothalamus is a crucial brain region for energy balance and regulation [61] and by acting upon it, metformin could reduce food intake both in diabetic [57] and non-diabetic [62] conditions. Exercise and metformin reduce circulating glucose levels by stimulating GLUT-4 membrane translocation and expression, both in adipose tissue and skeletal muscle which increases their glucose uptake. Indeed, exercise increases hepatic gluconeogenesis while metformin greatly reduces gluconeogenesis, thus reducing endogenous glucose synthesis up to 30% [54]. AICAR affects many organs and regulates a plethora of metabolic processes, in part by replicating the effects of exercise in both in vivo and in vitro studies. For instance, AICAR can mimic exercise by increasing glucose transporter type-4 (GLUT-4), hexokinase activity, resting glycogen content and muscle mitochondria numbers [30, 31].

AICAr, AMPK, Cancer, and Leukemia

(-)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.

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).

The actual efficacy of resveratrol alone still requires further studies, as there is contradictory evidence. In aged buy anabolic steroids online experience humans, 8 weeks of 250 mg/day resveratrol intake alone and in combination with high-intensity exercise training showed that resveratrol alone fails to improve muscle resistance and endurance in healthy aged men [113]. It has indeed been postulated that resveratrol might be more apt as a performance enhancer in the presence of exercise, rather than as a substitute for exercise entirely [111].

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].