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

In vitro studies on human umbilical cord cells showed that by increasing the activity and expression of the endothelial NOS (eNOS) enzyme through the SIRT1/AMPK pathway, resveratrol increases bioavailability of NO, therefore promoting endothelial vasculature [107, 108]. Specifically, six month old male ApoE-KO mice treated with 100 mg/kg resveratrol for 7 days, showed a marked elevation of a NOS cofactor tetrahydrobiopterin and reversed the uncoupling of eNOS. The vast beneficial consequences of exercise might not be within reach of debilitated, diseased and elderly patients. The development of compounds capable of activating cellular targets of exercise may be a new therapeutic approach. Indeed, recent research indicates that factors secreted by skeletal muscle during exercise may exert beneficial effects on brain function [6–9].

AICAR Treatment Markedly Increases the Antioxidant Abilities of the Liver in Sodium Taurocholate-Induced SAP Rats

AICAr-induced glucose uptake in skeletal muscle was abolished in the knockout of the α 2 [32,33,35] and α 3 isoforms of AMPK [34]. Both AICAr and treadmill exercise increased insulin sensitivity to stimulate glucose uptake, and these effects were not observed in mice with reduced or ablated AMPK activity in skeletal muscle [68,69]. However, the mechanisms of exercise- and AICAr-mediated glucose transport diverge at some point downstream of AMPK since AICAr-induced effects were absent in muscle-specific knockout of atypical PKC, and atypical PKC was not required in treadmill exercise [70]. Both AICAr and exercise induce AMPK activation and metabolic stress, but the mechanical stress is only caused by exercise, so that the combination of two may be useful in some conditions. In chronic inflammatory myopathy model mice, the combination of AICAr and exercise reverse apoptosis of fibro-adipogenic progenitors and improves muscle function and regeneration [70].

  • All rats and mice were fed randomly at 24 ± 2°C and 40–60% humidity with a 12 h dark cycle before the experiment.
  • 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].
  • In the meantime, many other studies described the beneficial effects of AICAr, especially in hematological malignancies, and most of these effects turned out to be AMPK-independent.
  • 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).

Statistical Analysis

For instance, metformin-induced AMPK activation was beneficial in a mouse model of Alzheimer’s disease, resulting in a protective effect on memory retention, albeit only in females [72]. Furthermore, in a Parkinson’s disease mouse model treatment for 21 days with oral metformin (500 mg/kg) increased levels of BDNF in substantia nigra pars compacta, reduced oxidative stress markers, and improved performance in motor skills [73]. To verify our hypothesis, we used Nrf2 KO mice and WT mice to conduct a comparative study in an L-arginine-induced PALI model with or without AICAR treatment.

AICAR Administration and Dosage:

Since AICAR is an AMP analog, it mimics a situation where the cell experiences energy deficiency or stress. Consequently, in the presence of AICAR, AMPK is activated even when cells are not exposed to energy stress. Yet, such high doses have shown an increased risk of kidney toxicity, which has led to discontinuation of the therapy in some subjects, despite the beneficial effects of the peptide on certain hematological parameters. The stilbene-structured compound named resveratrol is a polyphenol naturally occurring in plants [95]. The flavanols Resveratrol and (-)Epicatechin can partially mimic effects of exercise on body and brain (gray shading). The majority of these trials have used a single infusion in doses ranging from 5mg/kg of body weight to 315mg per kg of bodyweight.

Moreover, these changes in CC-treated SAP rats were accompanied by significantly increased hepatic expression of NLRP3, caspase-1 and cleaved IL-1β compared with SAP rats (Figures 6E,F), which results in a certain type of inflammatory response-related cell death called pyroptosis (Guo et al., 2021). Thus, we next compared the levels of IL-6, IL-1β and TNF-α in the liver tissues of SAP rats by q-PCR analysis with or without CC treatment. Consistent with our previous findings, the expression of these inflammatory cytokines was upregulated in the SAP groups, whereas CC treatment led to a further increase in the mRNA abundance of the aforementioned inflammatory genes (Figure 6G). Ultimately, our data suggest that inhibition of AMPK phosphorylation by CC aggravates PALI in sodium taurocholate-induced SAP rats, likely by repressing Nrf2-mediated antioxidant stress and anti-inflammatory roles.

Also, vasodilation and blood pressure are regulated by oral (-)epicatechin consumption in human subjects in a dose-dependent manner. This effect has been linked to NO levels as inhibition of NO synthase reduces effects of (-)epicatechin on the vasculature [128]. Resveratrol affects a plethora of functions and mechanisms throughout the body, such as inflammation, oxidative stress, and mitochondrial respiratory chain function. Interestingly, in vitro administration of resveratrol has been reported to affect SIRT1, either directly [98] or indirectly by activating AMPK, as seen in mouse myotubes after 8 hours of exposure to 50μM resveratrol [21]. This effect on the SIRT1-AMPK pathway, along with resveratrol-induced increased availability of cAMP, which in turns also activates PGC-1α highlights the potential of resveratrol as a metabolism-regulating, exercise-mimetic molecule.

Moreover, AICAR is known to increase skeletal muscle release of IL-6 into the bloodstream, which can cross the blood brain barrier and is an active pro-inflammatory cytokine [31]. As shown in Figure 3, AICA ribotide (AICAR) or ZMP is a normal cellular intermediate in de novo purine synthesis. AICAR or ZMP is increased in Lesch-Nyhan syndrome, one of the most common disorders of purine and pyrimidine metabolism. The Lesch-Nyhan results from a deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), so that the activity of the salvage pathway is diminished and the de novo pathway of purine nucleotide synthesis accelerated, leading to an accumulation of ZMP or AICAR [96]. Yeast is a good experimental system to study Oxymetholone costs the effects of AICAr that are AMPK-independent as the yeast AMPK orthologue SNF1 is activated by ADP rather than AMP, and genes strongly regulated by Snf1p are not identical to AICAr-regulated transcription.

Following decades of research into AMPK, the scientific community began to take interest in AICAR as “exercise in a pill.” Animal studies showed that AICAR treatment could enhance running endurance without subjecting the test subjects to any additional exercise [3]. Researchers looking to explore the benefits of AMP-kinase activation may be wondering how to establish the right AICAR dosage for their study. Despite its relatively low bioavailability, epicatechin has been extensively studied and shown to be biologically active on a different number of metabolic and structural processes.

The preferred route of administration is through continuous intravenous injection and that renders it quite unsuitable for chronic treatment of metabolic disorders like diabetes. Resveratrol, possibly via its direct effect on the SIRT1-AMPK pathway, shows beneficial effects on neuronal activity and brain functions. Old male C57Bl/6 mice, which received 150 mg resveratrol/kg food up to 12 months before testing, improved their spatial memory performance on a Y-maze test and displayed more stress-free behavior in the open-field test.