Cells Free Full-Text 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].

• Moreover, Nrf2 deficiency dramatically weakened these beneficial effects of AICAR in L-arginine-induced PALI mice.
• Interestingly, some indications that beneficial effects of exercise on the brain might be inducible by metformin treatment are starting to appear.
• Indeed, studies in both animal models and humans reported a promising link between (-)epicatechin consumption and cognition.
• In chronic myelogenous leukemia (CML) cell lines [12] and primary samples [111], AICAr had antiproliferative effects, but AMPK knock-down by shRNA failed to prevent the effect of AICAr, indicating an AMPK-independent mechanism [12].

AICAr, AMPK, Proliferation and Cell Cycle

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 https://superalba.es/genotropin-original-16-iu-pfizer-labs-results/ 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.

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-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].

Statistical Analysis

Pancreatic and liver tissues were collected, fixed immediately in 4% paraformaldehyde for 24 h, dehydrated in a graded ethanol series, and then embedded in paraffin. Then, pancreatic and liver sections were stained with hematoxylin and eosin (H&E) staining (G1120, Solarbio, Beijing, China) according to the manufacturer’s instructions. Nutrition is increasingly recognized as a crucial player in proper brain development and function.

Exercise in a Pill: The Latest on Exercise-Mimetics

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.

Divergence between effects of short and long administration correlates neural plasticity with a study in skeletal muscle, where 14 days of AICAR failed to increase SIRT1 expression, contrary to 7 days of administration [42]. In a recent study, we made a side-by-side comparison between effects of short- and long-term AICAR administration and exercise regimens, on gastrocnemius muscle and brain in young C57Bl/6 male mice. Both interventions induced similar AMPK pathway activation in skeletal muscle after both short (3–7 days) and longer (14 days) administration. Specifically, in the dentate gyrus of the hippocampus, brain-derived neurotrophin (BDNF) levels and neuronal proliferation were elevated by short-term treatment, while no increase was reported after longer administration [43].

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.