Exercise-mimetic AICAR transiently benefits brain function

Abstract

Exercise enhances learning and memory in animals and humans. The role of peripheral factors that may trigger the beneficial effects of running on brain function has been sparsely examined. In particular, it is unknown whether AMP-kinase (AMPK) activation in muscle can predict enhancement of brain plasticity. Here we compare the effects of running and administration of AMPK agonist 5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR, 500 mg/kg), for 3, 7 or 14 days in one-month-old male C57BL/6J mice, on muscle AMPK signaling. At the time-points where we observed equivalent running- and AICAR-induced muscle pAMPK levels (7 and 14 days), cell proliferation, synaptic plasticity and gene expression, as well as markers of oxidative stress and inflammation in the dentate gyrus (DG) of the hippocampus and lateral entorhinal cortex (LEC) were evaluated. At the 7-day time-point, both regimens increased new DG cell number and brain-derived neurotrophic factor (BDNF) protein levels. Furthermore, microarray analysis of DG and LEC tissue showed a remarkable overlap between running and AICAR in the regulation of neuronal, mitochondrial and metabolism related gene classes. Interestingly, while similar outcomes for both treatments were stable over time in muscle, in the brain an inversion occurred at fourteen days. The compound no longer increased DG cell proliferation or neurotrophin levels, and upregulated expression of apoptotic genes and inflammatory cytokine interleukin-1β. Thus, an exercise mimetic that produces changes in muscle consistent with those of exercise does not have the same sustainable positive effects on the brain, indicating that only running consistently benefits brain function.

Traumatic brain injury decreases AMP‐activated protein kinase activity and pharmacological enhancement of its activity improves cognitive outcome

“…The dose of AICAR was based on previous studies which utilized this drug to alter AMPK activity in rodents (Chen et al . ; Guerrieri and van Praag ). The dose of metformin was based upon the dose range for this compound in humans (12.5–25 mg/kg) after compensation for differences in body surface area (human : mouse = 12.3 : 1).…”

“…administration of AICAR and/or metformin can increase AMPK phosphorylation in the injured brain, 500 mg/kg AICAR, 250 mg/kg metformin or vehicle was administered intraperitoneally at 15 min and 24 h following controlled cortical impact injury to mice. The dose of AICAR was based on previous studies which utilized this drug to alter AMPK activity in rodents (Chen et al 2014;Guerrieri and van Praag 2015). The dose of metformin was based upon the dose range for this compound in humans (12.5-25 mg/kg) after compensation for differences in body surface area (human : mouse = 12.3 : 1).…”

AICAR Prevents Acute Olanzapine-Induced Disturbances in Glucose Homeostasis

“…Though not without controversy (Goodyear, 2008), the compound 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) has been suggested to act as an "exercise mimetic" (Narkar et al, 2008;Guerrieri and van Praag, 2015). AICAR is an adenosine analogue that is phosphorylated and converted into 5-aminoimidazole-4-carboxamide ribonucleoside 5'-monophosphate (ZMP) (Hasenour et al, 2014).…”

Annual banned‐substance review: analytical approaches in human sports drug testing

“…A significant increase was observed in expression levels for the peroxisome proliferator‐activated receptor (PPAR)‐γ coactivator 1α (PGC‐1α) and glucose transporter 4 proteins, and enhanced mitochondriogenesis was reported particularly for type II (B) muscle fibers. These exercise‐mimetic properties however did not translate to positive effects on the brain that are commonly observed with sport practice, but enhanced insulin signaling in skeletal muscle tissue was found, at least partially attributed to the downregulation of the microRNA‐29 . The performance‐enhancing effects of the PPARδ agonist GW1516 (or GW501516) were investigated using metabolomics approaches, and a variety of factors including the proportion of succinate dehydrogenase‐positive muscle fibers, serum galactose, β‐hydroxybutyrate, and unsaturated fatty acid levels were found to change significantly in mice studied under the influence of the discontinued drug candidate .…”