Carnosine is an endogenous
dipeptide composed of β-
alanine and
L-histidine. This naturally occurring molecule is present at high concentrations in several mammalian excitable tissues such as muscles and brain, while it can be found at low concentrations in a few invertebrates.
Carnosine has been shown to be involved in different cellular defense mechanisms including the inhibition of
protein cross-linking, reactive
oxygen and
nitrogen species detoxification as well as the counteraction of
inflammation. As a part of the immune response, macrophages are the primary cell type that is activated. These cells play a crucial role in many diseases associated with oxidative stress and
inflammation, including
atherosclerosis, diabetes, and
neurodegenerative diseases. In the present study,
carnosine was first tested for its ability to counteract oxidative stress. In our experimental model, represented by RAW 264.7 macrophages challenged with
phorbol 12-myristate 13-acetate (PMA) and
superoxide dismutase (SOD) inhibitors,
carnosine was able to decrease the intracellular concentration of
superoxide anions (O2-•) as well as the expression of Nox1 and Nox2
enzyme genes. This
carnosine antioxidant activity was accompanied by the attenuation of the PMA-induced Akt phosphorylation, the down-regulation of TNF-α and
IL-6 mRNAs, and the up-regulation of the expression of the anti-inflammatory mediators
IL-4,
IL-10, and TGF-β1. Additionally, when
carnosine was used at the highest dose (20 mM), there was a generalized amelioration of the macrophage energy state, evaluated through the increase both in the total
nucleoside triphosphate concentrations and the sum of the pool of intracellular nicotinic
coenzymes. Finally,
carnosine was able to decrease the oxidized (
NADP+)/reduced (
NADPH) ratio of
nicotinamide adenine dinucleotide phosphate in a concentration dependent manner, indicating a strong inhibitory effect of this molecule towards the main source of
reactive oxygen species in macrophages. Our data suggest a multimodal mechanism of action of
carnosine underlying its beneficial effects on macrophage cells under oxidative stress and
inflammation conditions.