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Carnosine Prevents A?-Induced Oxidative Stress and Inflammation in Microglial Cells: A Key Role of TGF-?1.

ABSTRACT: Carnosine (?-alanyl-L-histidine), a dipeptide, is an endogenous antioxidant widely distributed in excitable tissues like muscles and the brain. Carnosine is involved in cellular defense mechanisms against oxidative stress, including the inhibition of amyloid-beta (A?) aggregation and the scavenging of reactive species. Microglia play a central role in the pathogenesis of Alzheimer's disease, promoting neuroinflammation through the secretion of inflammatory mediators and free radicals. However, the effects of carnosine on microglial cells and neuroinflammation are not well understood. In the present work, carnosine was tested for its ability to protect BV-2 microglial cells against oligomeric A?1-42-induced oxidative stress and inflammation. Carnosine prevented cell death in BV-2 cells challenged with A? oligomers through multiple mechanisms. Specifically, carnosine lowered the oxidative stress by decreasing NO and O?^-• intracellular levels as well as the expression of iNOS and Nox enzymes. Carnosine also decreased the secretion of pro-inflammatory cytokines such as IL-1?, simultaneously rescuing IL-10 levels and increasing the expression and the release of TGF-?1. Carnosine also prevented A?-induced neurodegeneration in mixed neuronal cultures challenged with A? oligomers, and these neuroprotective effects were completely abolished by SB431542, a selective inhibitor of the type-1 TGF-? receptor. Our data suggest a multimodal mechanism of action of carnosine underlying its protective effects on microglial cells against A? toxicity with a key role of TGF-?1 in mediating these protective effects.

SUBMITTER: Caruso G

PROVIDER: S-EPMC6356400 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

Carnosine Prevents Aβ-Induced Oxidative Stress and Inflammation in Microglial Cells: A Key Role of TGF-β1.

Caruso Giuseppe G Fresta Claudia G CG Musso Nicolò N Giambirtone Mariaconcetta M Grasso Margherita M Spampinato Simona F SF Merlo Sara S Drago Filippo F Lazzarino Giuseppe G Sortino Maria A MA Lunte Susan M SM Caraci Filippo F

Cells 20190117 1

Carnosine (β-alanyl-L-histidine), a dipeptide, is an endogenous antioxidant widely distributed in excitable tissues like muscles and the brain. Carnosine is involved in cellular defense mechanisms against oxidative stress, including the inhibition of amyloid-beta (Aβ) aggregation and the scavenging of reactive species. Microglia play a central role in the pathogenesis of Alzheimer's disease, promoting neuroinflammation through the secretion of inflammatory mediators and free radicals. However, t ...[more]

PMID: 30658430

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Project description:Carnosine is an endogenous dipeptide composed of ?-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-? and IL-6 mRNAs, and the up-regulation of the expression of the anti-inflammatory mediators IL-4, IL-10, and TGF-?1. 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.

Dataset Information

Carnosine Prevents A?-Induced Oxidative Stress and Inflammation in Microglial Cells: A Key Role of TGF-?1.

Publications

Carnosine Prevents Aβ-Induced Oxidative Stress and Inflammation in Microglial Cells: A Key Role of TGF-β1.

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