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

Abstract

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, 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 Aβ1-42-induced oxidative stress and inflammation. Carnosine prevented cell death in BV-2 cells challenged with Aβ oligomers through multiple mechanisms. Specifically, carnosine lowered the oxidative stress by decreasing NO and O₂-• intracellular levels as well as the expression of iNOS and Nox enzymes. Carnosine also decreased the secretion of pro-inflammatory cytokines such as IL-1β, simultaneously rescuing IL-10 levels and increasing the expression and the release of TGF-β1. Carnosine also prevented Aβ-induced neurodegeneration in mixed neuronal cultures challenged with Aβ oligomers, and these neuroprotective effects were completely abolished by SB431542, a selective inhibitor of the type-1 TGF-β receptor. Our data suggest a multimodal mechanism of action of carnosine underlying its protective effects on microglial cells against Aβ toxicity with a key role of TGF-β1 in mediating these protective effects.

• Authors: Giuseppe Caruso, Claudia G Fresta, Nicolò Musso, Mariaconcetta Giambirtone, Margherita Grasso, Simona F Spampinato, Sara Merlo, Filippo Drago, Giuseppe Lazzarino, Maria A Sortino, Susan M Lunte, Filippo Caraci
• Journal: Cells (Cells) Vol. 8 Issue 1 (01 17 2019) ISSN: 2073-4409 [Print] Switzerland
• PMID: 30658430 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Amyloid beta-Peptides
• Cytokines
• Inflammation Mediators
• Neuroprotective Agents
• RNA, Messenger
• Transforming Growth Factor beta1
• Superoxides
• Nitric Oxide
• Carnosine
• Nitric Oxide Synthase Type II
• NADPH Oxidases

Topics

• Amyloid beta-Peptides (toxicity)
• Animals
• Carnosine (pharmacology)
• Cell Death (drug effects)
• Cell Line
• Cell Survival (drug effects)
• Cytokines (metabolism)
• Inflammation (pathology)
• Inflammation Mediators (metabolism)
• Mice
• Microglia (pathology)
• NADPH Oxidases (metabolism)
• Neurons (drug effects, metabolism, pathology)
• Neuroprotective Agents (pharmacology)
• Nitric Oxide (biosynthesis)
• Nitric Oxide Synthase Type II (metabolism)
• Oxidative Stress (drug effects)
• RNA, Messenger (genetics, metabolism)
• Rats
• Superoxides (metabolism)
• Transforming Growth Factor beta1 (genetics, metabolism)