Abstract
BackgroundMultiple sclerosis (MS) is a chronic autoimmune disease driven by sustained inflammation in the central nervous system. One of the pathological hallmarks of MS is extensive free radical production. However, the subsequent generation, potential pathological role, and detoxification of different lipid peroxidation-derived reactive carbonyl species during neuroinflammation are unclear, as are the therapeutic benefits of carbonyl quenchers. Here, we investigated the reactive carbonyl acrolein and (the therapeutic effect of) acrolein quenching by carnosine during neuroinflammation.MethodsThe abundance and localization of acrolein was investigated in inflammatory lesions of MS patients and experimental autoimmune encephalomyelitis (EAE) mice. In addition, we analysed carnosine levels and acrolein quenching by endogenous and exogenous carnosine in EAE. Finally, the therapeutic effect of exogenous carnosine was assessed in vivo (EAE) and in vitro (primary mouse microglia, macrophages, astrocytes).ResultsAcrolein was substantially increased in inflammatory lesions of MS patients and EAE mice. Levels of the dipeptide carnosine (β-alanyl-l-histidine), an endogenous carbonyl quencher particularly reactive towards acrolein, and the carnosine-acrolein adduct (carnosine-propanal) were ~ twofold lower within EAE spinal cord tissue. Oral carnosine treatment augmented spinal cord carnosine levels (up to > tenfold), increased carnosine-acrolein quenching, reduced acrolein-protein adduct formation, suppressed inflammatory activity, and alleviated clinical disease severity in EAE. In vivo and in vitro studies indicate that pro-inflammatory microglia/macrophages generate acrolein, which can be efficiently quenched by increasing carnosine availability, resulting in suppressed inflammatory activity. Other properties of carnosine (antioxidant, nitric oxide scavenging) may also contribute to the therapeutic effects.ConclusionsOur results identify carbonyl (particularly acrolein) quenching by carnosine as a therapeutic strategy to counter inflammation and macromolecular damage in MS.
Highlights
Multiple sclerosis (MS) is a chronic autoimmune disease driven by sustained inflammation in the central nervous system
To evaluate the downstream generation of acrolein, a highly reactive lipid-derived carbonyl that can induce significant protein modification [6], we examined acrolein-protein adduct formation in human brain samples containing demyelinated (PLP−) active MS lesions and mixed active/ inactive MS lesions by immunohistochemistry [30]
Acrolein-protein adducts displaying a specific cellular morphology were repeatedly observed in the lesion center, lesion border, or even outside of the lesion (proteolipid protein (PLP)+/CD68− area)
Summary
Multiple sclerosis (MS) is a chronic autoimmune disease driven by sustained inflammation in the central nervous system. The subsequent generation, potential pathological role, and detoxification of different lipid peroxidation-derived reactive carbonyl species during neuroinflammation are unclear, as are the therapeutic benefits of carbonyl quenchers. In multiple sclerosis (MS), the infiltration of circulating lymphocytes and monocytes triggers sustained central nervous system (CNS) inflammation leading. Even though elevated levels of lipid-derived carbonyls have already been reported in MS [10,11,12,13,14,15], very little is known about the processes underlying their generation, potential pathological role, and detoxification, nor on the therapeutic benefits of carbonyl quenchers to counter CNS inflammation and macromolecular damage
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