Carnosine quenches the reactive carbonyl acrolein in the central nervous system and attenuates autoimmune neuroinflammation

Abstract

Background Multiple 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. Methods The 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). Results Acrolein 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. Conclusions Our results identify carbonyl (particularly acrolein) quenching by carnosine as a therapeutic strategy to counter inflammation and macromolecular damage in MS.

Unveiling the Hidden Therapeutic Potential of Carnosine, a Molecule with a Multimodal Mechanism of Action: A Position Paper

“…In studies involving oral (drinking water) administration, one of the two “often used” ( Figure 1 ) administration routes, the dosage amounts vary widely, ranging from 0.5 g/L [ 98 , 116 ] to 30 g/L (60 times higher!) [ 109 , 118 ]. Furthermore, in the context of oral administration, at least five different units of measurement can be found within the research studies: mg or g/Kg [ 119 , 120 , 121 ], mg or g/L [ 98 , 115 , 116 ], mmol/L or Kg [ 99 , 122 , 123 , 124 ], mM [ 102 , 125 , 126 ], or % [ 127 , 128 , 129 ].…”

Acrolein-inducing ferroptosis contributes to impaired peripheral neurogenesis in zebrafish

“…According to our previous study, ACR could also destroy the insulin receptor signaling pathway, resulting in impaired glucose homeostasis ( Qi et al, 2021 ). In order to distinguish destructive neurogenesis in ACR treated embryos resulting from impaired glucose homeostasis or ACR itself, anti-ACR drug (L-carnosine) ( Zhao et al, 2019 ; Spaas et al, 2021 ) and hypoglycemic drug (PK11195) ( Wiggenhauser et al, 2020 ) were utilized. Interestingly, anti-ACR, but not hypoglycemic treatment, could rescue the shortened motor nerves ( Figure 4 ).…”

Absence of endogenous carnosine synthesis does not increase protein carbonylation and advanced lipoxidation end products in brain, kidney or muscle

“…Several studies, reviewed by Boldyrev et al ( 2013 ), have demonstrated that carnosine can reduce oxidative stress in vitro and in vivo. The anti-oxidant activity of carnosine is based on its reaction with superoxide anions (Kohen et al 1991 ; Klebanov et al 1997 ), reactive aldehydes like HNE and acrolein (Aldini et al 2002 ; Baba et al 2013 ; Zhao et al 2019 ; Spaas et al 2021 ) or carbonyl groups in oxidized proteins (Hipkiss et al 2001 ). Carnosine may also increase activity of anti-oxidant enzymes, such as superoxide dismutase or glutathione peroxidase (Kim et al 2011 ).…”