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Balenine possesses some of carnosine’s and anserine’s functions, yet it appears more resistant to the hydrolysing CN1 enzyme. The aim of this study was to elucidate the stability of balenine in the systemic circulation and its bioavailability in humans following acute supplementation. Two experiments were conducted in which (in vitro) carnosine, anserine and balenine were added to plasma to compare degradation profiles and (in vivo) three increasing doses (1–4–10 mg/kg) of balenine were acutely administered to 6 human volunteers. Half-life of balenine (34.9 ± 14.6 min) was respectively 29.1 and 16.3 times longer than that of carnosine (1.20 ± 0.36 min, p = 0.0044) and anserine (2.14 ± 0.58 min, p = 0.0044). In vivo, 10 mg/kg of balenine elicited a peak plasma concentration (Cmax) of 28 µM, which was 4 and 18 times higher than with 4 (p = 0.0034) and 1 mg/kg (p = 0.0017), respectively. CN1 activity showed strong negative correlations with half-life (ρ = − 0.829; p = 0.0583), Cmax (r = − 0.938; p = 0.0372) and incremental area under the curve (r = − 0.825; p = 0.0433). Overall, balenine seems more resistant to CN1 hydrolysis resulting in better in vivo bioavailability, yet its degradation remains dependent on enzyme activity. Although a similar functionality as carnosine and anserine remains to be demonstrated, opportunities arise for balenine as nutraceutical or ergogenic aid.

Additional file 3: Table S3. Primer sequences.

Additional file 4: Figure S1. Graphical summary of experimental designs. Graphical representation of the timing of carnosine treatment, EAE induction and sacrifice (tissue collection) for (a) analyses of control vs. EAE mice (data shown in Figure 2, Figure 3, Figure S2, Figure S3, Figure S4); (b) analysis of tissue carnosine loading in EAE (data shown in Figure 4); and (c) analyses of dose-dependent carnosine treatment effects (data shown in Figure 5, Figure 6, Figure S5, Figure S6). Figure S2. Spinal cord inflammatory activity during EAE. (a) Spinal cord mRNA expression in different stages of EAE compared to healthy controls (dashed line). n=6 animals/group. (b) Immunohistochemistry-based quantification of F4/80+ microglia/macrophage numbers in the spinal cord in different stages of EAE compared to healthy controls (dashed line). n=6 animals/group. Gene expression (a) and microglia/macrophage numbers (b) were increased in EAE vs. healthy controls (statistics not shown). Data are mean �� SD. One-way ANOVA or Kruskal-Wallis, post hoc testing *p

Additional file 2: Table S2. Oral carnosine treatment attenuates clinical disability in a monophasic rat EAE model.

Additional file 1: Table S1. Clinical details of human brain tissue.