C-Phycocyanin and Phycocyanobilin as Remyelination Therapies for Enhancing Recovery in Multiple Sclerosis and Ischemic Stroke: A Preclinical Perspective

Abstract

Myelin loss has a crucial impact on behavior disabilities associated to Multiple Sclerosis (MS) and Ischemic Stroke (IS). Although several MS therapies are approved, none of them promote remyelination in patients, limiting their ability for chronic recovery. With no available therapeutic options, enhanced demyelination in stroke survivors is correlated with a poorer behavioral recovery. Here, we show the experimental findings of our group and others supporting the remyelinating effects of C-Phycocyanin (C-PC), the main biliprotein of Spirulina platensis and its linked tetrapyrrole Phycocyanobilin (PCB), in models of these illnesses. C-PC promoted white matter regeneration in rats and mice affected by experimental autoimmune encephalomyelitis. Electron microscopy analysis in cerebral cortex from ischemic rats revealed a potent remyelinating action of PCB treatment after stroke. Among others biological processes, we discussed the role of regulatory T cell induction, the control of oxidative stress and pro-inflammatory mediators, gene expression modulation and COX-2 inhibition as potential mechanisms involved in the C-PC and PCB effects on the recruitment, differentiation and maturation of oligodendrocyte precursor cells in demyelinated lesions. The assembled evidence supports the implementation of clinical trials to demonstrate the recovery effects of C-PC and PCB in these diseases.

Keywords: C-phycocyanin; Multiple Sclerosis; Phycocyanobilin; recovery; remyelination; stroke.

Figure 1

C-PC-induced remyelination in an EAE model in Lewis rats. Panels show representative electron microscopy images of brain biopsies from (A) non-diseased; (B) EAE-vehicle treated and (C) EAE-C-PC 25 mg/Kg treated animals; (D) g-ratio = [axon diameter/(myelin + axon) diameter] (mean ± S.E.M. *** p < 0.001 vs. control group, ANOVA + Newman-Keuls tests by using GraphPad Prism Software). C-PC at 25 mg/Kg or the vehicle were administered i.p. once a day from day 0 until day 12 after immunization (n = 10 each group). Control (non-immunized) animals received saline instead of encephalitogen. Brain samples were taken at the end of the study period (day 24 post-immunization). Arrowheads or arrows indicate normal myelin structure/thickness or myelin damage/loss, respectively. Ax: axon. Bar = 200 nm.

Figure 2

C-PC-induced remyelination in the MOG_35–55-induced EAE model in C57BL/6 mice. Panels show representative electron microscopy images of spinal cord samples from (A) non-diseased; (B) EAE-vehicle treated and (C) EAE-C-PC 8 mg/Kg treated animals; (D) g-ratio = [axon diameter/(myelin + axon) diameter] (mean ± S.E.M. *** p < 0.001 vs. control group, ANOVA + Newman-Keuls tests using GraphPad Prism Software). C-PC at 8 mg/Kg or the vehicle were administered i.p. daily at disease onset (between days 11 and 12 post-immunization) for 15 days (n = 4–7 each group). Control (non-immunized) animals received phosphate buffered saline instead of encephalitogen. Spinal cord samples were taken at the end of the study period (day 29 post-immunization). Arrowheads or arrows indicate normal myelin structure/thickness or myelin damage/loss, respectively. Ax: axon. Bar = 200 nm.

Figure 3

PCB-induced remyelination in a focal transient cerebral ischemia model induced by endothelin-1 (ET-1) in Wistar rats. Panels show representative electron microscopy images of cerebral cortex samples from (A) sham; (B) ET-1-vehicle treated and (C) ET-1-PCB 200 µg/Kg treated animals. (D) g-ratio = [axon diameter/(myelin + axon) diameter] (mean ± S.E.M. *** p < 0.001 vs. control group, ANOVA + Newman-Keuls tests by using GraphPad Prism Software). ET-1 at 600 pmol was stereotaxically injected in the piriform cerebral cortex at the coordinates +0.9 mm (anterior), +5.2 mm (lateral), −8.3 mm (dorsoventral) respective to bregma, adjacent to the middle cerebral artery. PCB 200 µg/Kg or the vehicle, were administered i.p. in equal subdoses at 30 min, 1, 3 and 6 h post-surgery (n = 5 each group). Sham animals received saline instead of ET-1. Brain samples were taken 24 h after the ischemic insult. Arrowheads or arrows indicate normal myelin structure/thickness or myelin damage/loss, respectively. Ax: axon. Bar = 1 µm.