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

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

Cytoprotection in Multiple Sclerosis and Ischemic Stroke with C-Phycocyanin and Phycocyanobilin

Cytoprotection in human diseases can be achieved by avoiding and ameliorating tissue damage or by restoring the homeostatic balance either as a local or a systemic defense response. Multiple Sclerosis (MS) and Ischemic Stroke (IS) although being different central nervous system diseases, have common pathogenic aspects such as a deregulated inflammatory response, a toxic redox imbalance and a prominent neuronal dysfunction. C-Phycocyanin (C-PC), the main biliprotein of the Spirulina platensis cyanobacteria, and its associated chromophore named Phycocyanobilin (PCB), has shown strong antioxidant, anti-inflammatory and immunomodulatory properties. In this review, we describe the main experimental findings of our group supporting the medical application of C-PC/PCB as effective diseasemodifying therapies for MS and IS. We demonstrated that C-PC induced regulatory T cells and protected both mice and rats against the progression of experimental autoimmune encephalomyelitis. Both compounds exerted beneficial actions in several models of IS, either in vitro or in vivo. We also addressed the hypothesis of possible combinations of C-PC/PCB with already approved treatments for MS, such as beta IFN, to improve the effectiveness, lower the cost and achieve patient relief or recovery. The safety and tolerability of these compounds are also stressed. The gathered evidence supports the implementation of clinical trials to demonstrate the potential therapeutic effect of C-PC/PCB against these diseases.</p

Evaluación de la ficocianobilina y sus combinaciones en un modelo animal de esclerosis múltiple

INTRODUCTION: Multiple sclerosis is a chronic inflammatory disease of the central nervous system characterized by generalized areas of focal demyelination. The mainly used animal model is experimental autoimmune encephalomyelitis.OBJECTIVE: To demonstrate the effects of treatment with phycocyanobilin and their combinations. The PCB is a biliproteina derived from the cyanobacteria Spirulina platensis.METHODS: EAE was induced in mice C57BL / 6 with MOG35-55 in adjuvant full of Freund/emulsion of Mycobacterium tuberculosis and pertussis toxin. In this model was evaluated the effect of PCB/IFNbeta compared with the active ingredients in an independent way. The daily clinical progression was evaluated, and the concentrations of CCL5, CXCL10, IFN-γ, CXCL2, CCL2, IL-17A, IL-6 and IL-10 in homogenized tissue were determined by ELISA.RESULTS: EAE mice treated with the PCB/IFN-beta combination showed a significant decrease of the clinical score. On the other hand, PCB/IFN-beta combination treatment induced a significant decrease in the levels of IL-10 and IL-17 in homogenized's brain.CONCLUSION: The PCB/IFN-beta combination reduces the clinical progression of disease EAE, an effect possibly mediated in the brain by a decrease in the levels of IL-17A and IL-10.INTRODUCCIÓN: La esclerosis múltiple es una enfermedad inflamatoria crónica del sistema nervioso central caracterizada por áreas generalizadas de desmielinización focal. El modelo animal principalmente utilizado es la encefalomielitis autoinmune experimental.OBJETIVO: Demostrar los efectos del tratamiento con ficocianobilina y sus combinaciones. La PCB es una biliproteína derivada de la cianobacteria Spirulina platensis.MÉTODOS: Se indujo EAE en ratones C57BL / 6 con MOG35–55 en adyuvante completo de Freund/emulsión de Mycobacterium tuberculosis y la toxina pertussis. En este modelo fue evaluado el efecto de la PCB/IFNbeta en comparación con los ingredientes activos de forma independiente. La progresión clínica diaria fue evaluada, y se determinaron, mediante ELISA, las concentraciones de CCL5, CXCL10, IFN–γ, CXCL2, CCL2, IL–17A, IL–6 e IL–10 en homogeneizados de tejido.RESULTADOS: Los ratones con EAE tratados con la combinación PCB/IFN–beta mostraron una disminución significativa de la puntuación clínica. Por otro lado, el tratamiento de combinación PCB/IFN–beta indujo una disminución significativa de los niveles de IL–10 y IL–17 en homogeneizados de cerebro.CONCLUSIÓN: La combinación PCB/IFN–beta aminora la progresión clínica de la enfermedad EAE, un efecto posiblemente mediado en el cerebro por una disminución de los niveles de IL–17A e IL–10

Gossypitrin, A Naturally Occurring Flavonoid, Attenuates Iron-Induced Neuronal and Mitochondrial Damage

The disruption of iron homeostasis is an important factor in the loss of mitochondrial function in neural cells, leading to neurodegeneration. Here, we assessed the protective action of gossypitrin (Gos), a naturally occurring flavonoid, on iron-induced neuronal cell damage using mouse hippocampal HT-22 cells and mitochondria isolated from rat brains. Gos was able to rescue HT22 cells from the damage induced by 100 µM Fe(II)-citrate (EC50 8.6 µM). This protection was linked to the prevention of both iron-induced mitochondrial membrane potential dissipation and ATP depletion. In isolated mitochondria, Gos (50 µM) elicited an almost complete protection against iron-induced mitochondrial swelling, the loss of mitochondrial transmembrane potential and ATP depletion. Gos also prevented Fe(II)-citrate-induced mitochondrial lipid peroxidation with an IC50 value (12.45 µM) that was about nine time lower than that for the tert-butylhydroperoxide-induced oxidation. Furthermore, the flavonoid was effective in inhibiting the degradation of both 15 and 1.5 mM 2-deoxyribose. It also decreased Fe(II) concentration with time, while increasing O2 consumption rate, and impairing the reduction of Fe(III) by ascorbate. Gos–Fe(II) complexes were detected by UV-VIS and IR spectroscopies, with an apparent Gos-iron stoichiometry of 2:1. Results suggest that Gos does not generally act as a classical antioxidant, but it directly affects iron, by maintaining it in its ferric form after stimulating Fe(II) oxidation. Metal ions would therefore be unable to participate in a Fenton-type reaction and the lipid peroxidation propagation phase. Hence, Gos could be used to treat neuronal diseases associated with iron-induced oxidative stress and mitochondrial damage