LAUSR

BACKGROUND Ischemic stroke produces a large health impact worldwide, with scarce therapeutic options. OBJECTIVE This study aimed to reveal the role of NADPH oxidase and neuroinflammatory genes on the cerebral anti-ischemic effects of C-Phycocyanin (C-PC), the chief biliprotein of Spirulina platensis. METHODS Rats with either focal cerebral ischemia/reperfusion (I/R) or acute brain hypoperfusion, received C-PC at different doses, or a vehicle, for up to 6 h post-stroke. Neurological, behavioral and histochemical parameters were assessed in I/R rats at 24 h. Cerebral gene expression and hippocampal neuron viability were evaluated in hypoperfused rats at acute (24 h) or chronic phases (30 days), respectively. A molecular docking analysis between NOX2 and C-PC-derived Phycocyanobilin (PCB) was also performed. RESULTS C-PC, obtained with a purity of 4.342, significantly reduced the infarct volume and neurologic deficit in a dose-dependent manner, and improved the exploratory activity of the I/R rats. This biliprotein inhibited NOX2 expression, a crucial NAPDH oxidase isoform in the brain, and the superoxide increase produced by the ischemic event. Moreover, C-PC-derived PCB showed a high binding affinity in silico with NOX2. C-PC downregulated the expression of pro-inflammatory genes (IFN-γ, IL-6, IL-17A, CD74, CCL12) and upregulated immune suppressive genes (Foxp3, IL-4, TGF-β) in hypoperfused brain areas. This compound also decreased chronic neuronal death in the hippocampus of hypoperfused rats. CONCLUSION These results suggest that the inhibition of cerebral NADPH oxidase and the improvement of neuroinflammation are key mechanisms mediating the neuroprotective actions of C-PC against brain ischemia.