Title : Role of natural plant-derived baicalein on neurogenesis and brain remodelling in an endothelin-1 ischemic stroke model
Abstract:
Ischemic stroke is a major cerebrovascular disease that leads to mortality and adult disability worldwide. Recently, multipotent neural stem cell (NSC) grafting has emerged as potential therapy to regenerate the damaged brain tissue. However, the hostile microenvironment in the ischemic brain region is challenging for the survival of transplanted cells. In this regards, NSC culture was optimized with baicalein, a neuroprotective active compound, extracted from Oroxylum indicum plant to enhance the NSC therapeutic potential prior to transplantation into ischemic brain. O. indicum is a versatile medicinal herb plant reported to possess a wide range of pharmacological activities due to its high content of secondary metabolites such as flavonoids. Baicalein is one of the major flavonoids present in O. indicum with high potential as a neuroprotective agent. In this study, ischemic stroke rat model was established using endothelin-1 (ET-1) vasoconstrictor which constrict the middle cerebral artery (MCA) to induce ischemic damage in the brain. In vitro expandable NSCs were preconditioned with baicalein-enriched fraction (BEF) extracted from the O. indicum plant at optimum dosage of 3.125 μg/ml for 48 hours prior to transplantation into the ET-1 induced ischemic stroke rats. Rat behaviours and stroke severity were observed and recorded for 14 days. Results showed improvements in stroke behaviours occurred within 14 days after the transplantation of BEF-preconditioned NSC compared to non-preconditioned NSC transplantation group. Through TTC staining, the BEF-preconditioned NSC-treated group showed significant reduced brain infarct (11.535 ± 1.44%), compared to non-preconditioned NSC-treated group (17.784 ± 2.33%) and non-treated group (23.807 ± 2.60%). BEF-preconditioned NSC-treated group also showed significantly induced angiogenesis and reduced neuronal degradation, cell necrosis and inflammation, compared to the other groups. In addition, total RNA transcriptomic profiling also was performed using microarray assay to identify the key genes and pathways underlying the ischemic stroke recovery induced by the preconditioned-NSC transplantation. Based on the microarray result, it was found that GABRA6 (362.11-fold), CBLN3 (103.94-fold) and NEUROD1 (37.9-fold) were significantly downregulated while FCGR3A (17,26-fold), LCN2 (15.65-fold) and MS4A12 (9.02-fold) were significantly upregulated in animals treated with BEF-preconditioned NSCs, compared to those treated with non-preconditioned NSCs. In brief, this study provided novel knowledge regarding the underlying mechanism of BEF-preconditioned NSCs therapy to treat ischemic stroke based on the significant main expression of genes using microarray analysis.
