Neuroprotective Effects of Brain-Derived Neurotrophic Factor and Noggin-Modified Bone Mesenchymal Stem Cells in Focal Cerebral Ischemia in Rats

BACKGROUND:Administration of bone marrow stromal cells (BMSCs) has been reported to ameliorate functional deficits in rat ischemia models. In the present study, we tried to reveal the underlying mechanism of the improvement of neurological function after stroke by BMSCs transfected with brain-derived neurotrophic factor (BDNF) and/or Noggin. METHODS:BMSCs were transfected with BDNF or/and Noggin using the adenovirus method. Middle cerebral artery occlusion (MCAO) rat models were treated with different types of transfected BMSCs. The treatment effect was assessed by measuring the modified Neurological Severity Score and the expression levels of different stroke-related molecules using Western blot, immunohistochemistry assay (IHC), and enzyme-linked immunosorbent assay (ELISA). RESULTS:The injection of BDNF or/and Noggin-modified BMSCs could significantly improve the neurological function of MCAO animals. Western blot and IHC staining showed that the expression levels of vascular endothelial growth factor, BCL-2, p-GSK3β, and p-Akt were significantly upregulated, while the expressions of Bax, TLR4, and MyD88 were significantly downregulated. Moreover, ELISA assay revealed that the level of matrix metallopeptidase 9 (MMP-9) and reactive oxygen species were also significantly decreased. These results suggested that the treatment of BDNF or/and Noggin-modified BMSCs may suppress the ischemia-induced apoptosis and inflammation in the model animals, which might be through the Akt/GSK3β and TLR4/MyD88 pathways. CONCLUSION:BDNF or/and Noggin-modified BMSCs may exert neuroprotective effects through the Akt/GSK3β and TLR4/MyD88 pathways. Transplantation of BDNF or/and Noggin-modified BMSCs might be a potential therapeutic method for ischemic stroke in clinics.