Combination of endothelial progenitor cells and BB‑94 significantly alleviates brain damage in a mouse model of diabetic ischemic stroke

Abstract

Ischemic stroke is a complication of chronic macrovascular disease in type 2 diabetes. However, the pathogenesis of diabetic ischemic stroke has not yet been fully clarified. The aim of the present study was to investigate the underlying effects of endothelial progenitor cells (EPCs) and the matrix metalloproteinase inhibitor BB-94 on diabetic stroke. In vitro experiments were performed using oxygen-glucose deprivation/reoxygenation (OGD/R) model cells, established using HT22 mouse hippocampal cells. MTT assays and flow cytometry revealed that BB-94 prominently induced the proliferation of the OGD/R model cells and prevented their apoptosis. When EPCs and BB-94 were applied to the OGD/R model cells in combination, proliferation was further accelerated and oxidative damage was attenuated. In vivo experiments were also performed using a middle cerebral artery occlusion (MCAO) mouse model. The results of modified neurological severity scoring and oxidative stress marker analysis demonstrated that EPCs and BB-94 prominently alleviated cerebral ischemia/reperfusion injury in the MCAO model mice. Furthermore, reverse transcription-quantitative PCR and western blot assays revealed that EPCs in combination with BB-94 significantly downregulated the expression of matrix metalloproteinases (MMPs) and upregulated the expression of tissue inhibitor of metalloproteinases 1 in OGD/R cells and MCAO model mice. The results suggest that EPCs were successfully isolated and identified, and the OGD/R cell and MCAO mouse models were successfully established. They also indicate that EPCs alone or in combination with BB-94 may exert protective effects against ischemic stroke via the reduction of MMP expression.

Role of Matrix Metalloproteinases in Musculoskeletal Diseases

“…When cultured with a specific MMPs inhibitor (hydroxamic acid), mandibular explants showed an alteration in mandibular morphogenesis [ 83 ]. In addition, broad-spectrum MMPs inhibitors such as BB94 [ 84 ], GM6001 [ 85 ], and MMPs inhibitor II showed reduced cell migration in vitro [ 86 ].…”

Emerging diagnostic markers and therapeutic targets in post-stroke hemorrhagic transformation and brain edema

“…Some of the MMP inhibitors have been studied in the context of stroke. Batimastat (BB-94) is a broad-spectrum MMP inhibitor that has shown neuroprotective effects in animal models of stroke when administered either before or immediately after the onset of ischemia ( Zhou et al, 2021 ). Despite this, poor bioavailability and potential side effects restrict its clinical application.…”

Endothelial Progenitor Cells: A Brief Update

“…Sufficient amount of EPCs are required for EPC transplantation into vascular grafts surface or injection into ischemic area. Zhou et al (28) studied the combined effects of EPCs and MMPs inhibitor, BT-94, in diabetic ischemic stroke in in vitro and in vivo experiments. EPCs and BB-94 alleviated cerebral ischemia injury in the MCAO model mice and downregulated the expression of MMPs in OGD/R and MCAO model mice (28).…”