Protective effects of recombinant human bone morphogenetic protein-7 on focal cerebral ischemia–reperfusion injury

Abstract

This study was to investigate the protective effect of recombinant human bone morphogenetic protein-7 (rhBMP-7) on focal cerebral ischemia-reperfusion (IR) injuries and their underlying mechanisms. An intraluminal suture method was used to generate a middle cerebral artery occlusion model in rats, which was followed by reperfusion. A sham operation (SO) group underwent the procedure without occlusion, whereas an IR group and rhBMP-7 treated group (RT) underwent occlusion in the absence and presence of rhBMP-7 (250 μg/kg) administered via a femoral vein injection 30 minutes prior to reperfusion. Twenty-four hours after reperfusion, neurological function, brain water content and morphological alterations were examined. Apoptosis was detected using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assays, and immunohistochemical staining and Western blot assays were used to detect nuclear nuclear factor-kappa B (NF-κB) p65 expression. Compared with the SO group, IR rats showed a decrease in neurological function, an increase in brain water content, and pathological and morphological damage (p < 0.05). Higher levels of apoptosis were also detected in the infarct region area. In contrast, RT rats had reduced injury after IR. In addition, while immunohistochemical staining and western blot assays consistently detected increased expression of nuclear NF-κB after IR, these levels were reduced in the RT group. Administration of rhBMP-7 prior to reperfusion effectively inhibited the extent of IR injury by attenuating cerebral edema and ameliorating ultrastructural damage. The underlying mechanisms responsible for these observations potentially involve the inhibition of apoptosis induced by IR by rhBMP-7 via an NF-κB-related signaling cascade.

Bone Morphogenetic Protein-7 Ameliorates Cerebral Ischemia and Reperfusion Injury via Inhibiting Oxidative Stress and Neuronal Apoptosis

“…In this study, a great number of apoptotic cells were found in the penumbral cortex of vehicle group at 24 h after reperfusion, whereas BMP-7 treatment reduced neuronal apoptosis. These results are consistent with recent findings showing that the neuroprotection of BMP-7 is probably through inhibition of apoptosis [31,32]. …”

Bone Morphogenetic Protein–Based Therapeutic Approaches

“…Bmp7 expression increases following ischemic injury to the cerebrum (Chang et al 2003), raising the possibility that BMP signaling exerts protective or reparative actions in this tissue, and that augmenting its effect may be beneficial in the treatment of stroke. Support for this assertion comes from reports that administration of recombinant BMP-7 in a rodent model of transient ischemia before or at the onset of reperfusion leads to neuroprotection and decreased cerebral apoptosis through reduced activation of NF-kB, caspase 3, caspase 8, and caspase 9 (Pei et al 2013;Xu et al 2013). The translational potential of this strategy was further advanced by the showing that intracisternal administration of recombinant BMP-7 one day after reperfusion leads to rapid improvement of neurological function (Liu et al 2001).…”

Bone morphogenetic protein 9 serves a protective role in response to ischemic‑reperfusion in the brain by promoting ERK activation

“…Of these, certain members have been demonstrated to exert protective roles for cerebral I/R injuries. For example, Xu et al ( 11 ) demonstrated that the administration of rhBMP7 via a femoral vein injection 30 min prior to reperfusion significantly increases neurological function, decreases brain water content and pathological and morphological damage, and may be associated with reduced nuclear factor-κB activity. Using the same procedure, Pei et al ( 12 ) also demonstrated that BMP-7 significantly improves neurological deficiency and reduces the infarct volume via attenuating oxidative stress and inhibiting neuronal apoptosis following cerebral ischemia.…”