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

Abstract

The aim of the present study was to investigate the expression and function mechanism of bone morphogenetic protein 9 (BMP9) in cerebral ischemia-reperfusion (I/R) injuries in vivo and in vitro. A total of 40 Sprague-Dawley rats were randomly divided into four groups (n=10): i) Normal control; ii) sham surgery group, the procedure without occlusion; iii) I/R group, right middle cerebral artery occlusion (MCAO) followed by reperfusion; and iv) adenoviral vector (Ad)-BMP9 + I/R group, Ad-BMP9 intracerebroventricular injection was performed 2 days prior to MCAO. Neurological deficit score and infarct volume were measured at 24 h following reperfusion. To further test the mechanism of BMP9, astrocytes were isolated and treated with Ad-BMP9, Ad-BMP9 + extracellular signal-regulated kinase (ERK) inhibitor PD098059, Ad-BMP9 + c-Jun N-terminal kinase inhibitor SP600125 and Ad-BMP9 + p38 inhibitor SB203580 for 24 h, followed by undergoing oxygen-glucose deprivation and reoxygenation (OGD/R) treatment. Cell viability and death were assessed by 3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-(4-sulfophenyl)-2H-tetrazolium and lactate dehydrogenase release, respectively. Gene expression was determined by quantitative polymerase chain reaction and western blotting. BMP9 was identified to be upregulated at mRNA and protein levels in cerebral I/R animal and cell models. BMP9 pretreatment significantly reduced the neurological score and infarct volume compared with I/R rats. In astrocytes, overexpression of BMP9 significantly decreased cell death and improved cell viability, an effect which may be mediated by the ERK signaling pathway, as ERK was activated by BMP9 and the use of PD098059 partially reversed the protective effect of BMP9. Pretreatment with BMP-9 may be a promising treatment option for prevention of cerebral I/R injuries.

Hippocampal and Cerebellar Changes in Acute Restraint Stress and the Impact of Pretreatment with Ceftriaxone

“…Bone morphogenetic proteins (BMPs), particularly BMP9, are considered a cholinergic differentiation factor for BFCN [45]. BMP9 overexpression significantly decreased cell death in astrocytes [46]. BMP signaling in the hippocampus affects depressive activity [47].…”

Neuroprotective Effects of Curcumin against Oxygen-Glucose Deprivation/Reoxygenation-Induced Injury in Cultured Primary Rat Astrocyte by Improving Mitochondrial Function and Regulating the ERK Signaling Pathway

“…ERK is essential for the regulation of cell proliferation, differentiation, and survival [ 37 ], and its signaling pathway which is closely related to mitochondrial function and cell viability [ 38 , 39 ] is critical to the survival of astrocyte [ 40 ]. ERK phosphorylation is elevated after SCI [ 22 ], and overactivation of the ERK signaling pathway is involved in persistent inflammation and neuropathic pain sequela [ 41 ].…”

Curcumin inhibits cerebral ischaemia–reperfusion injury and cell apoptosis in rats through the ERK–CHOP–caspase-11 pathway

“…The ERK1/2 signal transduction pathway can promote cell proliferation and differentiation, inhibit apoptosis and reduce tissue inflammation after being activated by external stimuli. ERK activated by phosphorylation can prevent nerve functional defects and neuronal death and have a protective effect on cerebral ischaemia and reperfusion (Feng and Hu 2018 ; Yuan et al. 2018 ; Zhao et al.…”