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Nitric oxide (NO), a gaseous signaling molecule, induces apoptosis and mediates neurodegenerative diseases and brain injury. Biglycan (BGN), a member of the small leucine-rich proteoglycan family, was demonstrated to exert anti-apoptosis function in various disease models. However, little is known about the effect of BGN on NO-induced neurotoxicity. Here, for the first time, we reported that BGN protects against NO-induced apoptosis in human neuroblastoma SH-EP1 cells. This is supported by the finding that sodium nitroprusside (SNP), a NO donor, triggered downregulation of BGN in SH-EP1 cells, and over-expression of BGN strikingly attenuated NO-induced nuclear fragmentation and apoptosis of neuronal cells. More importantly, BGN remarkably blocked NO-induced phosphorylation of Erk1/2 and p38 signaling, but not JNK MAPK pathway in neuronal cells. Furthermore, inhibiting Erk1/2 by U0126 or p38 by SB203580 partially protected against NO-induced cell death. Conversely, downregulation of BGN by siRNA aggravated NO-induced neuronal cell death, which was not attenuated by U0126 or SB203580. These findings indicated that BGN, downregulated by NO, prevents NO-induced neuronal cell apoptosis via targeting Erk1/2 and p38 signaling pathways. Our results strongly suggest that BGN could be explored for the prevention of NO-induced neurodegenerative disorders.

Recently, the study of microRNA expression profile has shown that miR-224 was implicated in neuron injury, but the mechanism of miR-224 on regulating neuronal apoptosis is completely unclear until now. Therefore, the current study aims to illuminate the miR-224 and its target gene on the modulation of neuronal cell apoptosis induced by ischemic injury. In this study, we used oxygen/glucose deprivation (OGD)-induced human-derived HCN-2 cells to establish the model of cerebral ischemia injury. We found that miR-224 was upregulated in injured cells (human brain cortical neuron). Using bioinformatics analyses, we found that miR-224 targeted the 3'UTR of spastic paraplegia 7 (SPG7) and the miR-224 inhibitor promoted expression of SPG7 and promoter activity of SPG7 3'UTR. In addition, we further found that miR-224 inhibitor enhanced interaction SPG7 with mitochondrial voltage-dependent anion channel (VDAC1) detected by co-immunoprecipitation in injured cells. The knockdown of SPG7 reduced mitochondrial membrane potential and caused higher mitochondrial calcium retention in injured cells. Knockdown of SPG7 inhibits expression of nicotinic acetylcholine receptor. Besides, the miR-224 inhibitor reduced neuronal cell apoptosis was increased by knockdown of either SPG7 or VDAC1. Overall, miR-224 inhibitor may prevent neuronal cell apoptosis by targeting SPG7 3'UTR and promote interaction SPG7 with VDAC1 after cerebral ischemia. Downregulation of SPG7 induces VDAC1 to form mitochondria permeability transition pore probably by inhibiting expression of nicotinic acetylcholine receptor, resulting in mitochondrial membrane depolarization and higher mitochondrial calcium retention.