Abstract
Background: Our previous in vitro results demonstrated that 11-dehydrosinulariolide significantly reduced 6-hydroxydopamine-induced cytotoxicity and apoptosis in a human neuroblastoma cell line, SH-SY5Y, and suppressed the expression of inducible NO synthase (iNOS) and cyclooxygenase 2 in lipopolysaccharide-stimulated macrophage cells. The neuroprotective and anti-inflammatory effects of 11-dehydrosinulariolide may be suitable for treating spinal cord injury (SCI). Methods: In the present study, Wistar rats were pretreated with 11-dehydrosinulariolide or saline through intrathecal injection after a thoracic spinal cord contusion injury induced using a New York University (NYU) impactor. The apoptotic cells were assessed using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The expression and localization of proinflammatory, apoptosis-associated and cell survival-related pathway proteins were examined through immunoblotting and immunohistochemistry. Results: 11-Dehydrosinulariolide attenuated SCI-induced cell apoptosis by upregulating the antiapoptotic protein Bcl-2 and cell survival-related pathway proteins p-Akt and p-ERK, 8 h after SCI. Furthermore, the transcription factor p-CREB, which regulates Bcl-2 expression, was upregulated after 11-dehydrosinulariolide treatment. On day 7 after SCI, 11-dehydrosinulariolide exhibited an anti-inflammatory effect, attenuating SCI-induced upregulation of the inflammatory proteins iNOS and tumor necrosis factor-α. 11-Dehydrosinulariolide also induced an increase in the expression of arginase-1 and CD206, markers of M2 microglia, in the injured spinal cord on day 7 after SCI. Thus, the anti-inflammatory effect of 11-dehydrosinulariolide may be related to the promotion of an alternative pathway of microglia activation. Conclusion: The results show that 11-dehydrosinulariolide exerts antiapoptotic effects at 8 h after SCI and anti-inflammatory effects at 7 days after SCI. We consider that this compound may be a promising therapeutic agent for SCI.
Highlights
During central nervous system (CNS) insults, microglia are the first responders; they produce proinflammatory mediators such as chemokines and nitric oxide (NO) [1]
Bcl‐2 induction [26,27,28,29]; we examined the level of phosphorylated cyclic‐AMP response element‐binding protein (CREB) (p‐CREB) after of Bcl-2 induction [26,27,28,29]; we examined the level of phosphorylated CREB (p-CREB) after
The antiapoptotic effect may be due to PI3K/Akt-dependent CREB activation, whereas the anti-inflammatory effect may be due to M2 microglia polarization
Summary
During central nervous system (CNS) insults, microglia are the first responders; they produce proinflammatory mediators such as chemokines and nitric oxide (NO) [1]. Previous studies have reported that the implantation of activated microglia or macrophages into an injured rat spinal cord could promote axon regeneration after spinal cord injury (SCI) [3,4]. This acute inflammation is beneficial to the CNS for limiting the injury region, performing neurogenesis, and repairing damaged tissues [5,6]. These results suggest that microglial activation may exert beneficial effects after SCI. On day 7 after SCI, 11-dehydrosinulariolide exhibited an anti-inflammatory effect, attenuating SCI-induced upregulation of the inflammatory proteins iNOS and tumor necrosis factor-α
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