Abstract
Subarachnoid hemorrhage (SAH) is a devastating form of stroke that leads to incurable outcomes. Increasing evidence has proved that early brain injury (EBI) contributes mostly to unfavorable outcomes after SAH. A previously unknown mechanism of regulated cell death known as necroptosis has recently been reported. Necrostatin-1 (nec-1), a specific and potent inhibitor of necroptosis, can attenuate brain impairments after SAH. However, the effect of nec-1 on the hippocampus and its neuroprotective impact on synapses after SAH is not well understood. Our present study was designed to investigate the potential effects of nec-1 administration on synapses and its relevant signal pathway in EBI after SAH. Nec-1 was administrated in a rat model via intracerebroventricular injection after SAH. Neurobehavior scores and brain edema were detected at 24 h after SAH occurred. The expression of the receptor-interacting proteins 1 and 3 (RIP1and3) was examined as a marker of necroptosis. We used hematoxylin and eosin staining, Nissl staining, silver staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) to observe the morphological changes in hippocampus. The protective effect of nec-1 on synapses was evaluated using western blotting and electron microscopy and Western blotting was used to detect the cAMP responsive element binding (CREB) protein and brain-derived neurotrophic factor (BDNF), and we used transmission electron microscopy and TUNEL to detect the protective effects of nec-1 when a specific inhibitor of CREB, known as 666-15, was used. Our results showed that in the SAH group, RIP1, and RIP3 significantly increased in the hippocampus. Additionally, injection of nec-1 alleviated brain edema and improved neurobehavior scores, compared with those in the SAH group. The damage to neurons was attenuated, and synaptic structure also improved in the Sham+nec-1 group. Furthermore, nec-1 treatment significantly enhanced the levels of phospho-CREB and BDNF compared with those in the SAH group. The protective effect of nec-1 could hindered by 666-15. Thus, nec-1 mitigated SAH-induced synaptic impairments in the hippocampus through the inhibition of necroptosis in connection with the CREB-BDNF pathway. This study may provide a new strategy for SAH patients in clinical practice.
Highlights
Subarachnoid hemorrhage (SAH) is a devastating form of stroke that leads to a high mortality and disability rate (Bederson et al, 2009; Serrone et al, 2015)
We found that receptorinteracting protein 1 (RIP1) and receptor-interacting protein 3 (RIP3) are expressed in the CA3 subfield and the dentate gyrus of the hippocampus
We report that SAH induced necroptosis because of a subsequent increase in the levels of RIP1 and RIP3, inhibition of necroptosis by nec-1 ameliorated the morphological damage to the hippocampus
Summary
Subarachnoid hemorrhage (SAH) is a devastating form of stroke that leads to a high mortality and disability rate (Bederson et al, 2009; Serrone et al, 2015). More recent evidence shows that necrosis can be well-controlled via a caspase-independent mechanism known as necroptosis (Hanson, 2016; Wang et al, 2017). This form of controlled cell death is activated when apoptosis is inhibited on account of the suppression of caspase activity, and it shares both the controlled mechanism seen in apoptosis and the morphological features seen in necrosis (Ou et al, 2017). RIP1 is identified as a significant regulator of necrotic death in cells where caspase was inhibited. The neuroprotective functions of nec-1 as a result of suppressing necroptosis may provide new ideas for possible treatments for SAH (Zhang S. et al, 2017)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
