Rolipram Attenuates Early Brain Injury Following Experimental Subarachnoid Hemorrhage in Rats: Possibly via Regulating the SIRT1/NF-κB Pathway

Abstract

Early brain injury (EBI) is the primary cause of poor outcome in subarachnoid hemorrhage (SAH) patients. Rolipram, a specific phosphodiesterase-4 inhibitor which is traditionally used as an anti-depressant drug, has been recently proven to exert neuroprotective effects in several central nervous system insults. However, the role of rolipram in SAH remains uncertain. The current study was aimed to investigate the role of rolipram in EBI after SAH and explore the potential mechanism. Adult male Sprague-Dawley rats were subjected to an endovascular perforation process to produce an SAH model. Rolipram was injected intraperitoneally at 2 h after SAH with a dose of 10 mg/kg. We found that rolipram significantly ameliorated brain edema and alleviated neurological dysfunction after SAH. Rolipram treatment remarkably promoted the expression of Sirtuin 1 (SIRT1) while inhibited NF-κB activation. Moreover, rolipram significantly inhibited the activation of microglia as well as down-regulated the expression of pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6. In addition, rolipram increased the expression of protective cytokine IL-10. Furthermore, rolipram significantly alleviated neuronal death after SAH. In conclusion, these data suggested that rolipram exerts neuroprotective effects against EBI after SAH via suppressing neuroinflammation and reducing neuronal loss. The neuroprotective effects of rolipram were associated with regulating the SIRT1/NF-κB pathway. Rolipram could be a novel and promising therapeutic agent for SAH treatment.

Inflammation and immune cell abnormalities in intracranial aneurysm subarachnoid hemorrhage (SAH): Relevant signaling pathways and therapeutic strategies

“…As a PDE4 inhibitor, rolipram significantly enhanced SIRT1 expression, whereas NF-κB activation is repressed in EBI after SAH. Mechanically, rolipram can upregulate protective cytokine IL-10 expression and inhibit pro-inflammatory cytokine (TNF-α, IL-1ß, and IL-6) expression as well as downregulate microglial activation ( 160 ). Moreover, the robust cerebral inflammation following SAH was linked to a considerable activation of the HMGB1/NF-kB pathway ( 14 , 161 ).…”

Will Sirtuins Be Promising Therapeutic Targets for TBI and Associated Neurodegenerative Diseases?

“…Nampt, which is located primarily in neurons, regulates autophagy and apoptosis ( Wang et al, 2012 ). Rolipram, a phosphodiesterase-4 inhibitor, modulates inflammation and neuronal apoptosis via different SIRT1-dependent pathways ( Li Q. et al, 2018 ; Peng et al, 2018 ).…”

The Critical Role of Sirt1 in Subarachnoid Hemorrhages: Mechanism and Therapeutic Considerations

“…The activation of Sirt1 decreased the nucleocytoplasmic translocation of HMGB1 and inhibited the TLR4/NF-кB pathway, thereby ameliorating the subsequent induction of proinflammatory cytokines and secondary brain injury after a SAH [ 78 ]. Intriguingly, some researchers have indicated the suppression of SAH-triggered cerebral inflammation alleviation neurological dysfunction via the Sirt1/NF-κB pathway [ 79 , 80 ]. In another recent study, Berberine, a potential Sirt1 activator, ameliorated the state of neuroinflammation and subsequently improved the neurological behavior in mice through the Sirt1-modulated downregulation of HMGB1/NF-κB activity.…”