Progesterone Administration Modulates Cortical TLR4/NF-κB Signaling Pathway after Subarachnoid Hemorrhage in Male Rats

Abstract

Our previous study concerning brain trauma has shown that progesterone could regulate toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) signaling pathway in the brain, which also has been proved to play important roles in early brain injury (EBI) after subarachnoid hemorrhage (SAH). The aim of the current study was to investigate whether progesterone administration modulated TLR4/NF-κB pathway signaling pathway in the brain at the early stage of SAH. All SAH animals were subjected to injection of 0.3 ml fresh arterial, non-heparinized blood into prechiasmatic cistern in 20 seconds. Male rats were given 0 or 16 mg/kg injections of progesterone at post-SAH hours 1, 6, and 24. Brain samples were extracted at 48 h after SAH. As a result, SAH could induce a strong up-regulation of TLR4, NF-κB, pro-inflammatory cytokines, MCP-1, and ICAM-1 in the cortex. Administration of progesterone following SAH could down-regulate the cortical levels of these agents related to TLR4/NF-κB signaling pathway. Post-SAH progesterone treatment significantly ameliorated the EBI, such as the clinical behavior scale, brain edema, and blood-brain barrier (BBB) impairment. It was concluded that post-SAH progesterone administration may attenuate TLR4/NF-κB signaling pathway in the rat brain following SAH.

Progesterone Improves Neurobehavioral Outcome in Models of Intracerebral Hemorrhage

“…One interesting hypothesis may be progesterone modulation of aquaporin 4 channels [45], which are known to be associated with edema formation after ICH [46]. Another possibility lies in progesterone's known modulation of the NFκB pathway through TLRs [42,47,48], as supported by the present findings. Understanding the ICH-specific mechanisms of progesterone's action would improve the likelihood of its successful translation as a therapeutic.…”

TGFβ-activated Kinase 1 (TAK1) Inhibition by 5Z-7-Oxozeaenol Attenuates Early Brain Injury after Experimental Subarachnoid Hemorrhage

“…Then we found that inhibition of TAK1 resulted in less NF-B activation and less neuronal apoptosis in vivo (15). NF-B has emerged as one of the most promising molecular targets in the prevention of EBI (6,26). NF-B resides in the inactive state in the cytoplasm as a heterotrimer consisting of p50, p65, and IB␣ subunits.…”

“…In addition to MAPK signaling pathways, NF-B also plays a key role in the pathogenesis of early brain injury after SAH (6,26). To determine the effect of TAK1 inhibition on NF-B signaling in EBI in this study, we investigated the effect of OZ on IB, an inhibitor of NF-B.…”

Hydrogen-Rich Saline Attenuated Subarachnoid Hemorrhage-Induced Early Brain Injury in Rats by Suppressing Inflammatory Response: Possible Involvement of NF-κB Pathway and NLRP3 Inflammasome

“…As another pivotal signaling pathway, NF-κB pathway has been deemed to play a dominating role in inflammation post-SAH, which could be activated due to excess ROS generation. Accumulating evidence demonstrated that many agents (recombinant osteopontin, urinary trypsin inhibitor, trehalose, progesterone, et al) alleviated inflammatory response after SAH, partially via inhibiting NF-κB inflammatory pathway [24][25][26][27]. NLRP3 inflammasome is another key component of inflammatory response.…”