Melatonin alleviates secondary brain damage and neurobehavioral dysfunction after experimental subarachnoid hemorrhage: possible involvement of TLR4‐mediated inflammatory pathway

Abstract

Previous studies proved that melatonin protected against secondary brain damage by modulating oxidative stress after experimental subarachnoid hemorrhage (SAH), but it has not been evaluated yet about its effects on inflammatory pathway and secondary cognitive dysfunction in SAH model. This study was undertaken to evaluate the influence of melatonin on toll-like receptor 4 (TLR4) signaling pathway and neurobehavioral tests after SAH. Adult SD rats were divided into four groups: control group (n = 20), SAH group (n = 20), SAH+vehicle group (n = 20), and SAH+melatonin group (n = 20). The rat SAH model was induced by injection of 0.3 mL fresh arterial, nonheparinized blood into the prechiasmatic cistern in 20 s. In SAH+melatonin group, melatonin was administered i.p. at 150 mg/kg at 2 and 24 hr after the induction of SAH. Cognitive and memory changes were investigated in the Morris water maze. Treatment with melatonin markedly decreased the expressions of TLR4 pathway-related agents, such as high-mobility group box 1 (HMGB1), TLR4, nuclear factor-κB (NF-κB), myeloid differentiation factor 88 (MyD88), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS). Administration of melatonin following SAH significantly ameliorated spatial learning and memory deficits in this prechiasmatic blood injection model. Staining of apoptosis and necrosis indicated that fewer positive cells appeared in melatonin-treated group than SAH+vehicle group. In conclusion, melatonin may attenuate neurobehavioral dysfunction in this SAH model, and melatonin exhibits neuroprotection possibly not only through anti-oxidative pathway but also anti-inflammatory signaling after experimental SAH.

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

“…Therefore, terminating the translocation process of the activated NF-κB can intervene numerous genes transcription related to inflammation and, finally, mitigate SAH-related EBI. Previous studies have reported that some antioxidant agents or interval aimed at scavenging ROS exert positive results in experimental SAH, which is associated with inactivation of NF-κB [74,75,70,76]. Consistent with previous results, our findings showed that HS inhibited the nuclear translocation of p65 from cytoplasm; in addition, the gene expression of pro-inflammatory factors IL-1β, IL-6, and TNF-α elevated after SAH onset and suppressed by HS treatment, suggesting an inhibitory effect of HS on NF-κB activity and subsequent inflammatory response post-SAH.…”

Minocycline Protects Against NLRP3 Inflammasome-Induced Inflammation and P53-Associated Apoptosis in Early Brain Injury After Subarachnoid Hemorrhage

“…An increase in proinflammatory cytokines, including TNF-nflammatory cy-1β (IL-1β) and IL-6, is observed acutely after SAH [6]. The potential mechanisms underlying the upregulation of proinflammatory cytokines involve the activation of nuclear factor-κB (NF-κB) and the activation of the mitogenactivated protein kinase pathway and toll-like receptor 4 (TLR4) signaling pathway [6][7][8]. Recently, a study focused on the inflammasome axis, which controls the maturation and release of pro-inflammatory cytokines, demonstrated neuroprotective effects in early brain injury after SAH [9].…”

Hydrogen Sulfide Ameliorates Early Brain Injury Following Subarachnoid Hemorrhage in Rats

“…Despite the recent progress in microsurgical and endovascular surgical techniques, the outcome of patients who suffer a SAH remains unsatisfactory [2]. SAH is a complex clinical disease that early brain injury (EBI) is the main aspect which affect patients' outcome [3].…”