Regulation of enhanced cerebrovascular expression of proinflammatory mediators in experimental subarachnoid hemorrhage via the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway

Abstract

BackgroundSubarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. It is suggested that the associated inflammation is mediated through activation of the mitogen-activated protein kinase (MAPK) pathway which plays a crucial role in the pathogenesis of delayed cerebral ischemia after SAH. The aim of this study was first to investigate the timecourse of altered expression of proinflammatory cytokines and matrix metalloproteinase in the cerebral arteries walls following SAH. Secondly, we investigated whether administration of a specific mitogen-activated protein kinase kinase (MEK)1/2 inhibitor, U0126, given at 6 h after SAH prevents activation of the MEK/extracellular signal-regulated kinase 1/2 pathway and the upregulation of cerebrovascular inflammatory mediators and improves neurological function.MethodsSAH was induced in rats by injection of 250 μl of autologous blood into basal cisterns. U0126 was given intracisternally using two treatment regimens: (A) treatments at 6, 12, 24 and 36 h after SAH and experiments terminated at 48 h after SAH, or (B) treatments at 6, 12, and 24 h after SAH and terminated at 72 h after SAH. Cerebral arteries were harvested and interleukin (IL)-6, IL-1β, tumor necrosis factor α (TNF)α, matrix metalloproteinase (MMP)-9 and phosphorylated ERK1/2 (pERK1/2) levels investigated by immunohistochemistry. Early activation of pERK1/2 was measured by western blot. Functional neurological outcome after SAH was also analyzed.ResultsExpression levels of IL-1β, IL-6, MMP-9 and pERK1/2 proteins were elevated over time with an early increase at around 6 h and a late peak at 48 to 72 h post-SAH in cerebral arteries. Enhanced expression of TNFα in cerebral arteries started at 24 h and increased until 96 h. In addition, SAH induced sensorimotor and spontaneous behavior deficits in the animals. Treatment with U0126 starting at 6 h after SAH prevented activation of MEK-ERK1/2 signaling. Further, U0126 significantly decreased the upregulation of inflammation proteins at 48 and 72 h following SAH and improved neurological function. We found no differences between treatment regimens A and B.ConclusionsThese results show that SAH induces early activation of the MEK-ERK1/2 pathway in cerebral artery walls, which is associated with upregulation of proinflammatory cytokines and MMP-9. Inhibition of the MEK-ERK1/2 pathway by U0126 starting at 6 h post-SAH prevented upregulation of cytokines and MMP-9 in cerebral vessels, and improved neurological outcome.

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

“…Activated NF-κB in neurons plays an important role in regulating inflammatory gene expression in the brain after SAH [7]. Early activation of the mitogenactivated protein kinase (MEK)-extracellular signal-regulated kinase 1/2 (ERK 1/2) also increased the protein expression of IL-1β, IL-6, and MMP-9 after SAH [6]. 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].…”

“…However, in addition to the proteases MMP9, inflammation and cytokines may participate in the pathology of BBB disruption and brain edema. A variety of inflammatory cytokines, including IL-1β, IL-6, and TNF-α, are strongly associated with brain injury in rats [6]. Activated NF-κB in neurons plays an important role in regulating inflammatory gene expression in the brain after SAH [7].…”

“…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].…”

Neopterin plasma concentrations in patients with aneurysmal subarachnoid hemorrhage: correlation with infection and long-term outcome

“…After the hemorrhagic event, the blood clot in the subarachnoid space leads to recruitment of adhesion molecules at the surface of endothelial cells. 5,22,24,29 Immunological cells such as neutrophils and macrophages phagocytize the red blood cells and degranulate between 2 and 4 days after activation, releasing a large quantity of intracellular endothelins and reactive oxygen species (ROS). 26 The release of ROS causes a decrease in vasodilatation, leading to cerebral vasoconstriction and the development of angiographic vasospasm and DCI.…”

Upregulation of tissue inhibitor of metalloproteinase-1 contributes to restoration of the extracellular matrix in the rabbit basilar artery during cerebral vasospasm after subarachnoid hemorrhage

“…TIMP-1 binds with high affinity to MMP-9 , and TIMP-2 is an important inhibitor of MMP-2 . However, the roles of TIMPs and MMPs in the large cerebral artery during development of cerebral vasospasm remain unknown (Maddahi et al, 2011(Maddahi et al, , 2012Vikman et al, 2007;Wang et al, 2012;Yang et al, 2010).…”