I. (2011). HO\1, and other transmission transduction pathways in SAH\induced neuroinflammation. SAH, which resulted in reduced injury, and improved cognitive function. This could be due to increasing erythrophagocytosis, although CO’s effects are pleiotropic due to its gaseous nature. To this end, we found that administration of gaseous CO aids in normalizing circadian dysrhythmia after SAH (Schallner et al., 2017). We found that SAH induced at Gatifloxacin mesylate dawn compared to sunset resulted in worse cognitive function, more neuronal apoptosis, and an increased inflammatory milieu; all this correlated with reduced microglial HO\1 expression at dawn and was rescued with Gatifloxacin mesylate exogenous CO administration (Schallner et al., 2017). Additionally, CO seems to function similarly to nitric oxide (NO) as a vasodilator, neurotransmitter, and platelet aggregation inhibitor, as well as serving other anti\inflammatory functions (Hanafy, Oh, & Otterbein, 2013). It is thought to take action via soluble guanylyl cyclase (sGC), as ABL well as cyclic GMP (cGMP), and BKca channels leading to vasodilation in the vascular easy muscle mass cells (Hou, Xu, Heinemann, & Hoshi, 2008; Jaggar et al., 2005; Kaide et al., 2001; Wang, Wu, & Wang, 1997; Wu, Cao, Lu, & Wang, 2002), and thus the reduction of vasoconstriction. In addition, CO seems to inhibit TLR 2, 4, 5, and 9 signaling pathways in macrophages by interrupting their recruitment to membrane rafts (Nakahira et al., 2006). These rafts, are specialized lipid domains that contribute to immune transmission transduction. CO was shown to inhibit TLR trafficking to lipid rafts by suppressing NADPH oxidase\dependent ROS generation (Nakahira et al., 2006). 9.?CD163 Haptoglobin is a protein found in the plasma that binds free hemoglobin (Hb) released from RBCs forming the hemoglobinChaptoglobin complex (Kristiansen et al., 2001). Cluster of differentiation 163 (CD163) was found to be a specific receptor of the hemoglobinChaptoglobin complex and is exclusively expressed on monocytes and macrophages. CD163 is usually involved in the clearance and endocytosis of hemoglobinChaptoglobin complexes, and thus it may protect tissues from hemoglobin\mediated oxidative damage, serving as an alternative to the heme\TLR4/HO\1 pathway. To determine the potential role of CD163 in SAH patients, our lab performed circulation cytometry around the cerebrospinal fluid (CSF) from SAH patients and found increased expression of CD163 on macrophages from SAH patients compared to unruptured aneurysm controls. To verify these findings, we then performed immunohistochemistry around the CSF macrophages from SAH patients with increasing altered Fisher scales, where the Fisher scale refers to the RBC burden of an SAH patient noted on CT scan. As expected, we found increased CD163 expression on macrophages which experienced phagocytosed more blood. Surprisingly, we found an inverse correlation between CSF macrophage CD163 expression measured on day 1 after SAH, and 90?day outcome of these patients as measured by the modified Rankin Level (mRS). That is, increasing CD163 expression seemed to correlate with improved neurological end result, or a lower mRS. With further study, CSF macrophage CD163 expression may prove to be an important biomarker for SAH prognostication (Thomas, Ogilvy, Griessenauer, & Hanafy, 2018). Understanding why this is so might lead to novel immunotherapies. 10.?ANTI\INFLAMMATORY TREATMENTS IN SAH PATIENTS There is great desire for identifying an inflammatory biomarker that is associated with DND. Despite the fact that no biomarker has been validated to this end, a number of small level clinical Gatifloxacin mesylate trials have attempted to use numerous anti\inflammatory brokers in SAH, but to no avail. Acetylsalicylic acid (Dorhout Mees, Bergh, Algra, & Rinkel, 2007), steroids (Chyatte, Fode, Nichols, & Sundt, 1987; Gomis et al., 2010; Mohney et al., 2018), numerous nonsteroid anti\inflammatory brokers (Nassiri et al., 2016), immunosuppressants (Manno, Gress, Ogilvy, Stone, & Zervas, 1997; Ryba, Pastuszko, Iwanska, Bidzinski, & Dziewiecki, 1991), and IL\1 receptor antagonists (Singh et al., 2014) have all been failures. There are numerous potential explanations for these failures, but perhaps a more directed immune\based approach might be necessary, mirroring novel therapies in the oncology world like chimeric antigen receptor T cells, but for the innate immune system. 11.?CONCLUSION The mechanisms behind the adverse sequalae of SAH are still poorly understood; although a summary of the cerebral inflammatory transmission transduction pathways highlighted in this review are offered in Figure ?Physique1.1. While neuroinflammation itself is well known to cause cognitive dysfunction in diseases such as multiple sclerosis, poststroke recrudescence, and even systemic bacteremia; an exact mechanism behind the cognitive dysfunction in SAH has yet to be elucidated. Moreover, the high mortality rate of SAH patients makes it imperative to find new and better therapeutic Gatifloxacin mesylate treatments. SAH neuroinflammation seems to be caused primarily by the breakdown of hemoglobin in the subarachnoid space, which leads to the release of heme. Heme works as a potent TLR4 activator, and also activates.