\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[T2A]{fontenc}
\usepackage[ngerman,polish,greek,english]{babel}



\usepackage{float}








\begin{document}

\title{SAH and inflammation: Inflammatory Mechanisms after SAH (EBI and or
Vasospasm)}



\author[1]{XINGANG SUN}%
\author[2]{IVAN STEVE GODJE GODJE}%
\author[2]{HUIYU HU}%
\author[2]{XUEHONG CHU}%
\author[2]{LIJUAN ZHU}%
\affil[1]{Shanxi Medical University Second Affiliated Hospital}%
\affil[2]{Shanxi Medical University}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Despite breakthroughs in care and treatment, the consequences of a
subarachnoid hemorrhage (SAH) are still associated with morbidity and
mortality. Early brain injury is still a major source of clinical
deterioration in people with SAH. When a patient suffers a SAH, they are
more likely to develop long-term neurological problems, which can be
life-threatening. According to recent research, the management and
remission of SAH are dependent on inflammatory mechanisms. The
development of problems after SAH has recently been linked to
inflammation. Many investigations have failed to show how inflammatory
mechanisms affect SAH patients' prognosis and outcome. SAH procedures
and management will be improved by better understanding the various
inflammatory pathways that occur after SAH. It was the goal of this
review to outline some of the most important inflammatory pathways that
emerge after SAH and to provide a general understanding of SAH.%
\end{abstract}%



\sloppy


SAH and inflammation: Inflammatory Mechanisms after SAH (EBI and or
Vasospasm)

\textbf{First author: XIN-GANG SUN}

\textbf{Corresponding Author: XIN-GANG SUN}

\textbf{Department of Neurology, the Second Affiliated Hospital of
Shanxi Medical University, Taiyuan, CHINA}

\textbf{Order of Authors:}

\textbf{IVAN STEVE GODJE GODJE}

\textbf{HUI-YU HU}

\textbf{XUE-HONG CHU}

\textbf{LI-JUAN JU}

\textbf{ABSTRACT}

Despite breakthroughs in care and treatment, the consequences of a
subarachnoid hemorrhage (SAH) are still associated with morbidity and
mortality. Early brain injury is still a major source of clinical
deterioration in people with SAH.

When a patient suffers a SAH, they are more likely to develop long-term
neurological problems, which can be life-threatening. According to
recent research, the management and remission of SAH are dependent on
inflammatory mechanisms. The development of problems after SAH has
recently been linked to inflammation. Many investigations have failed to
show how inflammatory mechanisms affect SAH patients' prognosis and
outcome. SAH procedures and management will be improved by better
understanding the various inflammatory pathways that occur after SAH. It
was the goal of this review to outline some of the most important
inflammatory pathways that emerge after SAH and to provide a general
understanding of SAH.

\textbf{Keywords} : inflammation, EBI (early brain injury), cerebral
vasospasm, subarachnoid hemorrhage, secondary brain injury.

\textbf{INTRODUCTION} : Acute subarachnoid hemorrhage (SAH) is a
dangerous illness that affects many organ systems in addition to the
brain~(Cardentey-Pereda \& P\selectlanguage{ngerman}érez-Falero, 2002).

Subarachnoid hemorrhage (SAH) accounts for around 5\% of all strokes
(Hong, Tosun, Kurland, Gerzanich, Schreibman \& Simard, 2014), with more
than 30\% of patients dying as a result of the first or subsequent
bleeding (Ostrowski, Colohan \& Zhang, 2006). Brain injury that occurs
immediately after bleeding is well understood and occurs as a result of
a rise in intracranial pressure and a subsequent fall in cerebral
perfusion. Brain injury that occurs later has a variety of causes and
may necessitate a variety of treatment options because of the different
time windows of varying duration (Schneider, Xu \& Vajkoczy, 2018). ~The
fact that some SAH patients improve while others continue to deteriorate
after their initial spasm is also puzzling (Miller, Turan, Chau \&
Pradilla, 2014). Early brain injury (EBI) is primarily responsible for
the poor outcome of subarachnoid hemorrhage (SAH), which is intimately
linked to inflammation (Sun, Duan, Jing, Wang, Hou \& Zhang, 2019). In
individuals with subarachnoid hemorrhage (SAH), neuroinflammation is
directly linked to functional prognosis. Microglia are myeloid cells
that make up the CNS's innate immune system. In response to damage or
disease processes in the CNS, they become highly engaged. The use of
brain injury biomarkers could be useful not only for diagnosing and
identifying intracranial lesions, but also for assessing severity,
prognosis, and therapeutic efficacy (Mrozek, Dumurgier, Citerio, Mebazaa
\& Geeraerts, 2014).

SAH-related brain injury has been shown to be protected by inflammation
as a defensive mechanism. In the event of a stroke, blood components
such as red blood cells (RBCs), leukocytes (including macrophages), and
plasma proteins (including Endothelin-1) enter the brain instantly.
There is an inflammatory response as soon as there is blood present in
the parenchyma. Inflammatory cells are mobilized and activated during
this time period. The early inflammatory cells in reaction to the
extravascular blood component are believed to be microglia and
astrocytes.

\textbf{Inflammatory mechanisms following SAH} :

Following SAH, researchers began to look for probable links between
cerebral vasospasm and inflammatory alterations in the CSF, because at
the time, this condition was considered to be the primary, if not the
only, cause of secondary brain injury. SAH-related secondary brain
injury can result from a variety of factors, including traumatic brain
injury (TBI) and SAH. It has been established in both human and animal
research that inflammatory processes can occur in the central nervous
system in conjunction with, contribute to, or even initiate programmed
cell death (Minami, Tani, Maeda, Yamaura \& Fukami, 1992). The first
findings on systemic inflammation appeared around the end of the 1990s
and the beginning of the 2000s, and they outlined a peripheral immune
modulation after SAH (Yoshimoto, Tanaka \& Hoya, 2001)

Inflammation was merely accounted to occur alongside, or aggravate
cerebral vasospasm, rather than being comprehended as an unique
pathomechanism, when cerebral vasospasm was thought to be the only-or at
least biggest-contributor to subsequent brain injury following SAH
(Schneider, Xu \& Vajkoczy, 2018). With more recent studies, it is
believed that not only cerebral vasospasm is a main interest when
talking about secondary brain injury but also, early brain injury is an
important condition. Around this same time, in early 2000, many
mechanisms were studied to show effects of many substances on SAH
(Fassbender et al., 2000).

Although cellular components reach the subarachnoid region from within
the blood arteries, both cellular and molecular factors operate on the
vascular walls, raising the question of whether CSF inflammation is an
outside-in or inside-out event (Schneider, Xu \& Vajkoczy, 2018).

\textbf{Endothelium pathways}

\textbf{Serotonin:}

Numerous studies have shown that serotonin (5-hydroxytryptamine, 5-HT)
generated by active platelets and neurons causes cerebral vasospasm in
patients with SAH (Heros \& Zervas, 1983; Khey, Huard \& Mahmoud, 2020).
SAH patients' cerebrospinal fluid has been shown to cause considerable
constriction of isolated arteries, which may be prevented by the 5-HT
antagonist ketanserin. Additionally, tests of cerebral fluid
demonstrated elevated 5-HT levels during the acute, but not chronic,
spasm phase of SAH, while sustained exposure of arteries to 5-HT results
in desensitization (Szabò, Emilsson, Hardebo, Nystedt \& Owman, 1992).
Additionally, it has been claimed that SAH may result in a boost of the
expression of 5-HT receptors (Ansar, Vikman, Nielsen \& Edvinsson, 2007;
Hansen-Schwartz, 2004; Hansen-Schwartz, Hoel, Xu, Svendgaard \&
Edvinsson, 2003) . Additionally, it was suggested that activating 5-HT1B
receptors activates the PLA2 (phospholipase A2) enzyme. The eicosanoid
20-HETE is then synthesized via PLA2 and works to amplify
vasoconstriction (Cambj-Sapunar, Yu, Harder \& Roman, 2003) . Several
studies have shown that 5-HT receptors like 5-HT1B and 5-HT2A are
up-regulated after SAH, possibly via the MAPK-ERK1/2 pathway, hinting
that 5-HT receptors may be responsible for excessive vasoconstriction
(Ansar \& Edvinsson, 2008; Ansar \& Edvinsson, 2009; Ansar, Svendgaard
\& Edvinsson, 2007) . More than a few studies have shown that inhibiting
5-HT or degenerating axons that contain 5HT do not relieve
experimentally induced vasospastic rats (Khey, Huard \& Mahmoud, 2020).
The authors concluded that the disparity may be explained by the
cerebral arteries receiving insufficient 5-HT antagonist and 5-HT.

\textbf{Thrombin and Endothelin-1:}

\textbf{Thrombin:}

Vasospasm may be caused in part by thrombin, according to some research
(Zhang et al., 2001). Serine protease thrombin helps the coagulation
process by degrading fibrinogen and generating fibrin. Before,
Argatroban was discovered to improve neurological outcomes by reducing
BBB rupture and brain edema, as well as having anti-cell death and
anti-inflammatory effects that correspond to early brain injury after
SAH (Sugawara, Jadhav, Ayer, Chen, Suzuki \& Zhang, 2009). The discovery
that thrombin has a role in a wide range of CNS pathologies suggests a
therapeutic breakthrough (Krenzlin, Lorenz, Danckwardt, Kempski \&
Alessandri, 2016). Evidence from both in vivo and in vitro experiments
showed that high levels of thrombin in the brain parenchyma can be
harmful (Buisson, Nicole, Docagne, Sartelet, Mackenzie \& Vivien, 1998;
Jiang, Wu, Keep, Hua, Hoff \& Xi, 2002; Lee, Drury, Vitarbo \& Hoff,
1997; Vu, Hung, Wheaton \& Coughlin, 1991; Xi, Keep, Hua, Xiang \& Hoff,
1999). Thrombin, which also leads to ischemic brain injury, causes early
brain edema after intracerebral hemorrhage (Lee, Drury, Vitarbo \& Hoff,
1997; Vu, Hung, Wheaton \& Coughlin, 1991). As a result, the role of
thrombin activation in the pathophysiology of SAH is yet unknown.

\textbf{Endothelin-1:}

Endothelin is a long-acting, highly powerful vasoconstrictor found
throughout the brain. Endothelin helps to the maintenance of CBF by
working through its receptors, ETA and ETB, and is regarded as a major
auto regulating peptide (Graves \& Kreipke, 2015). ET-1 is a peptide
that is generated and released by the vascular endothelium in response
to substances like reactive oxygen species (ROS), cytokines, and
thrombin. ET-1 is also known to be produced by leukocytes and
macrophages (Fassbender et al., 2000). Although endothelin-1 is widely
acknowledged as a strong vasoconstrictor, its precise role in
autoregulation appears to be more elusive. Adults with elevated ET-1
levels in the CSF after TBI had poor clinical outcomes, including death,
permanent vegetative state, or severe debility, according to data
acquired by (Maier, Lehnert, Laurer \& Marzi, 2007) Endothelin-1 has
been associated to reduced CBF and poor prognosis post damage in several
animal models of TBI. According to the findings of the following studies
(Armstead \& Kreipke, 2011; Beuth, Kasprzak, Kotschy, Wo\selectlanguage{polish}ź\selectlanguage{english}niak, Kulwas \&
Sniegocki, 2001; Kreipke, Morgan, Roberts, Bagchi \& Rafols, 2007;
Lampl, Fleminger, Gilad, Galron, Sarova-Pinhas \& Sokolovsky, 1997;
Salonia et al., 2010; Sato \& Noble, 1998), TBI disrupts autoregulatory
systems by increasing endothelin-1-mediated vasoconstriction. Further
studies revealed that, while the drug significantly reduced vasospasm,
it did not result in significant improvements in the patient's
condition, showing that vasospasm may not be the primary cause of poor
outcome after subarachnoid hemorrhage but early brain injury may also be
a factor. To clarify the precise role of ET-1 in the development of EBI
after SAH, more research is needed.

\textbf{Platelet Activating Factor}

Platelet activating factor is a protein present in a variety of cells
throughout the body that participates in the activation of platelet,
leukocyte, and PLA2, which results in inflammatory and thrombotic
mechanisms. Many cell types produce platelet-activating factor
(1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine {[}PAF{]}), a
powerful lipid autocoid. When injected in vivo, PAF has a strong effect
on brain arteries and metabolism. PAF has direct neuronal actions in
vitro, such as suppression of acetylcholine release. Excessive PAF
production has been demonstrated in pathogenic nervous system conditions
such as neurotrauma and stroke (Yue \& Feuerstein, 1994) . PAF synthesis
and release may be enhanced in SAH as a result of activated immune cells
and endothelial cells driven by thrombin and IL-1 (Khey, Huard \&
Mahmoud, 2020). PAF produces tissue edema by increasing vascular
permeability in peripheral tissues, boosting platelet production of
granule-based enzymes, and increasing superoxide and arachidonate
metabolism in neutrophils, culminating in neurotoxicity and brain damage
following an ischemic stroke (Bladowski, Gawrys, Gajecki,
Szahidewicz-Krupska, Sawicz-Bladowska \& Doroszko, 2020; Lindsberg,
Hallenbeck \& Feuerstein, 1991; Zimmerman, McIntyre, Mehra \& Prescott,
1990).

\textbf{TREM-1 factor:}

Triggering receptors expressed on myeloid cells-1 is a key inflammatory
amplifier that interacts with a number of TLR pathways depending on the
severity of the inflammatory condition (He, Yang, Wang, Jia, Xie \&
Zhou, 2019; Youssef et al., 2009). According to Sun et al's research,
TREM-1 was first revealed to be produced in the context of SAH and has
been linked to the pathogenesis of BBB disruption. This is one of EBI's
most serious pathological symptoms (Sun, Duan, Jing, Wang, Hou \& Zhang,
2019; Sun, Ma, Jing, Wang, Hao \& Wang, 2017a; Sun, Ma, Jing, Wang, Hao
\& Wang, 2017b). According to a new research, TREM-1 is necessary for
SYK mobilization and downstream activation of CARD9/NF-\selectlanguage{greek}κ\selectlanguage{english}B and
NLRP3/caspase-1 in microglia following stroke (Xu et al., 2019a) .
TREM-1 inhibition by LP17 significantly reduced the severity of EBI, and
the protective effects were attributed to reduction of downstream
p38MAPK/MMP-9 activation and hence ZO-1 preservation (Sun, Duan, Jing,
Wang, Hou \& Zhang, 2019). TREM-1 activation can be inhibited by fusion
proteins or synthetic inhibitory peptides, which can reduce the
production of pro-inflammatory mediators and leukocyte recruitment
(Boufenzer et al., 2015; Schenk, Bouchon, Seibold \& Mueller, 2007).
Neuroinflammation has been linked to post-stroke impairment in the past
(Yirmiya \& Goshen, 2011). According to the findings of (Xu et al.,
2019a) , inhibiting TREM-1 improves long-term neurobehavioral deficits
in the hippocampus following ischemic stroke by boosting cell
proliferation and synaptic plasticity. According to the evidence
described above, TREM-1 may have a role in the inflammatory pathways
that contribute to EBI after SAH.

\textbf{Microglial polarization:}

Microglial polarization appears to play a significant part in the
pathogenic processes of neuroinflammation following subarachnoid
hemorrhage, according to increasing data (Gao et al., 2021). Microglia
responds quickly to a variety of brain injuries by modifying the shape
and polarization of their cytoplasmic structures. After a SAH,
neuroinflammation develops over time and plays a role in both EBI and
the long-term decline in cognitive function. As resident immune cells,
microglia coordinates neuroinflammation differently in neurological
disorders with varying degrees of polarization (Zheng, Lyu, Lam, Lam,
Poon \& Wong, 2020). After SAH, activated microglia are thought to
polarize into two phenotypes: classic M1 (pro-inflammatory) and
alternative M2 (anti-inflammatory), depending on the stimulus (Li \&
Barres, 2018). Lipopolysaccharide (LPS) and the pro-inflammatory
cytokine interferon-\selectlanguage{greek}γ \selectlanguage{english}(IFN-\selectlanguage{greek}γ\selectlanguage{english}) traditionally stimulate microglia to the
M1 phenotype through the release of pro-inflammatory cytokines such as
tumor necrosis factor-\selectlanguage{greek}α \selectlanguage{english}and interleukin-6 and When microglia are
stimulated by IL-4 or IL-13, they adopt an alternative M2 phenotype and
express anti-inflammatory molecules such as transforming growth factor
beta and IL-10 (Zheng, Lyu, Lam, Lam, Poon \& Wong, 2020). According to
(Liu et al., 2020), Hb-induced microglial pro-inflammatory polarization
was inhibited more effectively by the RvD1-ALX/FPR2 connection,
potentially by negatively modulating the signaling activities of
IRAK1/TRAF6/NF-\selectlanguage{greek}κ\selectlanguage{english}B or MAPKs. Similarly, (You et al., 2016) indicated
that, Rapamycin and AZD8055 may promote a selective modification of
microglia polarization to the M2 phenotype for SAH therapy by inhibiting
the mTOR pathway. RhMFG-E8 treatment reduces the microglial inflammatory
response, which is linked to the M2 microglial shift and may have direct
neuroprotective effects, and it may include the integrin 3/SOCS3/STAT3
signaling pathway (Gao et al., 2021). (Wei et al., 2017) study, showed
that Erythropoietin reduces EBI after SAH by regulating microglia
polarization through the EPOR/JAK2-STAT3 pathway. The above facts
suggest that, modulating M1 and M2 microglial polarization could be a
promising neuroprotective strategy. Further studies are needed to better
understand the application of microglial modulation in SAH.

\textbf{Toll-Like Receptors}

Toll-like receptors are pathogen-detection and clearance receptors.
Toll-like receptors (TLRs) are essential regulators of innate immunity
and are involved in the initiation of the inflammatory response in the
event of infection. TLRs initiate a series of signaling cascades in
leukocytes in response to DAMPs or pathogen-associated molecular
patterns (PAMPs), resulting in enhanced cytokine production and
activation (Okada \& Suzuki, 2017; Tang, Kang, Coyne, Zeh \& Lotze,
2012). TLR4 activation by DAMPs such as OxyHb metabolites and
fibrinogen, which are produced during aneurysm rupture, has been linked
to the pro-inflammatory state that follows SAH (Khey, Huard \& Mahmoud,
2020). TLR4 or its related pathways were inhibited with a variety of
medicines in experimental SAH, which reduced vasospasm, provided
neuroprotection, and offered anti-inflammatory effects (Chang, Wu \&
Kwan, 2014; Liu, Yang, Pan, Liu \& Ma, 2016). Fluoxetine was discovered
to reduce neuroinflammation and improve neurological function in SAH
rats. TLR4/MyD88/NF-\selectlanguage{greek}κ\selectlanguage{english}B signaling pathway is one of the probable pathways
involved (Liu et al., 2018). TLR4-deficient mice had reduced infarct
volumes and improved neurological and behavioral outcomes, according to
a research (Caso, Pradillo, Hurtado, Lorenzo, Moro \& Lizasoain, 2007).
TLR4 knockout mice had lower levels of mediators linked to brain injury,
including stroke-induced IRF-1, iNOS, and cyclooxygenase 2. In the
brains of TLR4-deficient rats, IFN- and the lipid peroxidation marker
malondialdehyde were found to be lower. After an artificial stroke, the
researchers found that in TLR4-deficient rats, the matrix
metalloproteinase 9 expression which helps to cause brain injury was
attenuated (Caso, Pradillo, Hurtado, Lorenzo, Moro \& Lizasoain, 2007).
TLR4 signaling appears to control the severity of ischemia-induced
neuronal damage, suggesting that TLR4 could be a target for SAH
prevention and treatment (Caso, Pradillo, Hurtado, Lorenzo, Moro \&
Lizasoain, 2007). TREM-1 was found to be dynamically raised in the brain
after eSAH, especially in microglia and vascular endothelial cells,
implying that it may improve EBI through interacting with the TLR4
pathway (Sun et al., 2021).

\textbf{Figure1}

\textbf{MAPK Pathway}

MAPKs are a type of threonine and serine protein kinase that has many
functions in cell biology. MAPK pathways are initiated when TLR, TNF,
and IL receptors, as well as receptor tyrosine kinases, are activated
(RTK). The three major MAPK families in humans are extracellular
signal-regulated kinase 1 and 2 (ERK1/2), p38 MAPK, and C-Jun N-terminal
kinase (JNK) (Khey, Huard \& Mahmoud, 2020). The majority of prior
investigations used MAPK inhibitors or inhibitors of their upstream
signaling molecules and demonstrated that MAPK inhibition prevented
vasospasm (Suzuki, Hasegawa, Kanamaru \& Zhang, 2011) conducted an
experiment and concluded that.~ (Maddahi, Povlsen \& Edvinsson, 2012)
found that IL-1, IL-6, MMP-9, and pERK1/2 protein expression levels in
cerebral arteries increased with time, with an early peak at roughly 6 h
and a late peak at 48 to 72 h post-SAH. The elevated expression of TNF
in cerebral arteries began at 24 hours and continued until 96 hours. In
addition, the animals developed sensorimotor and spontaneous behavioral
abnormalities as a result of SAH. They went on to say that SAH causes
early activation of the MEK-ERK1/2 pathway in cerebral artery walls,
which is linked to proinflammatory cytokines and MMP-9 upregulation.
U0126 (selective inhibitor) suppressed the MEK-ERK1/2(mitogen-activated
protein kinase kinase-extracellular signal-regulated kinases 1/2)
pathway 6 hours after SAH, reducing the activation of cytokines and
MMP-9 in cerebral arteries and improving neurological outcome. In canine
and rabbit models, blocking the p38 MAPK pathway was found to be
efficient in lowering inflammatory cytokine production, including IL-1,
IL-1, IL-8, and TNF-\selectlanguage{greek}α. \selectlanguage{english}In addition, as compared to the control group,
the scientists saw a decrease in vasospasm (Pan et al., 2013; Sasaki et
al., 2004). By activating p38MAPK/MMP-9 and degrading ZO-1, TREM-1 may
play a crucial role in the development of EBI following SAH. According
to the authors, TREM-1 inhibition alleviated the severity of SAH-induced
EBI, establishing a novel method for EBI treatment (Sun, Duan, Jing,
Wang, Hou \& Zhang, 2019).

\selectlanguage{greek}\textbf{NF-κB}\selectlanguage{english}

When cells are exposed to damaging stimuli, the protein NF-\selectlanguage{greek}κ\selectlanguage{english}B is
immediately activated and has been linked to a wide range of
inflammatory illnesses. Inflammation and innate immunity are both
affected by this protein complex, which controls DNA transcription. The
NF-\selectlanguage{greek}κ\selectlanguage{english}B pathway is activated by TLRs, TNF receptors, and IL receptors
recognizing different PAMPS and DAMPS (Okada \& Suzuki, 2017). Because
it regulates the development of a vasoconstrictor, NF-\selectlanguage{greek}κ\selectlanguage{english}B signaling and
its downstream cytokine products are crucial to the pathophysiology of
SAH. Using various drugs to inhibit NF-\selectlanguage{greek}κ\selectlanguage{english}B activity, several authors have
observed improved neurological scores, decreased neuronal death, reduced
BBB permeability, and lower inflammatory cytokines following SAH.
(Chang, Wu, Lin, Hwang \& Kwan, 2012; Liu, Yang, Pan, Liu \& Ma, 2016;
Zhang et al., 2015) , Future research on NF-\selectlanguage{greek}κ\selectlanguage{english}B is promising, and the
usefulness of employing this molecule as a therapeutic target in the
treatment of SAH in humans needs to be determined. In the study by Liu
et al. (Liu et al., 2016) Matrine was found to reduce EBI in rats
following subarachnoid hemorrhage by inhibiting NF-\selectlanguage{greek}κ\selectlanguage{english}B via PI3K/Akt and
inducing HO-1 via Keap1/Nrf2.

\textbf{Table 1}

\textbf{Eicosanoid Reactions and NLRP3 Inflammasome:}

\textbf{Eicosanoids}

Eicosanoids are bioactive signaling lipids generated from arachidonic
acid and related polyunsaturated fatty acids (PUFAs) that govern a wide
range of homeostatic and inflammatory processes associated with a
variety of illnesses (Dennis \& Norris, 2015). One of the most
well-known routes involved in inflammation is the eicosanoid pathway.
Inflammatory processes are the body's physiological response to numerous
stressors such as trauma, infections, or immunological reactions. These
processes are distinguished by the activation of cellular and humoral
mediator systems, as well as the production of a wide range of
inflammatory mediators such as interleukin-1 (IL-1) and tumor necrosis
factor-alpha (TNF-\selectlanguage{greek}α\selectlanguage{english}). Increased amounts of these mediators can cause
changes in microvascular tone and permeability, as well as activation of
eicosanoid production pathways (Homaidan, Chakroun, Haidar \& El-Sabban,
2002). The availability of free AA is critical for eicosanoid
production. When tissues are exposed to physiological or pathological
stimuli such as growth factors, hormones, or cytokines, AA is generated
from membrane phospholipids by the action of phospholipase A2 (PLA2)
enzymes and can then be converted into different eicosanoids. The three
principal enzymes capable of metabolizing AA are P-450 epoxygenase,
cyclooxygenases (COXs), and lipoxygenases (LOXs) (Harizi, Corcuff \&
Gualde, 2008). Following PLA2 cleavage, the freed AA is processed by
three different mechanisms: cyclooxygenase (COX), lipoxygenase (LOX),
and the P450 family (CYP). The COX system produces prostaglandins (PG)
and thromboxanes (TX), while the LOX system produces leukotrienes (LT),
hydroxyeicosatetraenoic acids (HETE), and lipoxins (LX). Finally, the
CYP pathway produces epoxyeicosatrienoic acids (EET) and
heterecosatrienoic acids (HETE). Although free arachidonic acid is
required for the majority of eicosanoid metabolism, it is typically kept
in esterified form. Phospholipase A2 (PLA2) enzymes are essential for
boosting free arachidonic acid levels for metabolism and eicosanoid
production under normal physiological settings, but especially after
inflammatory cell activation. PLA2 isoforms comprise various cystosolic,
calcium dependent, and secretory isoforms, in addition to phospholipases
A1, B, C, and D. Phospholipase activity can be influenced by calcium,
phosphorylation, and agonists that bind to G-protein coupled receptors.
These enzymes are generally involved in the physiological remodeling of
cellular membranes, with free fatty acids being extracted via
phospholipase activity and subsequently recycled with another free fatty
acid. Nonetheless, decreases in the cell's ability to sustain normal
metabolic function, as well as the resulting drop in ATP levels, might
result in the failure to recycle membrane phospholipids. Modification of
membrane phospholipids is likely to affect a variety of cellular
processes, including the capacity to accumulate excitotoxic amino acids.
It was discovered in this study that selective phospholipase inhibitors
limit the release of free fatty acids from in vivo rat brain. Following
this inhibition, the severity of cortical damage after focal ischemia,
forebrain ischemia, and cerebral trauma is reduced. Infarct volumes were
similarly shown to be smaller in mice with PLA2 deletion (Phillis \&
O'Regan, 2003). Further research is needed to completely understand the
role of Eicosanoids in events following SAH.

\textbf{The NLRP3 inflammasome}

The NLRP3 inflammasome is involved in caspase-1 activation and the
release of proinflammatory cytokines IL-1\selectlanguage{greek}β/\selectlanguage{english}IL-18 in response to
infection and cellular damage (Kelley, Jeltema, Duan \& He, 2019). In
response to an attack, pattern-recognition receptors (PRRs) activate the
innate immune system, which is the body's initial line of defense. Even
though NLRP3 inflammasome activation is still poorly understood, there
are several factors at play, including pathogen-associated molecular
patterns (PAMPs), damage-associated molecular patterns (DAMPs), and a
second signal that stimulates the assembly of NLRP3, ASC, and
pro-caspase-1 into the NLRP3 inflammasome complex via multiple
ROS-producing pathways (Abais, Xia, Zhang, Boini \& Li, 2015). When
these patterns are activated, it sets off a cascade of events that
clears the infection and repairs any harm it has caused. Inflammasome
activation results in the release of cytokines such as IL-1\selectlanguage{greek}β \selectlanguage{english}and IL-18,
as well as the generation of pyroptosis, an inflammatory form of cell
death (Kelley, Jeltema, Duan \& He, 2019; Sharma \& Kanneganti, 2016).
Studies have shown that pathogen-derived ligands include nucleic acids,
microbial wall components, and toxitoxins activate NLRP3. NLRP3 has also
been shown to be activated by environmental crystalline contaminants
such silica, asbestos, and alum (Man \& Kanneganti, 2015). When SAH
boosted TREM-1 expression, NLRP3 inflammasome components (NLRP3, ASC),
cleaved caspase-1, mature IL-1\selectlanguage{greek}β, \selectlanguage{english}and mature IL-18 were all elevated into
their active forms as well (Xu et al., 2021). Multiple studies have
shown that SAH activates the NLRP3 inflammasome, which has been shown to
be inhibited in those who have had the condition, For example, in both
the early and delayed phases after SAH. (Dodd, Noda, Martinez, Hosaka \&
Hoh, 2021)~found NLRP3 mediated neuroinflammation to be associated with
cerebrovascular impairment. EBI and DCI therapies could benefit from the
use of MCC950 and other NLRP3 inhibitors. (Xu et al., 2019b) found that
following SAH, the levels of APJ and AMPK rose. Despite the fact that
endogenous APJ and AMPK were increased, this was not enough to reduce
NLRP3 inflammasome activity or inflammatory cytokines in the body, as
previously described. Exogenous apelin-13 increased AMPK levels, which
prevented the NLRP3 inflammasome from activating and decreased Bip,
cleaved caspase-1,~IL-1\selectlanguage{greek}β, \selectlanguage{english}TNF-\selectlanguage{greek}α, \selectlanguage{english}MPO, and ROS levels while
simultaneously boosting AMPK levels. To make matters worse, the AMPK
inhibitor upregulated the production of NLRP3, cleaved caspase-1,~IL-1\selectlanguage{greek}β,
\selectlanguage{english}TNF-\selectlanguage{greek}α, \selectlanguage{english}MPO, and ROS in addition to negating the good effects of
anti-inflammatory and anti-oxidative stress, which made conditions to
further worsen. Microglial modulation has been linked to favorable
effects on the cerebrovascular system in studies by (Dodd, Noda,
Martinez, Hosaka \& Hoh, 2021), however these studies have not
demonstrated that NLRP3 suppression alleviates cerebrovascular
dysfunction through this mechanism. NLRP3-mediated neuroinflammation is
frequently attributed to microglia as the primary cause (Luo, Reis \&
Chen, 2019).

\textbf{Keap1-Nrf2-ARE}

One of the most essential defense systems against oxidative and/or
electrophilic stressors is the Keap1--Nrf2--ARE Kelch-like
ECH-Associating protein 1 nuclearfactor erythroid 2 related factor
2-antioxidant response element, which is linked to inflammatory
disorders. In response to ROS exposure, it activates a cytoprotective
mechanism. The Nrf2-ARE transcriptional pathway regulates genes that
encode proteins involved in the detoxification and elimination of
reactive oxygen species (ROS) and electrophiles (Nguyen, Nioi \&
Pickett, 2009). The Keap1--Nrf2--ARE pathway is important for cell
protection against oxidative and electrophilic stress. The ability of
Nrf2--ARE activators to boost a battery of critical cell-protective
genes involved in reducing oxidative damage and inflammation may be
exploited in the development of antioxidant, anti-inflammatory, and
anticancer medicines (Lu, Ji, Jiang \& You, 2016). The study of (Shang
et al., 2013) achieved two goals. It first identified the timing of
Keap1 inhibition and Nrf2 activation in rats during the early stages of
ICH. Nrf2 is an important endogenous regulator of cellular oxidative
stress resistance. Intravenous treatment of a Nrf2 activator (BARD)
significantly raised Nrf2 and HO-1 expression earlier, thereby
protecting neurons from IRI. Taken together, their findings revealed
that Nrf2 activators may be neuroprotective in patients with IRI (Takagi
et al., 2014). In the (Zhao et al., 2007) study, activation of Nrf2 by
SF was related with enhanced expression of many antioxidative enzymes
known to play essential roles in oxidative stress defense, including
catalase, SOD, NAD(P)H dehydrogenase, quinone-1, and glutathione
S-transferase. Nrf2 deficiency contributes to ROS-induced DNA damage and
death largely in neurons in the early stages of ICH, according to (Wang
et al., 2007) Activating Nrf2 prevents leukocytes from entering the
injury site and preventing excessive free radical damage to the brain
tissue. Despite the fact that more research with selective Nrf2 inducers
and inhibitors is needed, the data suggest that Nrf2 could be a
therapeutic target for the treatment of ICH. (Zhang et al., 2019) found
that MitoQ promotes mitophagy and reduces mitochondrial oxidative
stress-related neuronal apoptosis in EBI after SAH via the
Keap1/Nrf2/PHB2 pathway, which is linked to improved short- and
long-term neurological impairment. MitoQ could thus be used as an
antioxidant therapy for EBI as well as a treatment for delayed
neurological impairments following SAH. SalA (10 and 50 mg/kg/day)
administered intraperitoneally was shown to protect EBI following SAH,
at least in part due to its antioxidative, anti-inflammatory, and
antiapoptotic properties. The following is the evidence that led to this
conclusion: At 48 hours following a SAH in a rat model, SalA
dramatically alleviated neurological impairments, reduced brain edema
and BBB permeability, decreased inflammation factors, and repressed
oxidative stress and cortical neuron death. Furthermore, SalA reduced
MDA and ROS production produced by SAH while increasing GSH
concentration and GSH-Px activity. These findings suggested that
treating rats with SalA would be an effective way to protect their
brains from EBI after SAH (Gu et al., 2017). SAH treatment may one day
be based on this promising new discovery, but further studies are needed
to confirm it.

\textbf{High mobility group box~1 (HMGB1)}

The HMGB1 protein is a pro-inflammatory cytokine with pro-inflammatory
properties that acts as an initiator of neuroinflammation. It has been
associated with traumatic brain injury (TBI) and acute brain injury
(EBI) in the aftermath of a subarachnoid hemorrhage (SAH) (Paudel,
Angelopoulou, Piperi, Othman \& Shaikh, 2020). After SAH, HMGB1
expression rises, and it plays a role in the disease's development
(Murakami, Koide, Dumont, Russell, Tranmer \& Wellman, 2011). The
activation of Janus kinases 2 (JAK2)/Signal transducer and activator of
transcription by HMGB1 causes SAH-induced EBI (STAT3). In nuclei, HMGB1
is involved in chromatin structure preservation, transcription activity
modulation, and DNA repair. HMGB1, on the other hand, is considered a
typical damage-associated molecular pattern (DAMP) since it is
translocated and released extracellularly from a range of brain cells,
including neurons and microglia, and hence contributes to the
pathophysiology of many CNS diseases (Nishibori, Wang, Ousaka \& Wake,
2020). HMGB1 has been demonstrated to promote inflammatory cascades by
binding to TLR4/TLR2 and RAGE, leading in activation of NF-\selectlanguage{greek}κ\selectlanguage{english}B, IL-6,
IL-8, TNF-, MyD88, iNOS, ERK1 and ERK2 (Park et al., 2003).
Extracellular HMGB1 release could play a key role in activating the
early inflammatory responses by stimulating numerous receptors,
resulting in BBB breakdown (Nishibori, Wang, Ousaka \& Wake, 2020).
HMGB1 induced vascular smooth muscle cells (VSMCs) and regulated VSMC
phenotypic transition during SAH via interacting with IFN-\selectlanguage{greek}γ \selectlanguage{english}(Wang,
Zhang, Liang, Wu, Zhong \& Sun, 2019). After treatment with anti-HMGB1
mAb, the vascular remodeling and VSMC phenotypic shift found in SAH were
reported to be reduced, principally by reversing SAH-induced
up-regulation of HMGB1, microglial activation, and brain edema. HMGB1
was once assumed to be a negative cytokine, but it has now been revealed
to enhance the inflammatory response in acute stroke patients. On day 14
following SAH, however, (Tian et al., 2017) found that HMGB1 expression
was considerably higher than in the sham group. This finding suggested
that HMGB1 may play a role in the healing of brain injury following SAH.
The pro- and anti-inflammatory effects of HMGB1 demonstrate the
protein's complexity and role in circumstances following SAH, implying
that more research is needed to validate its involvement in occurrences
like EBI.

\textbf{JAK/STAT (Janus-kinase/signal activator and transducer of
transcription pathways)}

These are a collection of intracellular processes that regulate gene
expression. It's one of the most essential signaling channels for
transmitting cytokine-induced signals from the cell surface.
Inflammation of the central nervous system is also influenced by this
route. STAT is phosphorylated by JAK when it is activated, and then it
translocates into the nuclease to modify the expression of a specific
gene. Depending on the STAT isoform, various anti-inflammatory,
pro-inflammatory, proliferative, or apoptotic proteins can be expressed.
The JAK-STAT pathway's dysregulation in inflammation and
neurodegenerative illnesses makes it a key player in the majority of
brain diseases. STAT1 activity has been linked to a decrease in cell
viability in the brain, whereas STAT3 is thought to be a pro-survival
factor (Planas, Gorina \& Chamorro, 2006). Many investigations have
shown that after SAH, STAT1 and STAT2, as well as their activators JAK1
and JAK2, are active (Osuka et al., 2006; Samraj, M\selectlanguage{ngerman}üller, Grell \&
Edvinsson, 2014). (Gorina, Petegnief, Chamorro \& Planas, 2005)
discovered that anti-inflammatory cytokines such as IL-10 activated
STAT3 but not STAT1, whereas pro-inflammatory signals such as IFN-\selectlanguage{greek}γ
\selectlanguage{english}(interferon) activated both STAT1 and not STAT3, and IL-6 activated both
STAT1 and STAT3. Tyrphostin, a JAK2 inhibitor, was discovered to be
involved in the reported activation of STATs following IL-6 and IFN-\selectlanguage{greek}γ,
\selectlanguage{english}but not following IL-10 (AG490). Oxidative stress, which is produced in
the ischemic brain and contributes to ischemic brain damage, can also
activate STATs. The Gorina, Petegnief, Chamorro, and Planas
investigation went on to show that JAK2/STAT1 activation causes cell
death, which is consistent with the notion that STAT1 is activated in
neurons after ischemia and plays a role in ischemic brain injury
(Takagi, Harada, Chiarugi \& Moskowitz, 2002). According to Osuka et
al., after SAH, IL-6 expression causes JAK1-STAT3 phosphorylation, which
leads to the overexpression of COX-2, which is responsible for the
synthesis of PGI, an enzyme recognized for reducing vasospasm by
promoting vasodilation and inhibiting platelet aggregation. STAT1 and
STAT3 are activated by oxidative stress and certain cytokines through a
JAK2-dependent pathway (Planas, Gorina \& Chamorro, 2006). A number of
pro-inflammatory cytokines, including IL-10, activate STAT3, although
others, such as interferon, induce STAT1 phosphorylation through the
JAK2 pathway (Regis, Pensa, Boselli, Novelli \& Poli, 2008). Melatonin
therapy activates JAK1 and enhances the phosphorylation of STAT3,
according to(Li, Yang, Sun \& Hang, 2019). This effect is abolished by a
JAK1 antagonist, demonstrating that JAK activation is implicated in
Melatonin's protective benefits against EBI after SAH. Nonetheless, when
discussing events following SAH, the role of the JAK/STAT system remains
a subject of many unknowns, necessitating more research in this field.

\textbf{NITRIC OXIDE PATHWAY}

The enzyme nitric oxide synthase (NOS) catalyzes the interaction of
L-arginine with molecular oxygen to make L-citrulline and NO. There are
three forms of NOS that have been found so far: they constitutively
expressed, Neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible
NOS (iNOS) (Kleinert, Schwarz \& F\selectlanguage{ngerman}örstermann, 2003). NO, which is mostly
produced by iNOS, can be detrimental and pro-inflammatory in high doses.
However, the activities of nitric oxide are mostly influenced by the
cellular context, NO concentration (depending on distance from the NO
source), and the initial priming of immune cells, rather than the
enzymatic source (Guzik, Korbut \& Adamek-Guzik, 2003). The brain's NO
levels rise dramatically as a result of vertebral ischemia. This is
attributed to increased iNOS expression in reactive astrocytes and
neutrophils invading the ischemic brain 6--12 hours after the injury, as
well as increased eNOS and nNOS expression in the arteries and
parenchyma within an hour of the lesion (Iadecola, 1997; Kader,
Frazzini, Solomon \& Trifiletti, 1993; Zhang et al., 1994). NO has
pro-inflammatory and cytotoxic effects at high doses, but it is known to
have anti-inflammatory and vasodilator characteristics under certain
situations (Coleman, 2001; Sharma, Al-Omran \& Parvathy, 2007).
L-arginine treatment during the acute period improved symptoms in people
with mitochondrial myopathy, encephalopathy, and stroke-like episodes
(Koga et al., 2018). During an inhaled NO experiment, peripheral
vascular resistance was lowered in a child with traumatic brain injury,
despite no changes in middle cerebral artery blood flow, jugular bulb
oxygen saturations, or intracranial pressure (Vavilala, Roberts, Moore,
Newell \& Lam, 2001). According to the researchers, the NO donor had no
effect on cerebral blood flow, cerebral perfusion pressure, or cerebral
steal in these people (Willmot, Ghadami, Whysall, Clarke, Wardlaw \&
Bath, 2006). These disparities in results could explain NO toxicity or
insufficient NO exposure, which could be explained by differences in NO
concentration. More research is needed to determine the role of NO in
SAH, which is currently up for contention.

\textbf{Limitations}

After describing the aforementioned inflammatory pathways in response to
SAH and their impact on EBI, it's crucial to point out the review's
shortcomings. The majority of the evidence included in this study
regarding the inflammatory pathways following SAH was based only on in
vitro and animal research. When it comes to experimental SAH, several
methods have been used to simulate SAH for research aims. Two of the
most commonly used models are blood injection and endovascular
perforation. The blood injection model is less accurate than the
endovascular perforation model in simulating SAH because it does not
involve perforation of the cerebral artery. As a result, there may be
discrepancies in experimental outcomes due to the different models,
which we failed to account for in this review. When establishing the
pathways, there was no distinction made between the molecular expression
components of the pathways and the neurologic effects. Secondary brain
injury may emerge from the activation of several different inflammatory
pathways following SAH, although the severity of each pathway's ability
to control inflammation has not been studied in detail in this review.
After SAH, there was no distinction made in the inflammatory response
time since it may be critical in the development of SAH problems in
individuals who survive the first bleed. We highlight the majority of
inflammatory pathways, however we understand that there may be more
inflammatory pathways after SAH. The majority of the pathways included
in the research did not take into account the different grades of SAH
severity.

\textbf{Conclusion}

Multiple modes of action are implicated in the etiology of SAH, making
it a difficult disease to understand. SAH-induced inflammation appears
to be a complicated process. There have been numerous inflammatory
pathways explored in SAH, with varying degrees of evidence to support
each one. SAH-induced inflammation is mostly controlled by TLR, as
described in the above processes and pathways. Antioxidants and TLR
inhibitors that target these mediators may not only prevent the
activation of downstream inflammatory pathways, but may also improve the
prognosis for SAH patients. However, because to the intricacy of SAH,
inflammation may not be the only aspect to consider; other events may
either enhance or aggravate the symptoms after SAH. There have been
several recent studies suggesting that inflammation is the most
essential factor to consider in the prevention and treatment of issues
that may arise after SAH, such as EBI. Recently, new studies have
revealed how TREM-1 inhibition could improve the prognosis of EBI as a
secondary brain injury after SAH. Thus more investigations should be
carried in the mechanism of TREM-1. Despite the fact that inflammatory
pathways offer a wide range of potential targets, further study is
needed to determine the importance of these pathways in SAH. To assess
the clinical relevance of this discovery, additional clinical trials
will be required in the near future.

Acknowledgement: This study was funded by Shanxi Province's Great
Research Project (201903D321044) and Shanxi Health Committee's Project
(2019045).

Conflict of interest: The authors declare that they have no conflict of
interest.

Authors' contributions: All authors were involved in writing the review.

Abais JM, Xia M, Zhang Y, Boini KM, \& Li PL (2015). Redox regulation of
NLRP3 inflammasomes: ROS as trigger or effector? Antioxid Redox Signal
22\textbf{:} 1111-1129.

Acosta C, \& Davies A (2008). Bacterial lipopolysaccharide regulates
nociceptin expression in sensory neurons. J Neurosci Res
86\textbf{:}1077-1086.

Ansar S, \& Edvinsson L (2008). Subtype activation and interaction of
protein kinase C and mitogen-activated protein kinase controlling
receptor expression in cerebral arteries and microvessels after
subarachnoid hemorrhage. Stroke 39\textbf{:} 185-190.

Ansar S, \& Edvinsson L (2009). Equal contribution of increased
intracranial pressure and subarachnoid blood to cerebral blood flow
reduction and receptor upregulation after subarachnoid hemorrhage.
Laboratory investigation. J Neurosurg 111\textbf{:} 978-987.

Ansar S, Svendgaard NA, \& Edvinsson L (2007). Neurokinin-1 receptor
antagonism in a rat model of subarachnoid hemorrhage: prevention of
upregulation of contractile ETB and 5-HT1B receptors and cerebral blood
flow reduction. J Neurosurg 106\textbf{:} 881-886.

Ansar S, Vikman P, Nielsen M, \& Edvinsson L (2007). Cerebrovascular
ETB, 5-HT1B, and AT1 receptor upregulation correlates with reduction in
regional CBF after subarachnoid hemorrhage. Am J Physiol Heart Circ
Physiol 293\textbf{:} H3750-3758.

Armstead WM, \& Kreipke CW (2011). Endothelin-1 is upregulated after
traumatic brain injury: a cross-species, cross-model analysis. Neurol
Res 33\textbf{:} 133-136.

Beuth W, Kasprzak H, Kotschy M, Wo\selectlanguage{polish}ź\selectlanguage{english}niak B, Kulwas A, \& Sniegocki M
(2001). {[}Endothelin in the plasma and cerebrospinal fluid of patients
after head injury{]}. Neurol Neurochir Pol 35 Suppl 5\textbf{:} 125-129.

Bladowski M, Gawrys J, Gajecki D, Szahidewicz-Krupska E,
Sawicz-Bladowska A, \& Doroszko A (2020). Role of the Platelets and
Nitric Oxide Biotransformation in Ischemic Stroke: A Translative Review
from Bench to Bedside. Oxid Med Cell Longev 2020\textbf{:} 2979260.

Boufenzer A, Lemari\selectlanguage{ngerman}é J, Simon T, Derive M, Bouazza Y, Tran N\emph{, et
al.} (2015). TREM-1 Mediates Inflammatory Injury and Cardiac Remodeling
Following Myocardial Infarction. Circ Res 116\textbf{:} 1772-1782.

Bsibsi M, Ravid R, Gveric D, \& van Noort JM (2002). Broad expression of
Toll-like receptors in the human central nervous system. J Neuropathol
Exp Neurol 61\textbf{:} 1013-1021.

Buisson A, Nicole O, Docagne F, Sartelet H, Mackenzie ET, \& Vivien D
(1998). Up-regulation of a serine protease inhibitor in astrocytes
mediates the neuroprotective activity of transforming growth factor
beta1. Faseb j 12\textbf{:} 1683-1691.

Cambj-Sapunar L, Yu M, Harder DR, \& Roman RJ (2003). Contribution of
5-hydroxytryptamine1B receptors and 20-hydroxyeiscosatetraenoic acid to
fall in cerebral blood flow after subarachnoid hemorrhage. Stroke
34\textbf{:} 1269-1275.

Cameron JS, Alexopoulou L, Sloane JA, DiBernardo AB, Ma Y, Kosaras
B\emph{, et al.} (2007). Toll-like receptor 3 is a potent negative
regulator of axonal growth in mammals. J Neurosci
27\textbf{:}13033-13041.

Cardentey-Pereda AL, \& Pérez-Falero RA (2002). {[}Subarachnoid
hemorrhage{]}. Rev Neurol 34\textbf{:} 954-966.

Caso JR, Pradillo JM, Hurtado O, Leza JC, Moro MA, \& Lizasoain I
(2008). Toll-like receptor 4 is involved in subacute stress-induced
neuroinflammation and in the worsening of experimental stroke. Stroke
39\textbf{:} 1314-1320.

Caso JR, Pradillo JM, Hurtado O, Lorenzo P, Moro MA, \& Lizasoain I
(2007). Toll-like receptor 4 is involved in brain damage and
inflammation after experimental stroke. Circulation
115\textbf{:}1599-1608.

Chang CZ, Wu SC, \& Kwan AL (2014). Glycyrrhizin attenuates Toll like
receptor-2, -4 and experimental vasospasm in a rat model. J Immunol Res
2014\textbf{:} 740549.

Chang CZ, Wu SC, Lin CL, Hwang SL, \& Kwan AL (2012). Purine
anti-metabolite attenuates nuclear factor \selectlanguage{greek}κ\selectlanguage{english}B and related
pro-inflammatory cytokines in experimental vasospasm. Acta Neurochir
(Wien) 154\textbf{:} 1877-1885.

Coleman JW (2001). Nitric oxide in immunity and inflammation. Int
Immunopharmacol 1\textbf{:} 1397-1406.

Dennis EA, \& Norris PC (2015). Eicosanoid storm in infection and
inflammation. Nat Rev Immunol 15\textbf{:} 511-523.

Dodd WS, Noda I, Martinez M, Hosaka K, \& Hoh BL (2021). NLRP3
inhibition attenuates early brain injury and delayed cerebral vasospasm
after subarachnoid hemorrhage. J Neuroinflammation 18\textbf{:} 163.

Farina C, Krumbholz M, Giese T, Hartmann G, Aloisi F, \& Meinl E (2005).
Preferential expression and function of Toll-like receptor 3 in human
astrocytes. J Neuroimmunol 159\textbf{:} 12-19.

Fassbender K, Hodapp B, Rossol S, Bertsch T, Schmeck J, Sch\selectlanguage{ngerman}ütt S\emph{,
et al.} (2000). Endothelin-1 in subarachnoid hemorrhage: An acute-phase
reactant produced by cerebrospinal fluid leukocytes. Stroke
31\textbf{:}2971-2975.

Gao YY, Tao T, Wu D, Zhuang Z, Lu Y, Wu LY\emph{, et al.} (2021). MFG-E8
attenuates inflammation in subarachnoid hemorrhage by driving microglial
M2 polarization. Exp Neurol 336\textbf{:} 113532.

Gorina R, Petegnief V, Chamorro A, \& Planas AM (2005). AG490 prevents
cell death after exposure of rat astrocytes to hydrogen peroxide or
proinflammatory cytokines: involvement of the Jak2/STAT pathway. J
Neurochem 92\textbf{:} 505-518.

Graves JC, \& Kreipke CW (2015). Frontiers in Neuroengineering

Endothelin, Cerebral Blood Flow, and Traumatic Brain Injury:
Implications for a Future Therapeutic Target. In Brain Neurotrauma:
Molecular, Neuropsychological, and Rehabilitation Aspects. ed Kobeissy
F.H. CRC Press/Taylor \& Francis

© 2015 by Taylor \& Francis Group, LLC.: Boca Raton (FL).

Gu X, Zheng C, Zheng Q, Chen S, Li W, Shang Z\emph{, et al.} (2017).
Salvianolic acid A attenuates early brain injury after subarachnoid
hemorrhage in rats by regulating ERK/P38/Nrf2 signaling. Am J Transl Res
9\textbf{:} 5643-5652.

Guzik TJ, Korbut R, \& Adamek-Guzik T (2003). Nitric oxide and
superoxide in inflammation and immune regulation. J Physiol Pharmacol
54\textbf{:} 469-487.

Hansen-Schwartz J (2004). Receptor changes in cerebral arteries after
subarachnoid haemorrhage. Acta Neurol Scand 109\textbf{:} 33-44.

Hansen-Schwartz J, Hoel NL, Xu CB, Svendgaard NA, \& Edvinsson L (2003).
Subarachnoid hemorrhage-induced upregulation of the 5-HT1B receptor in
cerebral arteries in rats. J Neurosurg 99\textbf{:} 115-120.

Harizi H, Corcuff JB, \& Gualde N (2008). Arachidonic-acid-derived
eicosanoids: roles in biology and immunopathology. Trends Mol Med
14\textbf{:} 461-469.

He Y, Yang Q, Wang X, Jia A, Xie W, \& Zhou J (2019). Inhibition of
Triggering Receptor Expressed on Myeloid Cell-1 Alleviates Acute Gouty
Inflammation. Mediators Inflamm 2019\textbf{:} 5647074.

Heros RC, \& Zervas NT (1983). Subarachnoid hemorrhage. Annu Rev Med
34\textbf{:} 367-375.

Homaidan FR, Chakroun I, Haidar HA, \& El-Sabban ME (2002). Protein
regulators of eicosanoid synthesis: role in inflammation. Curr Protein
Pept Sci 3\textbf{:} 467-484.

Hong CM, Tosun C, Kurland DB, Gerzanich V, Schreibman D, \& Simard JM
(2014). Biomarkers as outcome predictors in subarachnoid hemorrhage--a
systematic review. Biomarkers 19\textbf{:} 95-108.

Hua F, Ma J, Ha T, Kelley J, Williams DL, Kao RL\emph{, et al.} (2008).
Preconditioning with a TLR2 specific ligand increases resistance to
cerebral ischemia/reperfusion injury. J Neuroimmunol 199\textbf{:}75-82.

Iadecola C (1997). Bright and dark sides of nitric oxide in ischemic
brain injury. Trends Neurosci 20\textbf{:} 132-139.

Jack CS, Arbour N, Manusow J, Montgrain V, Blain M, McCrea E\emph{, et
al.} (2005). TLR signaling tailors innate immune responses in human
microglia and astrocytes. J Immunol 175\textbf{:} 4320-4330.

Jackson AC, Rossiter JP, \& Lafon M (2006). Expression of Toll-like
receptor 3 in the human cerebellar cortex in rabies, herpes simplex
encephalitis, and other neurological diseases. J Neurovirol
12\textbf{:}229-234.

Jiang Y, Wu J, Keep RF, Hua Y, Hoff JT, \& Xi G (2002).
Hypoxia-inducible factor-1alpha accumulation in the brain after
experimental intracerebral hemorrhage. J Cereb Blood Flow Metab
22\textbf{:} 689-696.

Kader A, Frazzini VI, Solomon RA, \& Trifiletti RR (1993). Nitric oxide
production during focal cerebral ischemia in rats. Stroke
24\textbf{:}1709-1716.

Kelley N, Jeltema D, Duan Y, \& He Y (2019). The NLRP3 Inflammasome: An
Overview of Mechanisms of Activation and Regulation. Int J Mol Sci 20.

Khey KMW, Huard A, \& Mahmoud SH (2020). Inflammatory Pathways Following
Subarachnoid Hemorrhage. Cell Mol Neurobiol 40\textbf{:} 675-693.

Kilic U, Kilic E, Matter CM, Bassetti CL, \& Hermann DM (2008). TLR-4
deficiency protects against focal cerebral ischemia and axotomy-induced
neurodegeneration. Neurobiol Dis 31\textbf{:} 33-40.

Kim D, Kim MA, Cho IH, Kim MS, Lee S, Jo EK\emph{, et al.} (2007a). A
critical role of toll-like receptor 2 in nerve injury-induced spinal
cord glial cell activation and pain hypersensitivity. J Biol Chem
282\textbf{:} 14975-14983.

Kim Y, Zhou P, Qian L, Chuang JZ, Lee J, Li C\emph{, et al.} (2007b).
MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and
regulates neuronal survival. J Exp Med 204\textbf{:} 2063-2074.

Kleinert H, Schwarz P, \& Förstermann U (2003). Regulation of the
expression of inducible nitric oxide synthase. Biological chemistry
384\textbf{:} 1343-1364.

Koga Y, Povalko N, Inoue E, Nakamura H, Ishii A, Suzuki Y\emph{, et
al.}(2018). Therapeutic regimen of L-arginine for MELAS: 9-year,
prospective, multicenter, clinical research. J Neurol
265\textbf{:}2861-2874.

Kreipke CW, Morgan R, Roberts G, Bagchi M, \& Rafols JA (2007). Calponin
phosphorylation in cerebral cortex microvessels mediates sustained
vasoconstriction after brain trauma. Neurol Res 29\textbf{:} 369-374.

Krenzlin H, Lorenz V, Danckwardt S, Kempski O, \& Alessandri B (2016).
The Importance of Thrombin in Cerebral Injury and Disease. Int J Mol Sci
17.

Lafon M, Megret F, Lafage M, \& Prehaud C (2006). The innate immune
facet of brain: human neurons express TLR-3 and sense viral dsRNA. J Mol
Neurosci 29\textbf{:} 185-194.

Lampl Y, Fleminger G, Gilad R, Galron R, Sarova-Pinhas I, \& Sokolovsky
M (1997). Endothelin in cerebrospinal fluid and plasma of patients in
the early stage of ischemic stroke. Stroke 28\textbf{:} 1951-1955.

Lee KR, Drury I, Vitarbo E, \& Hoff JT (1997). Seizures induced by
intracerebral injection of thrombin: a model of intracerebral
hemorrhage. J Neurosurg 87\textbf{:} 73-78.

Lehnardt S, Lehmann S, Kaul D, Tschimmel K, Hoffmann O, Cho S\emph{, et
al.} (2007). Toll-like receptor 2 mediates CNS injury in focal cerebral
ischemia. J Neuroimmunol 190\textbf{:} 28-33.

Li Q, \& Barres BA (2018). Microglia and macrophages in brain
homeostasis and disease. Nat Rev Immunol 18\textbf{:} 225-242.

Li S, Yang S, Sun B, \& Hang C (2019). Melatonin attenuates early brain
injury after subarachnoid hemorrhage by the JAK-STAT signaling pathway.
Int J Clin Exp Pathol 12\textbf{:} 909-915.

Lindsberg PJ, Hallenbeck JM, \& Feuerstein G (1991). Platelet-activating
factor in stroke and brain injury. Ann Neurol 30\textbf{:} 117-129.

Liu FY, Cai J, Wang C, Ruan W, Guan GP, Pan HZ\emph{, et al.} (2018).
Fluoxetine attenuates neuroinflammation in early brain injury after
subarachnoid hemorrhage: a possible role for the regulation of
TLR4/MyD88/NF-\selectlanguage{greek}κ\selectlanguage{english}B signaling pathway. J Neuroinflammation 15\textbf{:}347.

Liu GJ, Tao T, Wang H, Zhou Y, Gao X, Gao YY\emph{, et al.} (2020).
Functions of resolvin D1-ALX/FPR2 receptor interaction in the
hemoglobin-induced microglial inflammatory response and neuronal injury.
J Neuroinflammation 17\textbf{:} 239.

Liu H, Yang M, Pan L, Liu P, \& Ma L (2016). Hyperbaric Oxygen
Intervention Modulates Early Brain Injury after Experimental
Subarachnoid Hemorrhage in Rats: Possible Involvement of TLR4/NF-x03BA;
B-Mediated Signaling Pathway. Cell Physiol Biochem
38\textbf{:}2323-2336.

Liu X, Zhang X, Ma K, Zhang R, Hou P, Sun B\emph{, et al.} (2016).
Matrine alleviates early brain injury after experimental subarachnoid
hemorrhage in rats: possible involvement of PI3K/Akt-mediated NF-\selectlanguage{greek}κ\selectlanguage{english}B
inhibition and Keap1/Nrf2-dependent HO-1 inductionn. Cell Mol Biol
(Noisy-le-grand) 62\textbf{:} 38-44.

Lu M, Ji J, Jiang Z, \& You Q (2016). The Keap1-Nrf2-ARE Pathway As a
Potential Preventive and Therapeutic Target: An Update. Medicinal
research reviews 36\textbf{:} 924-963.

Luo Y, Reis C, \& Chen S (2019). NLRP3 Inflammasome in the
Pathophysiology of Hemorrhagic Stroke: A Review. Curr Neuropharmacol
17\textbf{:} 582-589.

Ma Y, Li J, Chiu I, Wang Y, Sloane JA, L\selectlanguage{ngerman}ü J\emph{, et al.} (2006).
Toll-like receptor 8 functions as a negative regulator of neurite
outgrowth and inducer of neuronal apoptosis. J Cell Biol
175\textbf{:}209-215.

Maddahi A, Povlsen GK, \& Edvinsson L (2012). Regulation of enhanced
cerebrovascular expression of proinflammatory mediators in experimental
subarachnoid hemorrhage via the mitogen-activated protein kinase
kinase/extracellular signal-regulated kinase pathway. J
Neuroinflammation 9\textbf{:} 274.

Maier B, Lehnert M, Laurer HL, \& Marzi I (2007). Biphasic elevation in
cerebrospinal fluid and plasma concentrations of endothelin 1 after
traumatic brain injury in human patients. Shock 27\textbf{:} 610-614.

Man SM, \& Kanneganti TD (2015). Regulation of inflammasome activation.
Immunol Rev 265\textbf{:} 6-21.

Miller BA, Turan N, Chau M, \& Pradilla G (2014). Inflammation,
vasospasm, and brain injury after subarachnoid hemorrhage. Biomed Res
Int 2014\textbf{:} 384342.

Minami N, Tani E, Maeda Y, Yamaura I, \& Fukami M (1992). Effects of
inhibitors of protein kinase C and calpain in experimental delayed
cerebral vasospasm. J Neurosurg 76\textbf{:} 111-118.

Mrozek S, Dumurgier J, Citerio G, Mebazaa A, \& Geeraerts T (2014).
Biomarkers and acute brain injuries: interest and limits. Crit Care
18\textbf{:} 220.

Murakami K, Koide M, Dumont TM, Russell SR, Tranmer BI, \& Wellman GC
(2011). Subarachnoid Hemorrhage Induces Gliosis and Increased Expression
of the Pro-inflammatory Cytokine High Mobility Group Box 1 Protein.
Transl Stroke Res 2\textbf{:} 72-79.

Nguyen T, Nioi P, \& Pickett CB (2009). The Nrf2-antioxidant response
element signaling pathway and its activation by oxidative stress. J Biol
Chem 284\textbf{:} 13291-13295.

Nishibori M, Wang D, Ousaka D, \& Wake H (2020). High Mobility Group
Box-1 and Blood-Brain Barrier Disruption. Cells 9.

Okada T, \& Suzuki H (2017). Toll-like receptor 4 as a possible
therapeutic target for delayed brain injuries after aneurysmal
subarachnoid hemorrhage. Neural Regen Res 12\textbf{:} 193-196.

Ostrowski RP, Colohan AR, \& Zhang JH (2006). Molecular mechanisms of
early brain injury after subarachnoid hemorrhage. Neurol Res
28\textbf{:} 399-414.

Osuka K, Watanabe Y, Yamauchi K, Nakazawa A, Usuda N, Tokuda M\emph{, et
al.} (2006). Activation of the JAK-STAT signaling pathway in the rat
basilar artery after subarachnoid hemorrhage. Brain Res
1072\textbf{:}1-7.

Pan YX, Chen KF, Lin YX, Wu W, Zhou XM, Zhang XS\emph{, et al.} (2013).
Intracisternal administration of SB203580, a p38 mitogen-activated
protein kinase inhibitor, attenuates cerebral vasospasm via inhibition
of tumor-necrosis factor-\selectlanguage{greek}α. \selectlanguage{english}J Clin Neurosci 20\textbf{:} 726-730.

Park JS, Arcaroli J, Yum HK, Yang H, Wang H, Yang KY\emph{, et
al.}(2003). Activation of gene expression in human neutrophils by high
mobility group box 1 protein. Am J Physiol Cell Physiol
284\textbf{:}C870-879.

Paudel YN, Angelopoulou E, Piperi C, Othman I, \& Shaikh MF (2020).
HMGB1-Mediated Neuroinflammatory Responses in Brain Injuries: Potential
Mechanisms and Therapeutic Opportunities. Int J Mol Sci 21.

Phillis JW, \& O'Regan MH (2003). The role of phospholipases,
cyclooxygenases, and lipoxygenases in cerebral ischemic/traumatic
injuries. Crit Rev Neurobiol 15\textbf{:} 61-90.

Planas AM, Gorina R, \& Chamorro A (2006). Signalling pathways mediating
inflammatory responses in brain ischaemia. Biochem Soc Trans
34\textbf{:} 1267-1270.

Regis G, Pensa S, Boselli D, Novelli F, \& Poli V (2008). Ups and downs:
the STAT1:STAT3 seesaw of Interferon and gp130 receptor signalling.
Semin Cell Dev Biol 19\textbf{:} 351-359.

Salonia R, Empey PE, Poloyac SM, Wisniewski SR, Klamerus M, Ozawa
H\emph{, et al.} (2010). Endothelin-1 is increased in cerebrospinal
fluid and associated with unfavorable outcomes in children after severe
traumatic brain injury. J Neurotrauma 27\textbf{:} 1819-1825.

Samraj AK, M\selectlanguage{ngerman}üller AH, Grell AS, \& Edvinsson L (2014). Role of
unphosphorylated transcription factor STAT3 in late cerebral ischemia
after subarachnoid hemorrhage. J Cereb Blood Flow Metab
34\textbf{:}759-763.

Sasaki T, Kasuya H, Onda H, Sasahara A, Goto S, Hori T\emph{, et
al.}(2004). Role of p38 mitogen-activated protein kinase on cerebral
vasospasm after subarachnoid hemorrhage. Stroke 35\textbf{:} 1466-1470.

Sato M, \& Noble LJ (1998). Involvement of the endothelin receptor
subtype A in neuronal pathogenesis after traumatic brain injury. Brain
Res 809\textbf{:} 39-49.

Schenk M, Bouchon A, Seibold F, \& Mueller C (2007). TREM-1--expressing
intestinal macrophages crucially amplify chronic inflammation in
experimental colitis and inflammatory bowel diseases. J Clin Invest
117\textbf{:} 3097-3106.

Schneider UC, Xu R, \& Vajkoczy P (2018). Inflammatory Events Following
Subarachnoid Hemorrhage (SAH). Curr Neuropharmacol
16\textbf{:}1385-1395.

Shang H, Yang D, Zhang W, Li T, Ren X, Wang X\emph{, et al.} (2013).
Time course of Keap1-Nrf2 pathway expression after experimental
intracerebral haemorrhage: correlation with brain oedema and
neurological deficit. Free Radic Res 47\textbf{:} 368-375.

Sharma D, \& Kanneganti TD (2016). The cell biology of inflammasomes:
Mechanisms of inflammasome activation and regulation. J Cell Biol
213\textbf{:} 617-629.

Sharma JN, Al-Omran A, \& Parvathy SS (2007). Role of nitric oxide in
inflammatory diseases. Inflammopharmacology 15\textbf{:} 252-259.

Stevens SL, Ciesielski TM, Marsh BJ, Yang T, Homen DS, Boule JL\emph{,
et al.} (2008). Toll-like receptor 9: a new target of ischemic
preconditioning in the brain. J Cereb Blood Flow Metab
28\textbf{:}1040-1047.

Sugawara T, Jadhav V, Ayer R, Chen W, Suzuki H, \& Zhang JH (2009).
Thrombin inhibition by argatroban ameliorates early brain injury and
improves neurological outcomes after experimental subarachnoid
hemorrhage in rats. Stroke 40\textbf{:} 1530-1532.

Suh HS, Zhao ML, Rivieccio M, Choi S, Connolly E, Zhao Y\emph{, et
al.}(2007). Astrocyte indoleamine 2,3-dioxygenase is induced by the TLR3
ligand poly(I:C): mechanism of induction and role in antiviral response.
J Virol 81\textbf{:} 9838-9850.

Sun XG, Duan H, Jing G, Wang G, Hou Y, \& Zhang M (2019). Inhibition of
TREM-1 attenuates early brain injury after subarachnoid hemorrhage via
downregulation of p38MAPK/MMP-9 and preservation of ZO-1. Neuroscience
406\textbf{:} 369-375.

Sun XG, Ma Q, Jing G, Wang GQ, Hao XD, \& Wang L (2017a). Increased
levels of soluble triggering receptor expressed on myeloid cells-1 in
cerebrospinal fluid of subarachnoid hemorrhage patients. J Clin Neurosci
35\textbf{:} 139-143.

Sun XG, Ma Q, Jing G, Wang L, Hao XD, \& Wang GQ (2017b). Early elevated
levels of soluble triggering receptor expressed on myeloid cells-1 in
subarachnoid hemorrhage patients. Neurol Sci 38\textbf{:} 873-877.

Sun XG, Zhang MM, Liu SY, Chu XH, Xue GQ, Zhang BC\emph{, et al.}(2021).
Role of TREM-1 in the development of early brain injury after
subarachnoid hemorrhage. Exp Neurol 341\textbf{:} 113692.

Suzuki H, Hasegawa Y, Kanamaru K, \& Zhang JH (2011). Mitogen-activated
protein kinases in cerebral vasospasm after subarachnoid hemorrhage: a
review. Acta Neurochir Suppl 110\textbf{:} 133-139.

Szabò C, Emilsson K, Hardebo JE, Nystedt S, \& Owman C (1992). Uptake
and release of serotonin in rat cerebrovascular nerves after
subarachnoid hemorrhage. Stroke 23\textbf{:} 54-61.

Takagi T, Kitashoji A, Iwawaki T, Tsuruma K, Shimazawa M, Yoshimura
S\emph{, et al.} (2014). Temporal activation of Nrf2 in the penumbra and
Nrf2 activator-mediated neuroprotection in ischemia-reperfusion injury.
Free Radic Biol Med 72\textbf{:} 124-133.

Takagi Y, Harada J, Chiarugi A, \& Moskowitz MA (2002). STAT1 is
activated in neurons after ischemia and contributes to ischemic brain
injury. J Cereb Blood Flow Metab 22\textbf{:} 1311-1318.

Tang D, Kang R, Coyne CB, Zeh HJ, \& Lotze MT (2012). PAMPs and DAMPs:
signal 0s that spur autophagy and immunity. Immunol Rev
249\textbf{:}158-175.

Tang SC, Arumugam TV, Xu X, Cheng A, Mughal MR, Jo DG\emph{, et
al.}(2007). Pivotal role for neuronal Toll-like receptors in ischemic
brain injury and functional deficits. Proc Natl Acad Sci U S A
104\textbf{:}13798-13803.

Tian X, Sun L, Feng D, Sun Q, Dou Y, Liu C\emph{, et al.} (2017). HMGB1
promotes neurovascular remodeling via Rage in the late phase of
subarachnoid hemorrhage. Brain Res 1670\textbf{:} 135-145.

Vavilala MS, Roberts JS, Moore AE, Newell DW, \& Lam AM (2001). The
influence of inhaled nitric oxide on cerebral blood flow and metabolism
in a child with traumatic brain injury. Anesth Analg 93\textbf{:}351-353
, 353rd contents page.

Vu TK, Hung DT, Wheaton VI, \& Coughlin SR (1991). Molecular cloning of
a functional thrombin receptor reveals a novel proteolytic mechanism of
receptor activation. Cell 64\textbf{:} 1057-1068.

Wang J, Fields J, Zhao C, Langer J, Thimmulappa RK, Kensler TW\emph{, et
al.} (2007). Role of Nrf2 in protection against intracerebral hemorrhage
injury in mice. Free Radic Biol Med 43\textbf{:} 408-414.

Wang L, Zhang Z, Liang L, Wu Y, Zhong J, \& Sun X (2019). Anti-high
mobility group box-1 antibody attenuated vascular smooth muscle cell
phenotypic switching and vascular remodelling after subarachnoid
haemorrhage in rats. Neurosci Lett 708\textbf{:} 134338.

Wei S, Luo C, Yu S, Gao J, Liu C, Wei Z\emph{, et al.} (2017).
Erythropoietin ameliorates early brain injury after subarachnoid
haemorrhage by modulating microglia polarization via the EPOR/JAK2-STAT3
pathway. Exp Cell Res 361\textbf{:} 342-352.

Willmot M, Ghadami A, Whysall B, Clarke W, Wardlaw J, \& Bath PM (2006).
Transdermal glyceryl trinitrate lowers blood pressure and maintains
cerebral blood flow in recent stroke. Hypertension
47\textbf{:}1209-1215.

Xi G, Keep RF, Hua Y, Xiang J, \& Hoff JT (1999). Attenuation of
thrombin-induced brain edema by cerebral thrombin preconditioning.
Stroke 30\textbf{:} 1247-1255.

Xu P, Hong Y, Xie Y, Yuan K, Li J, Sun R\emph{, et al.} (2021). TREM-1
Exacerbates Neuroinflammatory Injury via NLRP3 Inflammasome-Mediated
Pyroptosis in Experimental Subarachnoid Hemorrhage. Translational stroke
research 12\textbf{:} 643-659.

Xu P, Zhang X, Liu Q, Xie Y, Shi X, Chen J\emph{, et al.} (2019a).
Microglial TREM-1 receptor mediates neuroinflammatory injury via
interaction with SYK in experimental ischemic stroke. Cell Death Dis
10\textbf{:} 555.

Xu W, Li T, Gao L, Zheng J, Yan J, Zhang J\emph{, et al.} (2019b).
Apelin-13/APJ system attenuates early brain injury via suppression of
endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome
activation and oxidative stress in a AMPK-dependent manner after
subarachnoid hemorrhage in rats. J Neuroinflammation 16\textbf{:} 247.

Yirmiya R, \& Goshen I (2011). Immune modulation of learning, memory,
neural plasticity and neurogenesis. Brain Behav Immun
25\textbf{:}181-213.

Yoshimoto Y, Tanaka Y, \& Hoya K (2001). Acute systemic inflammatory
response syndrome in subarachnoid hemorrhage. Stroke
32\textbf{:}1989-1993.

You W, Wang Z, Li H, Shen H, Xu X, Jia G\emph{, et al.} (2016).
Inhibition of mammalian target of rapamycin attenuates early brain
injury through modulating microglial polarization after experimental
subarachnoid hemorrhage in rats. J Neurol Sci 367\textbf{:} 224-231.

Youssef RE, Ledingham MA, Bollapragada SS, O'Gorman N, Jordan F, Young
A\emph{, et al.} (2009). The role of toll-like receptors (TLR-2 and -4)
and triggering receptor expressed on myeloid cells 1 (TREM-1) in human
term and preterm labor. Reprod Sci 16\textbf{:} 843-856.

Yue TL, \& Feuerstein GZ (1994). Platelet-activating factor: a putative
neuromodulator and mediator in the pathophysiology of brain injury. Crit
Rev Neurobiol 8\textbf{:} 11-24.

Zhang D, Yan H, Li H, Hao S, Zhuang Z, Liu M\emph{, et al.} (2015).
TGF\selectlanguage{greek}β-\selectlanguage{english}activated Kinase 1 (TAK1) Inhibition by 5Z-7-Oxozeaenol Attenuates
Early Brain Injury after Experimental Subarachnoid Hemorrhage. J Biol
Chem 290\textbf{:} 19900-19909.

Zhang T, Wu P, Budbazar E, Zhu Q, Sun C, Mo J\emph{, et al.} (2019).
Mitophagy Reduces Oxidative Stress Via Keap1 (Kelch-Like
Epichlorohydrin-Associated Protein 1)/Nrf2 (Nuclear Factor-E2-Related
Factor 2)/PHB2 (Prohibitin 2) Pathway After Subarachnoid Hemorrhage in
Rats. Stroke 50\textbf{:} 978-988.

Zhang Z, Nagata I, Kikuchi H, Xue JH, Sakai N, Sakai H\emph{, et
al.}(2001). Broad-spectrum and selective serine protease inhibitors
prevent expression of platelet-derived growth factor-BB and cerebral
vasospasm after subarachnoid hemorrhage: vasospasm caused by cisternal
injection of recombinant platelet-derived growth factor-BB. Stroke
32\textbf{:}1665-1672.

Zhang ZG, Chopp M, Gautam S, Zaloga C, Zhang RL, Schmidt HH\emph{, et
al.} (1994). Upregulation of neuronal nitric oxide synthase and mRNA,
and selective sparing of nitric oxide synthase-containing neurons after
focal cerebral ischemia in rat. Brain Res 654\textbf{:} 85-95.

Zhao X, Sun G, Zhang J, Strong R, Dash PK, Kan YW\emph{, et al.} (2007).
Transcription factor Nrf2 protects the brain from damage produced by
intracerebral hemorrhage. Stroke 38\textbf{:} 3280-3286.

Zheng ZV, Lyu H, Lam SYE, Lam PK, Poon WS, \& Wong GKC (2020). The
Dynamics of Microglial Polarization Reveal the Resident
Neuroinflammatory Responses After Subarachnoid Hemorrhage. Transl Stroke
Res 11\textbf{:} 433-449.

Ziegler G, Harhausen D, Schepers C, Hoffmann O, R\selectlanguage{ngerman}öhr C, Prinz V\emph{,
et al.} (2007). TLR2 has a detrimental role in mouse transient focal
cerebral ischemia. Biochem Biophys Res Commun 359\textbf{:} 574-579.

Zimmerman GA, McIntyre TM, Mehra M, \& Prescott SM (1990). Endothelial
cell-associated platelet-activating factor: a novel mechanism for
signaling intercellular adhesion. J Cell Biol 110\textbf{:} 529-540.

\textbf{Hosted file}

\verb`figure.doc`  available at \url{https://authorea.com/users/737799/articles/712507-sah-and-inflammation-inflammatory-mechanisms-after-sah-ebi-and-or-vasospasm}

\textbf{Hosted file}

\verb`table.doc`  available at \url{https://authorea.com/users/737799/articles/712507-sah-and-inflammation-inflammatory-mechanisms-after-sah-ebi-and-or-vasospasm}

\selectlanguage{english}
\FloatBarrier
\end{document}

