Brain Hemorrhages 1 (2020) 13–18

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Brain Hemorrhages
CHINESE ROOTS
GLOBAL IMPACT
journal homepage: www.keaipublishing.com/en/journals/brain-hemorrhages/

Review article

Intracerebral hemorrhage in translational research

Ruiyi Zhang a, Qian Bai a, Yang Liu a, Yan Zhang a, Zhaofu Sheng a, Mengzhou Xue a,⇑, V. Wee Yong b,⇑
a
The Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Henan Joint International Laboratory of Intracerebral Hemorrhagic Brain
Injury and Henan Medical Key Laboratory of Translational Cerebrovascular Diseases, Zhengzhou, Henan, China
b
Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada

a r t i c l e i n f o a b s t r a c t

Article history: Intracerebral hemorrhage (ICH) is a serious stroke subtype with high morbidity and mortality. The prog-
Received 25 December 2019 nosis of ICH is poor. In recent years, there have been many studies on how to improve the prognosis of
Received in revised form 10 February 2020 ICH. This article mainly summarizes the research progress of ICH in translational research, including its
Accepted 11 February 2020
risk factors and pathogenesis, course of disease, primary and secondary ICH brain injury, its prevention
Available online 28 February 2020
and treatment strategies.
Ó 2020 Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open
Keywords:
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Intracerebral hemorrhage
Brain injury
Neuroinflammation
Neuroimmunology
Neuronal death

Intracerebral hemorrhage (ICH) can be induced by a variety of
causes, including hypertension, cerebral amyloid angiopathy, brain
trauma, vascular malformations and drugs. The study of global dis-
ease burden showed that the number of ICH increased by 47% in
past 20 years, mostly gathered in low income and middle-income
countries.1 Understanding the pattern of brain injury induced by
ICH is a great significance to find the effective treatment. Here
we summarize the research progress of ICH from the view of trans-
lational medicine.
1. Risk factors and pathogenesis of ICH
Hypertension is the most common risk factor for ICH. About 80%
of ICH patients have elevated blood pressure on admission, and
most of them have a history of hypertension.2 Long-term hyperten-
sion makes cerebral arterioles suffer higher stress of blood flow,
triggers smooth muscle cell proliferation and death followed by
collagen replacement, weakens the strength of artery wall, and
makes it easy to occlusion and rupture. Perforating arteries such
as bean striation, thalamus and brainstem perforating artery bifur-
cation are the most common sites of bleeding, and the degree of
bleeding mainly depends on the size of arteriole wall space, blood
pressure and hemostatic mechanism. In non-hypertensive individ-
⇑ Corresponding authors at: 2 Jingba Road, Zhengzhou, Henan 450001, China
(M. Xue).
E-mail addresses: xuemengzhou@zzu.edu.cn (M. Xue), vyong@ucalgary.ca
(V.W. Yong).
uals, especially in the elderly, amyloid angiopathy is an important
cause of ICH. The deposition of amyloid protein in the media and
adventitia of capillaries, arterioles, cortex and pia meningeal arter-
ies causes vascular wall brittleness. The unique features of this
lesion are that hemorrhage tends to occur in the lobes of the brain
(especially in the posterior part of the brain), multifocal and recur-
rent.3 The traditional view believes that the difference between
hypertensive vascular disease and amyloid vascular disease lies
in the site of bleeding. ICH associated with amyloid angiopathy is
usually located in the lobe, and the hypertensive ICH is usually
located in the deep part of the brain. However, hypertension can
also lead to lobar hemorrhage, and hypertensive vascular disease
and amyloid vascular disease may be a co-disease, so the patho-
genesis of ICH is sometimes difficult to determine.
Smoking, alcohol abuse, low total and low-density lipoprotein
cholesterol levels all increased the risk of ICH. Warfarin increases
the risk of ICH by 2–5 times, and the risk of bleeding depends on
anticoagulant strength. The increase in the number of elderly peo-
ple taking oral anticoagulant drugs has led to an increasing number
of anticoagulant-related ICH. Antiplatelet therapy also increases
the risk of ICH. Although several case-control studies did not prove
that the use of antiplatelet drugs increased the risk of ICH, Meta-
analysis showed that platelet therapy slightly significantly
increased the risk of ICH. In addition, Meta-analysis showed that
the history of antiplatelet drugs increased the risk of death after
ICH, and another study showed that the history of antiplatelet
drugs was associated with an increase in early hematoma in ICH.
Compared with antiplatelet monotherapy, double anti-platelet

https://doi.org/10.1016/j.hest.2020.02.003
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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
14 R. Zhang et al. / Brain Hemorrhages 1 (2020) 13–18
therapy may further increase the risk of ICH. In patients with atrial
fibrillation, the risk of ICH in the aspirin combined with clopidogrel
group was almost twice as high as that in the aspirin alone
group.4,5
There have been many reports of associations between sympa-
thetic drugs such as cocaine, heroin, amphetamine and ephedrine
with ICH, especially in young patients. Especially in women, rela-
tively high doses of phenylpropanolamine are an independent fac-
tor for ICH, and low doses of phenylpropanolamine in cold cures is
also associated with ICH risk.6,7 In addition, chronic kidney disease
increases the risk of ICH, and chronic kidney disease may be a mar-
ker of cerebral microvascular disease.4,8
2. Progression of ICH
After vascular rupture, the formation of hematoma begins and
progresses within 60 min. The sudden influx of blood flow into
the brain leads to mechanical destruction of the brain parenchyma,
distortion and displacement of the brain tissue, increases the risk
of cerebral hernia and ischemia, and triggers brain cell death
including necrosis and apoptosis, inflammation and edema.9 About
1/3 of the patients had enlarged hematoma within 3 h, and about
2/3 of them occurred within 1 h after ICH.10 Even without the coag-
ulation disorders, the hematoma will increase too, and the mecha-
nism of hematoma increase is not clear, which may be related to
the continued bleeding at the initial bleeding site and the satellite
bleeding around the blood clot caused by the destruction of adja-
cent small blood vessels. Alcohol abuse, irregular bleeding, low
levels of fibrinogen and prothrombin, diabetes and liver diseases
are all risk factors for hematoma enlargement.3 Computed tomo-
graphic angiography (CTA) can predict the risk of hematoma
enlargement. The spot sign of CTA is highly correlated with hema-
toma enlargement.10 CTA spot sign was first described in 2007, it
was defined as focal or multifocal enhancer spillover from normal
or abnormal blood vessels around hematoma after ICH, which pre-
dicted hematoma enlargement and became an independent indica-
tor of poor clinical prognosis.11 Subsequent large clinical studies
found that about 30% of ICH patients had spot sign. Multiple CTA
tests could further help predict hematoma enlargement, and the
clinical prognosis of patients with spot sign within 23 s of enhancer
injection was poor.12 Intraventricular hemorrhage (IVH) can occur
with ICH or within 24–72 h after ICH, accounting for about 20%–
55% of patients with ICH, which is another important factor in
the poor prognosis of ICH. Compared with patients without IVH,
the prognosis of patients with IVH was worse.13
ICH patients developed brain edema within a few hours after
the onset of symptoms and reached the peak at 1–2 weeks. The
blood composition is closely related to the brain edema around
the hematoma.
Within 1 h after ICH, the blood clot contracts and the plasma
move out from the clot to the tissue around the hematoma, form-
ing edema adjacent to hematoma. 24 h after bleeding, thrombin
cascade reaction and thrombin production are involved in the for-
mation of early edema. Erythrocyte lysis, hemoglobin and its
decomposition products, and carbonic anhydrase-1, another com-
ponent of erythrocytes, lead to late edema. The blood–brain barrier
(BBB) remained intact within a few hours after ICH, but the perme-
ability of BBB increased after 8–12 h. Although there are many
forms of edema after ICH, angiogenic edema is the main form of
ICH.10 The imaging findings of brain edema were low density on
CT scan and high signal on T2 weighted or Flair of magnetic reso-
nance imaging (MRI). The most severe edema was located around
the clot, mainly along the white matter.3
The degree of cerebral ischemia around hematoma after ICH is
still controversial. Large hematoma increases intracranial pressure,
resulting in cerebral hernia and slow blood flow velocity, which
may lead to a further decrease in blood flow if the supply of collat-
eral circulation in the brain area supplied by ruptured blood ves-
sels is poor. However, few clinical and animal studies have
reported whether changes in blood flow around the hematoma
can lead to ischemic injury. It should be noted that the changes
of blood flow velocity around the hematoma mix metabolism
and hematoma formation and other factors. In ICH patients, the
blood flow and oxygen metabolic rate around the hematoma
decreased, resulting in the decrease of oxygen uptake fraction,
indicating that there is a low perfusion area around the hematoma.
Recent data have shown that the decline in brain metabolism may
reflect mitochondrial damage rather than cerebral ischemia.14
ICH may also trigger the protective defense mechanism of the
body. Up-regulation of a variety of endogenous proteins after ICH
may help protect the brain from damage. For example, ferritin
and nuclear factor 2 related factor 2 (NF-E2 related factor 2, Nrf
2) were significantly up-regulated and participated in the mecha-
nism of antioxidant defense. In Nrf2 knockout mice, collagenase
leads to more brain injury by inducing ICH than that in wild-type
mice.14
3. Primary brain injury induced by ICH and its prevention and
treatment strategy
ICH firstly destroys the brain structure. Hematoma may
increase intracranial pressure, oppress brain areas, potentially
affect blood flow and cause cerebral hernia. In view of the physical
compression of hematoma, many clinical trials have explored the
effect of surgical removal of blood clots, but no clinical trials have
confirmed the benefits of ICH patients. One possible explanation is
that the side effects of surgery offset the beneficial effects of blood
clot removal. It is worth noting that the location of ICH affects the
prognosis, and surgical decompression can save lives in patients
with cerebellar hemorrhage. Because it is more difficult to remove
hematoma in small animals, there are relatively few preclinical
studies on the effect of removing blood clots, and most studies
use pigs, which confirms that early removal of hematoma may
benefit, but there are many problems with ultra-early clearance
of blood clots. In clinical, some patients will continue to bleed or
easily bleed again.10 Moreover, a clinical trial shows that removing
acute intracerebral hematomas in early phase by minimally inva-
sive surgery which has been widely used recently is safe and effec-
tive to bring better neurological prognosis in ICH patients.15
Preventing hematoma enlargement may be another way to
reduce the space occupying effect. Many patients suffered rapid
elevated blood pressure after ICH which could result in further
bleeding and edema. Some clinical trials exhibit that although
there are no differences between intensive lowering of systolic
pressure under 140 mmHg and under 180 mmHg as guideline in
death or severe disability, rapid reduction of the blood pressure
may contributes to improved functional outcomes.16,17 And many
studies have focused on finding drugs that change the process of
coagulation cascade or fibrinolysis. Clinical trials have confirmed
that activated coagulation factor VII (VIIa), which can reduce
hematoma enlargement but cannot improve prognosis and may
induce thromboembolic complications. There are also some clini-
cal trials to explore which patients are suitable for the treatment
of activated coagulation factor VIIa.18 Some studies have shown
that patients with enlarged hematoma or patients with ICH who
take anticoagulant or antiplatelet drugs benefit the most. Other
methods are also being tested clinically, such as platelet transfu-
sion in patients receiving antiplatelet therapy, or the use of amino-
caproic acid, an antifibrinolytic agent. Early platelet transfusion
can benefit from low platelet activity or antiplatelet therapy. In
 R. Zhang et al. / Brain Hemorrhages 1 (2020) 13–18
the rat model of ICH induced by collagenase, activated coagulation
factor VIIa reduced early hematoma enlargement.19 Vasodilator in
plasma can inhibit platelet aggregation and inhibit vasodilator can
reduce the enlargement of hematoma. In the mouse ICH model
induced by warfarin anticoagulant and collagenase, prothrombin
complex concentrate and frozen plasma could reduce bleeding,
and the effects of activated coagulation factor VIIa and tranexamic
acid were poor.14,20
The increase of blood pressure after ICH is the result of the
superposition of many mechanisms, including pre-onset hyperten-
sion, increased intracranial pressure, autonomic nerve and neu-
roendocrine activation. Clinical trials to reduce hematoma also
include lowering blood pressure. There is a dilemma in the treat-
ment of elevated blood pressure. On the one hand, acute hyperten-
sion may be protective, ensuring cerebral blood flow supply in the
case of elevated intracranial pressure to prevent ischemic stroke,
on the other hand, hypertension increases the risk of edema. Pro-
mote hematoma enlargement by continuing bleeding and rebleed-
ing. According to the American Heart and Stroke Association
guidelines, blood pressure is safe at 150–220 mmHg after ICH.
Some clinical trials have confirmed that the target value of blood
pressure reduction within 1 h after ICH is not less than 140 mmHg,
which has no obvious negative effect on neural state and has noth-
ing to do with serious adverse events. Recent clinical trials have
shown that the target value of hypotension at 110 mmHg is still
safe.21 It is not known whether antihypertensive treatment has
long-term benefits, but there is evidence that it can reduce hema-
toma enlargement. There are few preclinical studies on the effect
of blood pressure on hematoma enlargement. After injection of col-
lagenase, there was no significant difference in bleeding volume
between spontaneously hypertensive rats and normal blood pres-
sure rats. However, the injury induced by ICH in spontaneously
hypertensive rats is more serious, indicating that hypertension
does not mediate ICH-induced injury by regulating the volume of
hematoma. Rapid changes in blood pressure may have a greater
impact on hematoma enlargement than persistent hypertension.
Pathological examination of ICH rat model showed that there
was no significant difference in bleeding volume between sponta-
neously hypertensive rats and normal hypertensive rats, but there
was more bleeding in normotensive rats with sharply elevated
blood pressure.14
Many studies have focused on the application of drug-enhanced
defense mechanisms. Nrf2 can be up-regulated by a range of drugs,
including sulforaphane, a component of broccoli, which reduces
ICH-induced brain injury in rats and mice through a Nrf2-
dependent mechanism. Peroxisome proliferator-activated
receptor-c (PPAR-c) agonists can also play a beneficial role by
up-regulating cellular defense mechanisms, including hydrogen
peroxide.14
4. Secondary brain injury induced by ICH and its prevention and
treatment strategy
Secondary brain injury after ICH may be caused by a series of
events induced by primary injury, including body/tissue responses
to hematoma, such as inflammation, microglia/macrophage activa-
tion and neutrophil infiltration,22 release of clot components (e.g.
hemoglobin/iron).14 Following factors are involved in secondary
brain injury induced by ICH (Fig. 1).
The initial response of the body to ICH is the activation of the
hemostatic mechanism to limit bleeding. Thrombin plays an
important role in homeostasis, but there is also a lot of evidence
that thrombin can be involved in ICH-induced brain injury.23 The
most important role of thrombin is to break down fibrinogen into
fibrin, while the other effects are mediated by three protease-
15
activated receptors (PARs). PAR-1, PAR-3 and PAR-4 are thrombin
receptors.24 It has been found that neurons and astrocytes express
mRNA of thrombin receptors and the immunoreactivity of which in
human brain. Studies have shown that PAR-1 mediates some
pathological effects of thrombin and participates in the pathophys-
iological mechanism induced by ICH.25 Infusion of high doses of
thrombin directly into the brain can cause inflammatory cell infil-
tration, mesenchymal cell proliferation, scar formation, brain
edema and seizures.23,24,26,27 Thrombin acts on many cell types,
including endothelial cells, which leads to the destruction of BBB
and the formation of brain edema. Neurons and astrocytes are acti-
vated by Src kinase and can be killed by high concentration of
thrombin in vitro. Microglia can be activated by thrombin. Animal
experiments showed that inhibition of thrombin by hirudin, a
specific thrombin inhibitor,23,24,27 could reduce the damage
induced by ICH. Clinical trials have also confirmed that thrombin
mediated brain injury. Argatroban, a thrombin inhibitor, can signif-
icantly reduce brain edema around the hematoma following ICH.
In addition, there is evidence that thrombin is associated with
brain recovery and neuronal regeneration after ICH.27–29
There are obvious inflammatory reactions after ICH, including
microglia activation, leukocyte infiltration and inflammatory
mediator formation, which play an important role in ICH-induced
injury and brain recovery.30 In ICH animal model, the activation
of microglia was an early reaction, which appeared within 1 h after
ICH, reached the peak at 3–7 days after ICH, and maintained for 3–
4 weeks.23,24,26 Tuftsin or minocycline plays a protective role after
ICH by inhibiting microglia activation.31–33 A meta-analysis includ-
ing 4 clinical trials and 14 rodent studies displays therapeutic
effects on acute ischemic stroke. But the study about minocycline
treatment on ICH remains less. A pilot study of minocycline in
ICH patients shows that 400 mg dose can produce neuroprotective
effects,34 but further study in different doses or usage still need to
be done. For brain injury after ICH, microglia/macrophage are a
double-edged sword, which can promote inflammation reactions
leading secondary injury or mediate inflammation and dissolve
blood clots,22 and the net effect may change with time.35 Neu-
trophils are the first leukocytes to enter the brain after ICH. Neu-
trophils participate in ICH-induced brain injury by producing
reactive oxygen species (ROS), pro-inflammatory proteases and
destroying BBB. Monocytes also enter the brain after ICH, and
recent studies have shown that consumption of neutrophils
reduces the number of monocytes entering the brain. Toll-like
receptor 4 on leukocytes mediates the infiltration of neutrophils
and monocytes. The two types of cells that have received little
attention in the ICH study are mast cells and infiltrating lympho-
cytes in the brain. Recent studies have shown that the both may
mediate ICH-induced brain injury.31 In animals and humans, brain
injury induced by ICH is associated with the significant upregula-
tion of a variety of inflammatory mediators, such as tumor necrosis
factor-a (TNF-a) and interleukin-1 b (IL-1b), chemokines, adhesion
molecules, and matrix metalloproteinase (MMPs) such as MMP-9
and -3.27,29,36,37 The secondary reaction of inflammation after ICH
leads to the destruction of BBB, which can aggravate inflammation
by promoting leukocyte infiltration. ROS, pro-inflammatory cytoki-
nes, chemokines and MMPs from leukocytes are all involved in the
destruction of BBB.38 In addition to promoting inflammation, the
destruction of BBB also leads to the formation of vascular edema
after ICH. There have been clinical trials to verify whether
cyclooxygenase inhibitor celecoxib, anti-inflammatory hypo-
glycemic drug pioglitazone can reduce brain injury after ICH, but
no clear conclusion has been drawn. Some clinical trials focused
on two kinds of lipid-lowering drugs, rosuvastatin and simvastatin,
which had anti-inflammatory effects. Rosuvastatin had a positive
effect, but simvastatin trial could not continue because of difficulty
in recruiting volunteers.39,40
16 R. Zhang et al. / Brain Hemorrhages 1 (2020) 13–18

Fig. 1. In the earliest stage of ICH, the primary brain injury made by hematoma and edema causes blood products (Fe2+, Hb, thrombin) to leak into the damage area to
activate microglia/macrophages and other peripheral immune cells to express high levels of IL-6, IL-1b, TNFa, GMCSF, INFc, ROS, RNS, CCLs, HO-1, and MMPs. These changes
result in the secondary brain injury, which extend the brain damage such as brain edema, cell death, blood–brain barrier disruption, and neurologic deficits.

The complement system involves immune responses, including
cell lysis and inflammation. The plasma protein components of the
complement system are usually blocked out of the brain by the
BBB, but they may enter the brain after ICH as part of the blood
or after BBB is damaged. Membrane attack complex (MAC, C5b-
9) is formed after ICH and complement activation. MAC partici-
pates in the cleavage of red blood cells and mediates the release
of hemoglobin and iron, resulting in damage to surrounding tis-
sues. It may also cause direct damage to neurons, glial cells and
blood vessels around the hematoma. In addition, complement cas-
cade activation produces C3a and C5a, leukocyte chemokines,
microglia and mast cell activators, which promotes inflammation
after ICH. Several studies have confirmed that consumption of
complements using antagonists or gene knockout can reduce
ICH-induced brain injury.41 However, the conclusions on C5 are
not consistent. C5a inhibitors are protective, while the brain injury
induced by ICH in C5 gene deficient mice is significantly increased,
which may reflect the compensatory changes in C5 gene deficient
mice. Similar to inflammation, although complement activation
after ICH promotes brain damage, there is also evidence that com-
plement is beneficial to the long-term recovery of the brain.42
There is growing evidence that hemoglobin and iron released
from hematoma are the main causes of brain damage caused by
ICH. Injection of lysed red blood cells into the rodent brain induces
brain damage, and infusion of hemoglobin and iron into the brain
has a similar effect. After ICH, iron accumulates in the tissues
around the hematoma. In rat and pig models, the use of iron chela-
tor deferoxamine can reduce brain damage induced by ICH.43
Deferoxamine has shown protective effects and reduction of
injuries in ICH rats and piglets,44,45 and deferoxamine mesylate
has been used in clinical trials.46 Heme oxygenase breaks down
blood into bilirubin, carbon dioxide and iron. Inhibition of heme
oxygenase or knockout serum heme oxygenase-1 can reduce brain
damage caused by ICH.47 One possible mechanism of tissue dam-
age caused by iron is the production of free radicals. Free radical
mediated ICH injury, animal experiments showed that free radical
scavengers reduce the damage induced by ICH. However, it should
be pointed out that there may be a variety of sources of free radi-
cals after ICH. NXY-059 is a free radical spin trap used in clinical
trials in patients with ICH.48 It has not been confirmed whether
patients benefit or not. The cause of this negative result has not
yet been determined, but it may reflect that the increase in the per-
meability of BBB after ICH is not sufficient to neutralize a large
number of free radicals.49 Although hemoglobin is the main com-
ponent of red blood cells, it is not the only one. A recent study
has shown that intracerebral injection of carbonic anhydrase 1,
another major component of red blood cells, may lead to brain
damage, and carbonic anhydrase inhibitors reduce ICH-induced
damage in rats.50
Although glutamate-induced excitability plays an important
role in cell death after cerebral ischemia, there is some evidence
that glutamate may also be involved in ICH-induced brain injury
and through specific potential mechanisms. The primary hemor-
rhage leads to glutamate outflow, and the production of thrombin
after ICH leads to the activation of Src kinase. Src kinase can phos-
phorylate NMDA receptor and enhance its function. Compared
with cerebral ischemia, there are few clinical trials to verify the
role of glutamate receptor antagonists in ICH, except for a small
 R. Zhang et al. / Brain Hemorrhages 1 (2020) 13–18
clinical trial of NMDA antagonist CP-101606, which focuses on
traumatic brain injury.51,52
ICH causes brain cell death and brain atrophy around the hema-
toma. The pathway of cell death involves apoptosis, necrosis and
autophages, which the dominant way is controversial. The necrosis
of the brain around the blood clot may be related to the mechanical
pressure of hematoma, the composition of blood clot and its degra-
dation. Although apoptosis is associated with peri-hematoma brain
cell death, the importance of apoptosis in ICH-induced brain injury
is not clear.10 A large number of studies have used ICH model to
find possible ways to reduce apoptosis and brain injury, such as
taurodeoxycholic acid, membrane stabilizer cytidine diphosphate
choline.14 There is also evidence that autophagy occurs after
ICH.14 Autophagy is the degradation process of cells. Proteins and
organelles are isolated in bilayer vesicles and transported to lyso-
somes, which are digested by lysosomal hydrolases. ICH can induce
programmed cell death in the form of autophagy, and iron plays an
important role in the process of autophagy.53 As with other neuro-
logical diseases, it is necessary to further confirm whether autop-
hagy is protective (removing dead cells) or nociceptive (inducing
multiple cell deaths).54 In clinical and animal experiments, cell
death after ICH can lead to brain atrophy.10,55
5. From bench to clinic
Due to absence of effective treatment for ICH,56 many research-
ers devote into discover new therapeutic targets and pathophysiol-
ogy with the help of different animal models including
microballoon insertion,57 autologous whole blood injection,58 col-
lagenase,59 thrombin,23 hypertensive stroke model,60 neonatal
PVH/IVH61 and other newly developed models. But none of these
animal models can completely mimic the condition of human
ICH. Each of them has advantages and disadvantages. Autologous
blood injection model may imitate the effects of hematoma most
accurately but cannot reproduce the process of bleeding.62 Collage-
nase can disrupt capillary basal lamina and cause bleeding,63 but it
is artificial and may lead to direct damage of brain tissue besides
the effects of hemorrhage.64 Thrombin released after ICH activates
microglia and promotes cytokine production that causes neuroin-
flammation and brain cell death, but this model may be not suit-
able for research other than effects of thrombin. Hence, an
animal model needs to be selected deliberately according to the
purpose and condition of a preclinical research of ICH.
Many preclinical studies focused on inflammation response
after ICH and as the most important immune cells in central nerval
system, microglia/macrophage are very popular and promising.65
As a double side’s sword, activated pro-inflammatory microglia
increase their production of numerous proinflammatory and
potentially neurotoxic mediators which may contribute to ICH
neuronal injury while increasing evidence indicates that activated
microglia in the later phase of ICH phagocytose/resorb hematoma
and resolve edema, contributing to improved white matter integ-
rity, repair and functional recovery.66 Some promising drugs tar-
geting on shift the balance between pro-inflammatory and
regulatory phenotypes of microglia/macrophage after ICH achieved
therapeutic effects in preclinical or clinical trials. Some of these
medications focus on inhibit the generation of pro-inflammatory
cells including minocycline,67 C5aRA, rCTRP9, NLRP3 blocker,68
LTB4 receptor antagonist, TLR4 inhibitors,69 Fingolimod70 and
bortezomib71 while others dedicate to promote the transformation
of regulatory microglia/macrophage such as SIPR agonists,72
Statins,73 CB2R agonist, PPARc activators,74 mTOR inhibiters75
and sinomenine.76 All of these promising candidates still need to
be further discovered in mechanism and tested in usage and doses
in both laboratory and clinical situation.
17
6. Conclusion
In summary, our understanding of the mechanism of brain
damage caused by ICH has increased over the past 20 years, and
the conduct of many clinical trials offers hope for the relief of sev-
ere ICH. However, it should be noted that ICH covers a variety of
hematoma in different locations and sizes. As a result, there is
probably no treatment that is most suitable for all patients.77 For
different individuals, the combination of different treatments
may provide the best way to alleviate ICH brain injury.77,78
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgements
The authors acknowledge operating grant support from the
National Natural Science Foundation of China (grants nos.:
81870942, 81471174 and 81520108011), National Key Research
and Development Program of China (grant no.: 2018
YFC1312200), and Innovation Scientists and Technicians Troop
Constructions Projects of Henan Province of China (for MX); and
from the Canadian Institutes of Health Sciences (VWY).
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