YEXNR-12030; No.

of pages: 9; 4C:
Experimental Neurology xxx (2015) xxxxxx

Contents lists available at ScienceDirect

Experimental Neurology
journal homepage: www.elsevier.com/locate/yexnr

Peripheral to central: Organ interactions in stroke pathophysiology

Shubei Ma a, Haiping Zhao a, Xunming Ji c,, Yumin Luo a,b,
a
b
c

Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing 100053, China
Center of Stroke, Beijing Institute for Brain Disorders, Beijing 100053, China
Department of Neurosurgery, Xuanwu Hospital of Capital Medical University, Beijing 100053, China

a r t i c l e

i n f o

Article history:
Received 22 January 2015
Received in revised form 20 May 2015
Accepted 23 May 2015
Available online xxxx
Keywords:
Stroke
Organ
Interaction
Pathophysiology
Brain

a b s t r a c t
Stroke is associated with a high risk of disability and mortality, and with the exception of recombinant tissue-type
plasminogen activator for acute stroke, most treatments have proven ineffective. Clinical translation of promising
experimental therapeutics is limited by inadequate stroke models and a lack of understanding of the mechanisms
underlying acute stroke and how they affect outcome. Bidirectional communication between the ischemic brain
and peripheral immune system modulates stroke progression and tissue repair, while epidemiological studies
have provided evidence of an association between organ dysfunction and stroke risk. This crosstalk can determine the fate of stroke patients and must be taken into consideration when investigating the pathophysiological
mechanisms and therapeutic options for stroke. This review summarizes the current evidence for interactions between the brain and other organs in stroke pathophysiology in basic and clinic studies, and discusses the role of
these interactions in the progression and outcome of stroke and how they can direct the development of more
effective treatment strategies.
2015 Elsevier Inc. All rights reserved.

1. Introduction
Stroke is a neurological impairment attributed to acute focal injury
in the central nervous system with a vascular origin, and includes cerebral ischemia, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). Although it is a major cause of death and disability
worldwide, there is no singularly effective treatment for stroke to
date. Recombinant tissue-type plasminogen activator is currently the
only agent recommended for treatment of ischemic stroke (F. Chen
et al., 2014; Jauch et al., 2013). Most therapies that have appeared promising in experimental models have failed to produce results in patients.
One reason for this is that the pathophysiological mechanisms underlying stroke are complex and have a global impact. The normal functioning of the human body depends on the interaction of all organs, and
injury to one can impact the others and produce compensatory effects
or secondary injury. Conversely, severe brain injury resulting from
stroke, trauma, or infection can lead to multiple organ failure.
Interactions between peripheral organs can also exacerbate brain
damage and affect the recovery of stroke patients. For instance, these
patients are more likely to have chronic kidney disease (CKD), which
is secondary to hypertension, small vessel disease associated with diabetes, and cardiovascular disease (Nongnuch et al., 2014). The present
review presents evidence for crosstalk between the brain and other
Corresponding author.
Correspondence to: Y. Luo, Cerebrovascular Diseases Research Institute, Xuanwu
Hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, China.
E-mail addresses: jixm@ccmu.edu.cn (X. Ji), yumin111@ccmu.edu.cn (Y. Luo).

organs and discusses what is known about the clinical manifestations,

pathophysiology, mechanisms, and treatment of stroke.
2. Brain and spleen
The brain and immune system interact during each stage of stroke.
The spleen is the largest secondary immune organ in the body and functions in both innate and adaptive immunities. This section discusses
how immune cells in the spleen are modulated by and recruited to the
brain and contributes to neuroinammatory damage and brain tissue
repair (Fig. 1).
2.1. Splenic injury induced by stroke
Cerebral ischemia affects the total number of spleen cells and lymphocyte population size and function. Transient splenic atrophy in experimental models of ischemic stroke is characterized by a reduction
in spleen size, reduction in splenocyte number, and induction of apoptosis (Offner et al., 2006b). The decrease in the splenocyte population is
accompanied by increased efux of immune cellssuch as natural killer
cells, monocytes, and cluster of differentiation (CD)4+ and CD8+ T
cellsfrom the spleen into the peripheral circulation (Offner et al.,
2006b; Seifert et al., 2012). Spleen and blood B cell populations are
markedly reduced in experimental stroke, which may compromise the
functioning of the humoral immune system (Offner et al., 2006b). Released immune cells inltrate into the ischemic brain and exacerbate
brain injury by secreting proinammatory cytokines and chemokines
(Ahmad and Graham, 2010; Offner et al., 2006a,b; Seifert et al., 2012).

http://dx.doi.org/10.1016/j.expneurol.2015.05.014
0014-4886/ 2015 Elsevier Inc. All rights reserved.

Please cite this article as: Ma, S., et al., Peripheral to central: Organ interactions in stroke pathophysiology, Exp. Neurol. (2015), http://dx.doi.org/
10.1016/j.expneurol.2015.05.014

S. Ma et al. / Experimental Neurology xxx (2015) xxxxxx

Fig. 1. Interactions between the brain and spleen in stroke pathophysiology. Black arrows indicate the effects of stroke on the spleen; blue arrows indicate the contribution of the spleen to
stroke. APC, antigen-presenting cell; DAMP, danger-associated molecular pattern; NK, natural killer cell; HPA, hypothalamuspituitaryadrenal axis; Treg: regulatory T cell. (For interpretation of the references to color in this gure legend, the reader is referred to the web version of this article.)

Thus, splenic atrophy results not only from splenocyte apoptosis but
also from the migration of cells from the spleen to the injured brain
via the circulation.
In the early phase of ischemic injury, the immune system is activated
by endogenous stress signals known as danger-associated molecular
patterns (DAMPs) (Matzinger, 2002a,b) that include adenosine triphosphate, nicotinamide adenine dinucleotide, heat shock protein, and highmobility group box 1 protein released from damaged cerebral tissue
(Magnus et al., 2012). DAMPs are recognized by antigen-presenting
cells and link innate and adaptive immune responses, leading to the recruitment of immune cells from the spleen to the brain (Famakin,
2014). Moreover, chemokines secreted from brain cells in the infarct
area can travel through the blood and recruit immune cells from the
spleen back to the ischemic lesion (Gan et al., 2014; Zhang et al.,
2014). Additionally, the brain and spleen communicate via the activated
sympathetic nervous system and hypothalamicpituitaryadrenal
(HPA) axis, which induces the release of catecholamines and steroids
that alter spleen function (Schulze et al., 2014). Thus, the activation of
the autonomic nervous system and HPA axis following stroke can trigger an efux of immune cells from the spleen to the site of brain injury
via DAMPs and chemokines derived from injured brain tissue.

2.2. Contribution of immunomodulatory therapies to stroke

Splenectomy has been proposed as a prophylactic intervention for
cerebral ischemia (Izci, 2010). Evidence from rats has shown that splenectomy performed before cerebral ischemia can reduce infarct volume
and decrease the numbers of activated microglia, macrophages, and
neutrophils in brain tissue (Ajmo et al., 2008). However, it is unclear
whether splenectomy has adverse secondary effects, given the role of
the spleen in sustaining normal immune function. The immune response changes as stroke progresses; therefore, pharmacological and
cell-based therapies that target the interaction between the brain and

peripheral immune system have potential for stroke treatment (An

et al., 2014; Pennypacker, 2014).
Immunomodulatory therapies involving specic immune cells are
an alternative to splenectomy. Regulatory T cells (Tregs) and interleukin
10-producing regulatory B cells are specialized lymphocytes that exert
neuroprotection following cerebral ischemia (Bodhankar et al., 2013;
Offner and Hurn, 2012). Intravenous delivery of spleen-derived Tregs
protects against ischemia by suppressing neutrophil-derived matrix
metallopeptidase 9 production (Li et al., 2013a) without exacerbating
post-stroke immunosuppression (Li et al., 2013b). Splenic CD19+ B
cells relieve brain injury in mice by reducing inammatory cell inltration in the ischemic brain, and also block ischemia-induced splenic atrophy, inhibit the pro-inammatory activities of T cells and monocytes in
the periphery, and enhance peripheral Treg and programmed death 1
expression in mice after middle cerebral artery occlusion (MCAO)
(Bodhankar et al., 2013).
Most experimental and clinical studies on immune responses during
stroke have focused on ischemic stroke; there is comparatively little information on hemorrhagic stroke, which has a distinct pathogenesis. In
clinical trials, pharmacological intervention with ngolimod has been
used to attenuate the immune response after ischemic stroke to minimize injury. In an MCAO model, cellular immune therapy has demonstrated effective neuroprotection without immunosuppression. An
optimal pharmacological or cell-based intervention is one that can mitigate the splenic response to stroke and prevent neurodegeneration induced by the immune response without exacerbating post-stroke
immunosuppression.
3. Brain and heart
The association between the brain and heart was rst observed by
topographic electrocardiography (Remond et al., 1957); later studies
showed that cerebral vascular disorder induced changes in the electrocardiogram (Manning and Wallace, 1968). Since then, the interaction

Please cite this article as: Ma, S., et al., Peripheral to central: Organ interactions in stroke pathophysiology, Exp. Neurol. (2015), http://dx.doi.org/
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S. Ma et al. / Experimental Neurology xxx (2015) xxxxxx

between the brain and heart is always considered in the diagnosis,

treatment, and prevention of stroke and heart disease (van der Wall
and van Gilst, 2013). In this section, we summarize the reciprocal effects
of ischemic stroke and cardiac disorders (Fig. 2).

3.1. Cardiac disorders induced by stroke

Central nervous system diseases such as acute ischemic and hemorrhagic stroke often lead to cardiac abnormalities such as arrhythmias,
takotsubo cardiomyopathy (TTC), autonomic dysfunction, myocardial
infarction, and paroxysmal arterial hypertension (Finsterer and
Wahbi, 2014; Mathias et al., 2014; Simula et al., 2014; Xiong et al.,
2014; Young et al., 2014). The development of arrhythmias following
stroke is poorly understood, but is known to be associated with autonomic nervous system dysfunction. Cardiac functioning is represented
in the insular cortex, which may modulate cardiovascular and sympathetic nervous system responses in conjunction with the limbic system.
Stimulating the insular cortex can up-/downregulate sympathetic/
parasympathetic tone (Gelow et al., 2009; Oppenheimer et al., 1992).
Given the close connection between these two organ systems, the cardiovascular status of acute stroke patients must be evaluated and clinically signicant cardiac arrhythmias that decrease cerebral perfusion
should be treated (Jauch et al., 2013).
TTC, a non-ischemic cardiomyopathy with sudden onset, is characterized by transient hypokinesis of the left ventricular apex
(Komamura et al., 2014). A possible pathological mechanism is catecholamine depletion by cardiac sympathetic overstimulation induced
by cerebral ischemic or hemorrhagic stroke (Finsterer and Wahbi,
2014). Cerebral ischemia and acute myocardial infarction (AMI) have
similar atherosclerotic mechanisms and risk factors (Amarenco et al.,
2011; Gongora-Rivera et al., 2007), and AMI has been reported following ischemic stroke: one clinical study found that 4.9% of ischemic
stroke patients experienced AMI, who had worse outcome than those
without AMI (Mathias et al., 2014).

3.2. Contribution of cardiac abnormalities to stroke

Stroke can lead to cardiac dysfunction; conversely, cardiac abnormalities such as AMI, patent foramen ovale (PFO), and atrial brillation
(AF) can induce stroke (Suarez, 2006). AF is the most frequent cause of
cardioembolic stroke and is responsible for up to 25% of all strokes in the
elderly (Lloyd-Jones et al., 2010); it can be treated with adjusted-dose
warfarin (Hart et al., 2000). Non-hemorrhagic stroke occurs in 0.1%
1.3% of AMI patients treated by thrombolysis and is associated with
high mortality (17%) and disability (80%) (Mahaffey et al., 1998). The
risk of ischemic stroke in AMI patients has decreased from 2.4%3.5%
to about 0.6%1.8% through the use of thrombolytics or anticoagulants
during the acute phase (Hurlen et al., 2002; Komrad et al., 1984;
Mahaffey et al., 1998). Around 40% of patients with acute ischemic
stroke of unknown cause are classied as cryptogenic cases (Sacco
et al., 1989); some of these result from emboli in the venous system
that traverse the PFO into the left-sided circulation, a condition known
as paradoxical embolism (Elmariah et al., 2014). Although some clinical
studies suggest a possible association between PFO and cryptogenic
stroke (Bogousslavsky et al., 1996; Homma et al., 2002), a causeeffect
relationship has yet to be denitively established (Meissner et al.,
2006). A recent meta-analysis demonstrated that in cryptogenic stroke
patients, transcatheter PFO closure may be more effective than medical
treatment in terms of reducing the risk of recurrent cerebral ischemia
(Rengifo-Moreno et al., 2013).
The incidence of stroke following AMI is complicated by multiple factors. Sympathetic activation after AMI can promote coagulation by inducing platelet activation and von Willebrand factor and clotting factor
VIII production while inhibiting the brinolytic cascade, thereby contributing to stroke (Yun et al., 2005). Moreover, serum C-reactive protein
level is often elevated in AMI (de Beer et al., 1982). Enhanced thrombotic
tendency or diffuse intravascular inammation may contribute to
thrombus formation inside or outside the ventricular cavity, with subsequent cerebral embolization or rupture of a vulnerable plaque in the remote cerebral circulation; these effects may be aggravated by long

Fig. 2. Interactions between the brain and heart in stroke pathophysiology. Red arrows indicate the effects of stroke on the heart; blue arrows indicate the contribution of the heart to
stroke. Yellow arrows indicate common pathogenic mechanisms and risk factors. AMI, acute myocardial infarction; PFO, patent foramen ovale; TTC, takotsubo cardiomyopathy. (For interpretation of the references to color in this gure legend, the reader is referred to the web version of this article.)

Please cite this article as: Ma, S., et al., Peripheral to central: Organ interactions in stroke pathophysiology, Exp. Neurol. (2015), http://dx.doi.org/
10.1016/j.expneurol.2015.05.014

S. Ma et al. / Experimental Neurology xxx (2015) xxxxxx

periods of myocardial ischemia (Van de Graaff et al., 2006). High plasma

levels of brain natriuretic peptide (BNP) and D-dimer are independent
risk factors for cardioembolic stroke (Montaner et al., 2008). In addition,
plasma BNP level was transiently increased in patients with large-artery
atherosclerosis independent of heart disease, reecting infarct volume
and the severity of acute ischemic stroke (Tomita et al., 2008). The dysfunction of the automatic nervous system due to stroke can not only
trigger arrhythmias, but can also contribute to systemic inammation
and cause secondary brain damage. The combined effect of these
processes leads to poor outcome. Additional experimental studies and
clinical trials are needed to determine whether existing antidysrhythmic
drugs can be used to prevent immune system-induced injury to the brain
during stroke.
4. Brain and kidney
Cerebrorenal interactions are the basis for the interdependence of
cerebrovascular diseases and CKD (Toyoda and Ninomiya, 2014).
Renal dysfunction and stroke share vascular risk factors such as aging,
diabetes, hypertension, dyslipidemia, and obesity (Ninomiya, 2013).
Given the anatomical and functional similarities in the microvasculature
of the kidney and brain, both organs are vulnerable to arteriosclerotic
injury (Mogi and Horiuchi, 2011). A recent genome-wide association
study found a polygenic correlation between renal disease and largeartery atherosclerotic stroke, suggesting common genetic components
(Holliday et al., 2014).

nerve hyperactivity, thrombogenesis, and hyperhomocysteinemia leading to endothelial dysfunction (Toyoda and Ninomiya, 2014).
The benets and risks of antiplatelet and anticoagulation therapy
and intravenous thrombolysis must be balanced in ischemic stroke
patients with CKD. The risk of cardioembolic stroke due to the coexistence of AF is high in CKD, and although anticoagulation therapy is
safe and effective, patients who take oral anticoagulants have a high
risk of intracerebral hemorrhagic due to reduced renal clearance
(Reinecke et al., 2013). In ischemic stroke patients, decreased eGFR is
associated with early symptomatic ICH, higher mortality, and a poor
outcome 3 months after intravenous thrombolysis (Naganuma et al.,
2011). Clinical guidelines also advocate the use of antiplatelet therapy
for preventing ischemic stroke, which has been effective in nondialysis CKD patients (Jardine et al., 2010). Given that the effects of antithrombotic and thrombolytic agents are altered by renal dysfunction,
stroke treatment regimens should be optimized for each individual
based on pre-existing CKD.
Large-scale clinical trials of drugs for stroke treatment have generally
excluded patients with advanced renal dysfunction because of safety
issues. For instance, mannitol is used to attenuate brain edema in the
treatment of hemorrhagic stroke, but may exacerbate renal injury.
Although this problem has long been acknowledged, research into and
development of better drugs has not signicantly improved in part due
to the limited knowledge of the relationship between the brain and kidney. A deeper understanding of cerebrorenal interactions can lead to
the development of drugs with both neuro- and nephroprotective
effects.

4.1. Renal dysfunction induced by stroke

5. Brain and lungs
About 25% of patients were hospitalized for subarachnoid hemorrhage and acute stroke experience acute kidney injury (AKI) (Tsagalis
et al., 2009; Zacharia et al., 2009). Stroke can directly affect the kidney
by inducing the hyperactivation of the renal sympathetic nervous
systemwhich in turn alters renal blood ow and glomerular
ltrationand by increasing vasopressin release, leading to electrolyte
imbalance and consequently, cerebral salt wasting, hemodynamic instability, hormonal disturbances, and a heightened immunologic response,
triggering an inammatory cascade in the kidney. Moreover, strokeinduced sympathetic hyperactivation and increased plasma catecholamine concentrations result in systolic hypertension, a compensatory
mechanism that preserves blood ow to injured brain areas but can
also lead to red blood cell fragmentation, hemolysis, and AKI as a consequence of red blood cell thrombus accumulation in glomeruli (Maesaka
et al., 2009; Nongnuch et al., 2014).
4.2. Contribution of renal dysfunction to stroke
AKI can enhance the long-term risk and mortality of stroke (Wu
et al., 2014). This association may be due to non-traditional risk factors such as endothelial or progenitor cell dysfunction, oxidative
stress, inammation, hyperhomocysteinemia, and thrombogenesis
(Bonventre, 2010; Sun et al., 2012; Wu et al., 2013), each of which
can potentially accelerate atherosclerosis in the kidney and brain,
thereby contributing to stroke. In addition, the sudden decrease in
systemic blood pressure during dialysis in AKI patients can cause a
reduction in cerebral perfusion and lead to endothelial injury and
stroke.
CKD is a risk factor for stroke: a meta-analysis of clinical trials
found that proteinuria/albuminuria increased stroke risk by 71%
92%, while a decrease in evaluated glomerular ltration rate (eGFR)
increased the risk by 43% (Lee et al., 2010a,b). Although the reasons
for the increase in stroke risk in CKD are not well understood, it may
be related to common traditional vascular factors such as aging, hypertension, diabetes, dyslipidemia, and obesity-induced arteriosclerosis, as
well as other vascular factors such as chronic inammation, oxidative
stress, an imbalance in dimethylarginine concentration, sympathetic

The lungs ensure sufcient oxygenation of tissues for metabolism;

the brain is more sensitive to hypoxia than other organs. Conversely,
the brain controls breathing rhythm and other lung functions via the autonomic nervous system.
5.1. Pulmonary dysfunction induced by stroke
Impaired lung function in stroke survivors is characterized by decreases in forced expiratory volume in 1 s, forced vital capacity, peak
expiratory ow, and chest excursion, which may result from weakened respiratory muscles (Ezeugwu et al., 2013). An inpatient
study in the U.S. reported that about 30% of SAH patients develop
acute respiratory distress syndrome, which is associated with poor
outcome (Kahn et al., 2006) likely due to neurogenic pulmonary
edema (NPE), an acute, life-threatening complication after stroke
that occurs in about 23% of SAH patients (Baumann et al., 2007)
and is associated with high mortality (Fontes et al., 2003). NPE may
develop by rapid systemic sympathetic discharge following the activation of trigger zones such as the dorsal nucleus of the vagus and
medial reticular nuclei of the medulla oblongata by increased intracranial pressure after stroke (Sedy et al., 2015). Injury to dorsal and solitary
tract nucleiwhich suppress sympathetic activityincreases pulmonary vascular permeability and promotes NPE (Inobe et al., 2000).
There are currently no effective interventions for NPE; however, the selective P2X purinoceptor 7 antagonist Brilliant Blue G has been used to
treat NPE after SAH in a rat model (S. Chen et al., 2014), suggesting a potential clinical application.
5.2. Contribution of pulmonary dysfunction to stroke
Sleep-related breathing disorders are a risk factor for stroke and
transient ischemia (McArdle et al., 2003). Obstructive sleep apnea syndrome (OSA) signicantly increases the risk of stroke or death from any
cause independently of other risk factors, including hypertension (Yaggi
et al., 2005). The correlation between the OSA severity and plasma
levels of the procoagulant brinogen in stroke patients suggests a

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S. Ma et al. / Experimental Neurology xxx (2015) xxxxxx

possible pathophysiological basis for the increased risk of stroke in OSA

(Wessendorf et al., 2000).
Asthma is another risk factor for stroke that is independent of basal
lung functioning (Schanen et al., 2005). Asthma may directly cause cerebral hypoxemic episodes that can damage cerebral tissue if they are
of sufcient duration and severity; indeed, stroke-like symptoms have
been reported after severe asthma attacks (Morris et al., 1998). On the
other hand, asthma can indirectly increase stroke risk by inducing
blood hypertension, pulmonary hypertension, and AF (Salako and
Ajayi, 2000; Schanen et al., 2005).
Although impaired lung function due to chronic lung inammation
induces a low-grade systemic inammatory response that affects
blood vessels (Tamagawa and van Eeden, 2006), the mechanisms underlying the association between reduced lung function and ischemic
stroke incidence are as yet unclear. It is therefore critical to identify
mechanisms through which lung impairment inuences atherosclerosis
and triggers acute vascular events such as stroke.
6. Brain and liver
The liver is responsible for the synthesis and metabolism of blood coagulation factors and brinolytic enzymes that play important roles in
the pathophysiology of stroke. The hypothalamus signals to peripheral
organs such as the liver by stimulating autonomic nerves and by releasing hormones from the pituitary gland (Uyama et al., 2004).
6.1. Liver dysfunction induced by stroke
Liver injury is observed in experimental ischemic stroke and is associated with the activation of extracellular signal-regulated kinase, c-jun
N-terminal kinase, and caspase-3, as well as increases in tumor necrosis
factor level and DNA fragmentation in rat striatum and liver, suggesting the activation of inammatory and apoptotic responses (Ottani
et al., 2009). In addition, during the acute phase of stroke, the levels of
liver enzymes such as -glutamyl transpeptidase and glutamateoxaloacetate transaminase (GOT) increase, while that of unconjugated
bilirubin decreases; these events are linked to inammation (Muscari
et al., 2014). Glutamate released from cerebral infarct tissue enters the
cerebrospinal uid and bloodstream (Castillo et al., 1996), and the resultant glutamate toxicity may trigger the synthesis of GOT (Muscari et al.,
2014), a liver enzyme that exerts a protective function by metabolizing
blood glutamate following stroke (Campos et al., 2011). Notably, decreased serum GOT and increased glutamate levels are independently
associated with larger infarct volume and poor functional outcome at
3 months (Campos et al., 2011; Muscari et al., 2014). Additional studies
are needed to clarify the link between cerebral infarct size and serum
GOT levels.
6.2. Contribution of liver dysfunction to stroke
Liver dysfunction can affect stroke occurrence and prognosis. Early
clinical studies have found that liver cirrhosis is a causal factor in
spontaneous intracerebral hemorrhage (Niizuma et al., 1988b) and is
correlated with ICH volume and re-bleeding (Niizuma et al., 1988a);
moreover, the severity of liver cirrhosis is associated with ICH patient
prognosis (Huang et al., 2008). On the contrary, a 9-year follow-up
study revealed a trend of increased ICH incidence in patients with
liver cirrhosis (Lai et al., 2011). Thus, there is controversy as to whether
ICH incidence is associated with liver cirrhosis. Furthermore, it is unclear why liver dysfunction is associated with a high risk for developing
ICH, but hemostatic dysregulation such as thrombocytopenia and coagulation disorders observed in these patients may play a signicant role
(Pluta et al., 2010). Antiplatelet therapy is an essential component of ischemic stroke treatment and prevention (Jauch et al., 2013), while abnormal liver function due to cirrhosis can induce a hemorrhagic state
(Bianchini et al., 2014). Antiplatelet therapy is safe and effective for

ischemic stroke prevention in patients with cirrhosis (Chen et al.,

2012). Although a positive correlation has been observed between
liver cirrhosis and intracerebral hemorrhaging, details of this interaction
remain to be elucidated.
7. Brain and pancreas
The pancreas functions as a digestive organ and as part of the endocrine system, and is innervated by automatic nerves. The brain
endocrinepancreas axis secretes insulin to regulate blood glucose
concentration (Uyama et al., 2004). Pancreatic dysfunction, including hypo- and hyperglycemia, can lead to metabolic disturbance
and cerebrovascular disease.
7.1. Pancreatic dysfunction induced by stroke
Stroke can alter the digestive functions of the pancreas. An early
clinical study found that the levels of serum pancreatic enzymes, including amylase and lipase, were elevated in stroke patients (Pezzilli
et al., 1997) possibly due to the action of the automatic nervous system (Larson et al., 1985). Acute stroke can also cause abnormal glucose
metabolismknown as stress hyperglycemia (SH) (Hafez et al., 2014;
Kruyt et al., 2010)which is usually resolved spontaneously after the
acute phase of stroke (Dungan et al., 2009). SH during stroke is partly
caused by HPA axis activation, which leads to the release of catecholamine that acts on the 2 receptor of pancreatic cells, inhibiting insulin secretion (Dungan et al., 2009; Keahey et al., 1989). Increased
catecholamine levels also cause insulin resistance (Dungan et al.,
2009; Kruyt et al., 2010), which can exacerbate SH. These ndings suggest that changes in serum pancreatic enzyme levels can have a nonpancreatic origin in stroke patients.
7.2. Contribution of pancreatic dysfunction to stroke
The risk of acute and recurrent ischemic stroke is higher in diabetic
than in non-diabetic patients (Emerging Risk Factors et al., 2010;
Hillen et al., 2003), especially those younger than 50 years of age
(Putaala et al., 2011). Hemoglobin A1c concentrations N 42 mmol/mol
(6%) increase the risk of ischemic stroke by 2- to 3-fold (Selvin et al.,
2010). In one clinical study, hyperglycemia was exacerbated after administration of recombinant tissue plasminogen activator in patients
with large-vessel occlusion (Mandava et al., 2014); diabetes also increases the risk of long-term cognitive decits, including post-stroke
dementia (Megherbi et al., 2003; Pendlebury and Rothwell, 2009).
Brain vasculature is severely compromised in diabetes (Elgebaly
et al., 2011; Sima, 2010), which can impair autoregulation of cerebral
blood owknown as diabetic autonomic neuropathy (Mankovsky
et al., 1996)and thereby create a hypoxic environment that can trigger
cerebral neovascularization (Ergul et al., 2009; Kelly-Cobbs et al., 2012).
Increased vascular endothelial growth factor and peroxynitrite formation along with the downregulation of the guidance molecule
Roundabout-4 in diabetes may contribute to perturbed cerebral neovascularization (Ergul et al., 2014). Additionally, matrix metalloproteinase
activity is increased in a spontaneous type 2 diabetic rat model, which
leads to high vascular permeability and greater susceptibility to hemorrhagic transformation after ischemia (Li et al., 2010; Prakash et al.,
2012). These factors contribute to abnormal vascularization, which is
associated with increased risk and poor outcome in ischemic stroke patients with diabetes or hyperglycemia. Although there is at present no
conclusive evidence supporting the benets of glucose-lowering treatment for stroke prevention in diabetes, reducing blood pressure in patients with type II diabetes may decrease stroke risk (Group et al.,
2010; Patel et al., 2007).
Ischemic preconditioning has neuroprotective effects during stroke.
Post-stroke stress-induced hyperglycemia and cerebral blood supply
deciency in the ischemic penumbrawhich reduce glucose and

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S. Ma et al. / Experimental Neurology xxx (2015) xxxxxx

oxygen suppliescan contribute to brain damage after stroke. Decreasing glycemic variability may be associated with a better outcome in ischemic stroke (Gonzalez-Moreno et al., 2014). Whether
hyper- or hypoglycemia preconditioning can provide neuroprotection during stroke requires further investigation.
8. Brain and the gastrointestinal (GI) system
The brain can modulate the GI system during stroke through automatic nervous system hyperactivation and systemic inammation. The
intestinal immune system, consisting of Peyer's patches and individual
immune cells dispersed within the intestinal epithelium and the lamina
propria, provides an immune barrier between gut microbiota and systemic circulation and is under the control of the sympathetic nervous
system (Straub et al., 2006). The GI system undergoes various changes
following stroke, as detailed below.
8.1. GI dysfunction induced by stroke
Stroke disrupts communication between the central nervous and
GI systems, leading to dysphagia, GI hemorrhage, delayed GI evacuation, and colorectal dysfunction (Schaller et al., 2006). Gastroduodenal ulcers and GI bleeding are the most common complications
in the acute and chronic stages of ischemic stroke and are associated
with poor outcome (Camara-Lemarroy et al., 2014). A previous study

found that the autonomic nervous and pituitaryadrenal systems

have distinct roles in the gastric changes that occur in acute stroke
(Kitamura and Ito, 1976).
Stroke has been shown to disrupt the gut barrier in animal
models, leading to diffuse edema in gastric mucosa, splinter hemorrhage and erosion, endothelial cell necrosis, mucosal dissociation,
and inammatory cell inltration (Feng et al., 2010). Cerebral ischemia has variable effects on the cellularity of gut-associated lymphoid
tissue, including a reduction in T and B cell counts in Peyer's patches
(Schulte-Herbruggen et al., 2009). The loss of mucosal integrity and
immune cell dysfunction allows bacterial translocation (Tascilar
et al., 2010). It has been suggested that a catecholamine-mediated
defect in early lymphocyte activation is a major cause of impaired
antibacterial immune response after stroke in mice (Prass et al.,
2003). Reduced gastric mucosal blood ow, stress, systemic inammation, and oxidative stress may also contribute to post-stroke injury to GI
mucosa (Camara-Lemarroy et al., 2014; Hung, 2006; Kawakubo et al.,
1996). Calcitonin gene-related peptide has been investigated for its potential function in protecting gastric mucosa after cerebral ischemia/reperfusion (Feng et al., 2010).
8.2. Potential function of GI system on stroke
Helicobacter pylori is a Gram-negative bacterium that can cause
chronic gastritis, peptic ulcer disease, and gastric cancer (Correa,

Fig. 3. Organ interactions in stroke pathophysiology. Yellow arrows indicate the effects of stroke on peripheral organs; blue arrows indicate the contribution of peripheral organs to stroke.
AF, atrial brillation; AKI, acute kidney injury; AMI, acute myocardial infarction; ANS, autonomic nervous system; CKD, chronic kidney disease; CRP, C-reactive protein; -GT, gamma
glutamyl transpeptidase; GOT, glutamateoxaloacetate transaminase; GI, gastrointestinal; HPA, hypothalamuspituitaryadrenal; ICP, intracranial pressure; NPE, neurogenic pulmonary
edema; PFO, patent foramen ovale; PH, pulmonary hypertension; SRBD, sleep-related breathing disorders; TTC, takotsubo cardiomyopathy.

Please cite this article as: Ma, S., et al., Peripheral to central: Organ interactions in stroke pathophysiology, Exp. Neurol. (2015), http://dx.doi.org/
10.1016/j.expneurol.2015.05.014

S. Ma et al. / Experimental Neurology xxx (2015) xxxxxx

1997; Marshall and Warren, 1984); it is detected in carotid atherosclerotic lesions and is signicantly associated with the incidence
of atherosclerotic ischemic stroke (Rozankovic et al., 2011). The
role of H. pylori in the pathogenesis of atherosclerosis may be related
to an autoimmune mechanism that destabilizes carotid atherosclerotic plaques, leading to thrombosis and acute ischemic stroke
(Rozankovic et al., 2011). H. pylori infection can induce the breakdown of the bloodbrain barrier via release of inammatory mediators, which may underlie the pathogenesis of various neuropathies
including stroke (Kountouras, 2009; Zhang et al., 2008), although
the link between H. pylori infection and ischemic stroke has been disputed by other studies (Heuschmann et al., 2001; Yu et al., 2014).
H. pylori infection is treatable, which has important implications for
stroke prevention and treatment if a physiological connection does
in fact exist.
9. Conclusion
This review described the interactions during stroke between the
brain and peripheral organs (Fig. 3), which are anatomically and functionally linked via the automatic nervous system by humoral regulation
and direct innervation. The interaction between the brain and immune
system is well-established and affects other organ systems and consequently, the outcome of stroke. Obviously, neuro-immunology plays a
dominant role in all the organ interactions discussed, especially in
renal dysfunction and stroke, splenic changes after stroke, and pulmonary diseases and stroke. In addition, arrhythmias, TTC, and AMI also
serve as an important part in neurocardiology. Of notice, among the
organ interactions discussed, brain and pancreas crosstalk has received
more attention than the others due to the close relationship between diabetes and stroke. The other manifestations after stroke that need to be
concerned include severe NPE, increased serum level of GOT and -GT
related with liver damage. Moreover, gastrointestinal bleeding presents
as the common complication of stroke. Thus, understanding the molecular basis of these interactions is critical for stroke prevention and treatment. However, many outstanding questions remain. For instance, how
the interactions between central and peripheral mechanisms contribute
to stroke progression and prognosis must be claried. The morbidity associated with stroke is not fully understood, and there is a lack of experimental models that can recapitulate all of its aspects (Xi et al., 2014);
this is exemplied by the variability in behavioral decits and patterns
of recovery after stroke among different rat strains (Kunze et al.,
2014). Addressing these issues will lead to greater progress in our understanding of stroke pathophysiology in the context of interactions between the brain and peripheral organs and the development of more
effective treatments.
List of abbreviations
AF
atrial brillation
AKI
acute kidney injury
AMI
acute myocardial infarction
BNP
brain natriuretic peptide
CKD
chronic kidney disease
DAMPs danger-associated molecular patterns
eGFR
evaluated glomerular ltration rate
GI
gastrointestinal
GOT
glutamate-oxaloacetate transaminase
HPA
hypothalamicpituitaryadrenal
ICH
intracerebral hemorrhage
MCAO
middle cerebral artery occlusion
NPE
neurogenic pulmonary edema
PFO
patent foramen ovale
SAH
subarachnoid hemorrhage
SH
stress hyperglycemia
Tregs
regulatory T-cells
TTC
takotsubo cardiomyopathy

Details of authors' contributions

All authors contributed to the conception, writing, critical review,
and revision of the manuscript.
Declaration of interests
The authors declare no competing interests.
Acknowledgments
This work was supported by Natural Science Foundation in China
(grant nos. 81271461, 81201028, 81471340, and 81401090).
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Please cite this article as: Ma, S., et al., Peripheral to central: Organ interactions in stroke pathophysiology, Exp. Neurol. (2015), http://dx.doi.org/
10.1016/j.expneurol.2015.05.014