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Peripheral to central: Organ interactions in stroke pathophysiology
Shubei Ma a, Haiping Zhao a, Xunming Ji c,⁎, Yumin Luo a,b,⁎⁎a Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing 100053, Chinab Center of Stroke, Beijing Institute for Brain Disorders, Beijing 100053, Chinac Department of Neurosurgery, Xuanwu Hospital of Capital Medical University, Beijing 100053, China
⁎ Corresponding author.⁎⁎ Correspondence to: Y. Luo, Cerebrovascular DiseasHospital of Capital Medical University, 45 Changchun Stre
Stroke is associatedwith a high risk of disability andmortality, andwith the exception of recombinant tissue-typeplasminogen activator for acute stroke,most treatments have proven ineffective. Clinical translation of promisingexperimental therapeutics is limited by inadequate strokemodels and a lack of understanding of themechanismsunderlying acute stroke and how they affect outcome. Bidirectional communication between the ischemic brainand peripheral immune system modulates stroke progression and tissue repair, while epidemiological studieshave provided evidence of an association between organ dysfunction and stroke risk. This crosstalk can deter-mine the fate of stroke patients andmust be taken into consideration when investigating the pathophysiologicalmechanisms and therapeutic options for stroke. This review summarizes the current evidence for interactions be-tween the brain and other organs in stroke pathophysiology in basic and clinic studies, and discusses the role ofthese interactions in the progression and outcome of stroke and how they can direct the development of moreeffective treatment strategies.
Stroke is a neurological impairment attributed to acute focal injuryin the central nervous system with a vascular origin, and includes cere-bral ischemia, intracerebral hemorrhage (ICH), and subarachnoid hem-orrhage (SAH). Although it is a major cause of death and disabilityworldwide, there is no singularly effective treatment for stroke todate. Recombinant tissue-type plasminogen activator is currently theonly agent recommended for treatment of ischemic stroke (F. Chenet al., 2014; Jauch et al., 2013).Most therapies that have appeared prom-ising in experimental models have failed to produce results in patients.One reason for this is that the pathophysiological mechanisms underly-ing stroke are complex and have a global impact. The normal function-ing of the human body depends on the interaction of all organs, andinjury to one can impact the others and produce compensatory effectsor secondary injury. Conversely, severe brain injury resulting fromstroke, trauma, or infection can lead to multiple organ failure.
Interactions between peripheral organs can also exacerbate braindamage and affect the recovery of stroke patients. For instance, thesepatients are more likely to have chronic kidney disease (CKD), whichis secondary to hypertension, small vessel disease associated with dia-betes, and cardiovascular disease (Nongnuch et al., 2014). The presentreview presents evidence for crosstalk between the brain and other
es Research Institute, Xuanwuet, Beijing 100053, [email protected] (Y. Luo).
eral to central: Organ interact
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 func-tions in both innate and adaptive immunities. This section discusseshow immune cells in the spleen are modulated by and recruited to thebrain and contributes to neuroinflammatory damage and brain tissuerepair (Fig. 1).
2.1. Splenic injury induced by stroke
Cerebral ischemia affects the total number of spleen cells and lym-phocyte population size and function. Transient splenic atrophy in ex-perimental models of ischemic stroke is characterized by a reductionin spleen size, reduction in splenocyte number, and induction of apopto-sis (Offner et al., 2006b). The decrease in the splenocyte population isaccompanied by increased efflux of immune cells—such as natural killercells, monocytes, and cluster of differentiation (CD)4+ and CD8+ Tcells—from the spleen into the peripheral circulation (Offner et al.,2006b; Seifert et al., 2012). Spleen and blood B cell populations aremarkedly reduced in experimental stroke, which may compromise thefunctioning of the humoral immune system (Offner et al., 2006b). Re-leased immune cells infiltrate into the ischemic brain and exacerbatebrain injury by secreting proinflammatory cytokines and chemokines(Ahmad and Graham, 2010; Offner et al., 2006a,b; Seifert et al., 2012).
ions in stroke pathophysiology, Exp. Neurol. (2015), http://dx.doi.org/
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 tostroke. APC, antigen-presenting cell; DAMP, danger-associatedmolecular pattern; NK, natural killer cell; HPA, hypothalamus–pituitary–adrenal axis; Treg: regulatory T cell. (For interpre-tation of the references to color in this figure legend, the reader is referred to the web version of this article.)
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Thus, splenic atrophy results not only from splenocyte apoptosis butalso from the migration of cells from the spleen to the injured brainvia the circulation.
In the early phase of ischemic injury, the immune system is activatedby endogenous stress signals known as danger-associated molecularpatterns (DAMPs) (Matzinger, 2002a,b) that include adenosine triphos-phate, nicotinamide adenine dinucleotide, heat shock protein, and high-mobility group box 1 protein released from damaged cerebral tissue(Magnus et al., 2012). DAMPs are recognized by antigen-presentingcells and link innate and adaptive immune responses, leading to the re-cruitment of immune cells from the spleen to the brain (Famakin,2014). Moreover, chemokines secreted from brain cells in the infarctarea can travel through the blood and recruit immune cells from thespleen back to the ischemic lesion (Gan et al., 2014; Zhang et al.,2014). Additionally, the brain and spleen communicate via the activatedsympathetic nervous system and hypothalamic–pituitary–adrenal(HPA) axis, which induces the release of catecholamines and steroidsthat alter spleen function (Schulze et al., 2014). Thus, the activation ofthe autonomic nervous system and HPA axis following stroke can trig-ger an efflux of immune cells from the spleen to the site of brain injuryvia DAMPs and chemokines derived from injured brain tissue.
2.2. Contribution of immunomodulatory therapies to stroke
Splenectomy has been proposed as a prophylactic intervention forcerebral ischemia (Izci, 2010). Evidence from rats has shown that sple-nectomy performed before cerebral ischemia can reduce infarct volumeand decrease the numbers of activated microglia, macrophages, andneutrophils in brain tissue (Ajmo et al., 2008). However, it is unclearwhether splenectomy has adverse secondary effects, given the role ofthe spleen in sustaining normal immune function. The immune re-sponse changes as stroke progresses; therefore, pharmacological andcell-based therapies that target the interaction between the brain and
Please cite this article as: Ma, S., et al., Peripheral to central: Organ interact10.1016/j.expneurol.2015.05.014
peripheral immune system have potential for stroke treatment (Anet al., 2014; Pennypacker, 2014).
Immunomodulatory therapies involving specific immune cells arean alternative to splenectomy. Regulatory T cells (Tregs) and interleukin10-producing regulatory B cells are specialized lymphocytes that exertneuroprotection following cerebral ischemia (Bodhankar et al., 2013;Offner and Hurn, 2012). Intravenous delivery of spleen-derived Tregsprotects against ischemia by suppressing neutrophil-derived matrixmetallopeptidase 9 production (Li et al., 2013a) without exacerbatingpost-stroke immunosuppression (Li et al., 2013b). Splenic CD19+ Bcells relieve brain injury in mice by reducing inflammatory cell infiltra-tion in the ischemic brain, and also block ischemia-induced splenic atro-phy, inhibit the pro-inflammatory activities of T cells and monocytes inthe periphery, and enhance peripheral Treg and programmed death 1expression in mice after middle cerebral artery occlusion (MCAO)(Bodhankar et al., 2013).
Most experimental and clinical studies on immune responses duringstroke have focused on ischemic stroke; there is comparatively little in-formation on hemorrhagic stroke, which has a distinct pathogenesis. Inclinical trials, pharmacological intervention with fingolimod has beenused to attenuate the immune response after ischemic stroke to mini-mize injury. In an MCAO model, cellular immune therapy has demon-strated effective neuroprotection without immunosuppression. Anoptimal pharmacological or cell-based intervention is one that can mit-igate the splenic response to stroke and prevent neurodegeneration in-duced by the immune response without exacerbating post-strokeimmunosuppression.
3. Brain and heart
The association between the brain and heart was first observed bytopographic electrocardiography (Remond et al., 1957); later studiesshowed that cerebral vascular disorder induced changes in the electro-cardiogram (Manning and Wallace, 1968). Since then, the interaction
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between the brain and heart is always considered in the diagnosis,treatment, and prevention of stroke and heart disease (van der Walland van Gilst, 2013). In this section,we summarize the reciprocal effectsof ischemic stroke and cardiac disorders (Fig. 2).
3.1. Cardiac disorders induced by stroke
Central nervous system diseases such as acute ischemic and hemor-rhagic stroke often lead to cardiac abnormalities such as arrhythmias,takotsubo cardiomyopathy (TTC), autonomic dysfunction, myocardialinfarction, and paroxysmal arterial hypertension (Finsterer andWahbi, 2014; Mathias et al., 2014; Simula et al., 2014; Xiong et al.,2014; Young et al., 2014). The development of arrhythmias followingstroke is poorly understood, but is known to be associated with auto-nomic nervous system dysfunction. Cardiac functioning is representedin the insular cortex, which may modulate cardiovascular and sympa-thetic 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 car-diovascular status of acute stroke patients must be evaluated and clini-cally significant cardiac arrhythmias that decrease cerebral perfusionshould be treated (Jauch et al., 2013).
TTC, a non-ischemic cardiomyopathy with sudden onset, is char-acterized by transient hypokinesis of the left ventricular apex(Komamura et al., 2014). A possible pathological mechanism is cate-cholamine depletion by cardiac sympathetic overstimulation inducedby cerebral ischemic or hemorrhagic stroke (Finsterer and Wahbi,2014). Cerebral ischemia and acute myocardial infarction (AMI) havesimilar atherosclerotic mechanisms and risk factors (Amarenco et al.,2011; Gongora-Rivera et al., 2007), and AMI has been reported follow-ing ischemic stroke: one clinical study found that 4.9% of ischemicstroke patients experienced AMI, who had worse outcome than thosewithout AMI (Mathias et al., 2014).
Fig. 2. Interactions between the brain and heart in stroke pathophysiology. Red arrows indicastroke. Yellow arrows indicate common pathogenic mechanisms and risk factors. AMI, acute mterpretation of the references to color in this figure legend, the reader is referred to the web ve
Please cite this article as: Ma, S., et al., Peripheral to central: Organ interact10.1016/j.expneurol.2015.05.014
3.2. Contribution of cardiac abnormalities to stroke
Stroke can lead to cardiac dysfunction; conversely, cardiac abnor-malities such as AMI, patent foramen ovale (PFO), and atrial fibrillation(AF) can induce stroke (Suarez, 2006). AF is the most frequent cause ofcardioembolic stroke and is responsible for up to 25% of all strokes in theelderly (Lloyd-Jones et al., 2010); it can be treated with adjusted-dosewarfarin (Hart et al., 2000). Non-hemorrhagic stroke occurs in 0.1%–1.3% of AMI patients treated by thrombolysis and is associated withhigh mortality (17%) and disability (80%) (Mahaffey et al., 1998). Therisk 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 anticoagulantsduring the acute phase (Hurlen et al., 2002; Komrad et al., 1984;Mahaffey et al., 1998). Around 40% of patients with acute ischemicstroke of unknown cause are classified as cryptogenic cases (Saccoet al., 1989); some of these result from emboli in the venous systemthat traverse the PFO into the left-sided circulation, a condition knownas paradoxical embolism (Elmariah et al., 2014). Although some clinicalstudies suggest a possible association between PFO and cryptogenicstroke (Bogousslavsky et al., 1996; Homma et al., 2002), a cause–effectrelationship has yet to be definitively established (Meissner et al.,2006). A recent meta-analysis demonstrated that in cryptogenic strokepatients, transcatheter PFO closure may be more effective than medicaltreatment in terms of reducing the risk of recurrent cerebral ischemia(Rengifo-Moreno et al., 2013).
The incidence of stroke following AMI is complicated bymultiple fac-tors. Sympathetic activation after AMI can promote coagulation by in-ducing platelet activation and von Willebrand factor and clotting factorVIII productionwhile inhibiting the fibrinolytic cascade, thereby contrib-uting to stroke (Yun et al., 2005). Moreover, serum C-reactive proteinlevel is often elevated in AMI (de Beer et al., 1982). Enhanced thrombotictendency or diffuse intravascular inflammation may contribute tothrombus formation inside or outside the ventricular cavity, with subse-quent cerebral embolization or rupture of a vulnerable plaque in the re-mote cerebral circulation; these effects may be aggravated by long
te the effects of stroke on the heart; blue arrows indicate the contribution of the heart toyocardial infarction; PFO, patent foramen ovale; TTC, takotsubo cardiomyopathy. (For in-rsion of this article.)
ions in stroke pathophysiology, Exp. Neurol. (2015), http://dx.doi.org/
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periods of myocardial ischemia (Van de Graaff et al., 2006). High plasmalevels of brain natriuretic peptide (BNP) and D-dimer are independentrisk factors for cardioembolic stroke (Montaner et al., 2008). In addition,plasma BNP level was transiently increased in patients with large-arteryatherosclerosis independent of heart disease, reflecting infarct volumeand the severity of acute ischemic stroke (Tomita et al., 2008). The dys-function of the automatic nervous system due to stroke can not onlytrigger arrhythmias, but can also contribute to systemic inflammationand cause secondary brain damage. The combined effect of theseprocesses leads to poor outcome. Additional experimental studies andclinical trials are needed to determinewhether existing antidysrhythmicdrugs can be used to prevent immune system-induced injury to the brainduring stroke.
4. Brain and kidney
Cerebrorenal interactions are the basis for the interdependence ofcerebrovascular 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 themicrovasculatureof the kidney and brain, both organs are vulnerable to arterioscleroticinjury (Mogi and Horiuchi, 2011). A recent genome-wide associationstudy found a polygenic correlation between renal disease and large-artery atherosclerotic stroke, suggesting common genetic components(Holliday et al., 2014).
4.1. Renal dysfunction induced by stroke
About 25% of patients were hospitalized for subarachnoid hemor-rhage and acute stroke experience acute kidney injury (AKI) (Tsagaliset al., 2009; Zacharia et al., 2009). Stroke can directly affect the kidneyby inducing the hyperactivation of the renal sympathetic nervoussystem—which in turn alters renal blood flow and glomerularfiltration—and by increasing vasopressin release, leading to electrolyteimbalance and consequently, cerebral salt wasting, hemodynamic insta-bility, hormonal disturbances, and a heightened immunologic response,triggering an inflammatory cascade in the kidney. Moreover, stroke-induced sympathetic hyperactivation and increased plasma catechol-amine concentrations result in systolic hypertension, a compensatorymechanism that preserves blood flow to injured brain areas but canalso lead to red blood cell fragmentation, hemolysis, and AKI as a conse-quence of red blood cell thrombus accumulation in glomeruli (Maesakaet 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 (Wuet al., 2014). This association may be due to non-traditional risk fac-tors such as endothelial or progenitor cell dysfunction, oxidativestress, inflammation, hyperhomocysteinemia, and thrombogenesis(Bonventre, 2010; Sun et al., 2012; Wu et al., 2013), each of whichcan potentially accelerate atherosclerosis in the kidney and brain,thereby contributing to stroke. In addition, the sudden decrease insystemic blood pressure during dialysis in AKI patients can cause areduction in cerebral perfusion and lead to endothelial injury andstroke.
CKD is a risk factor for stroke: a meta-analysis of clinical trialsfound that proteinuria/albuminuria increased stroke risk by 71%–92%, while a decrease in evaluated glomerular filtration rate (eGFR)increased the risk by 43% (Lee et al., 2010a,b). Although the reasonsfor the increase in stroke risk in CKD are not well understood, it maybe related to common traditional vascular factors such as aging, hyper-tension, diabetes, dyslipidemia, and obesity-induced arteriosclerosis, aswell as other vascular factors such as chronic inflammation, oxidativestress, an imbalance in dimethylarginine concentration, sympathetic
Please cite this article as: Ma, S., et al., Peripheral to central: Organ interact10.1016/j.expneurol.2015.05.014
nerve hyperactivity, thrombogenesis, and hyperhomocysteinemia lead-ing to endothelial dysfunction (Toyoda and Ninomiya, 2014).
The benefits and risks of antiplatelet and anticoagulation therapyand intravenous thrombolysis must be balanced in ischemic strokepatients with CKD. The risk of cardioembolic stroke due to the coex-istence of AF is high in CKD, and although anticoagulation therapy issafe and effective, patients who take oral anticoagulants have a highrisk of intracerebral hemorrhagic due to reduced renal clearance(Reinecke et al., 2013). In ischemic stroke patients, decreased eGFR isassociated with early symptomatic ICH, higher mortality, and a pooroutcome 3 months after intravenous thrombolysis (Naganuma et al.,2011). Clinical guidelines also advocate the use of antiplatelet therapyfor preventing ischemic stroke, which has been effective in non-dialysis CKD patients (Jardine et al., 2010). Given that the effects of an-tithrombotic and thrombolytic agents are altered by renal dysfunction,stroke treatment regimens should be optimized for each individualbased on pre-existing CKD.
Large-scale clinical trials of drugs for stroke treatment have generallyexcluded patients with advanced renal dysfunction because of safetyissues. For instance, mannitol is used to attenuate brain edema in thetreatment of hemorrhagic stroke, but may exacerbate renal injury.Although this problem has long been acknowledged, research into anddevelopment of better drugs has not significantly improved in part dueto the limited knowledge of the relationship between the brain and kid-ney. A deeper understanding of cerebrorenal interactions can lead tothe development of drugs with both neuro- and nephroprotectiveeffects.
5. Brain and lungs
The lungs ensure sufficient oxygenation of tissues for metabolism;the brain is more sensitive to hypoxia than other organs. Conversely,the brain controls breathing rhythmand other lung functions via the au-tonomic nervous system.
5.1. Pulmonary dysfunction induced by stroke
Impaired lung function in stroke survivors is characterized by de-creases in forced expiratory volume in 1 s, forced vital capacity, peakexpiratory flow, and chest excursion, which may result from weak-ened respiratory muscles (Ezeugwu et al., 2013). An inpatientstudy in the U.S. reported that about 30% of SAH patients developacute respiratory distress syndrome, which is associated with pooroutcome (Kahn et al., 2006) likely due to neurogenic pulmonaryedema (NPE), an acute, life-threatening complication after strokethat occurs in about 23% of SAH patients (Baumann et al., 2007)and is associated with high mortality (Fontes et al., 2003). NPE maydevelop by rapid systemic sympathetic discharge following the acti-vation of trigger zones such as the dorsal nucleus of the vagus andmedial reticular nuclei of the medulla oblongata by increased intracra-nial pressure after stroke (Sedy et al., 2015). Injury to dorsal and solitarytract nuclei—which suppress sympathetic activity—increases pulmo-nary vascular permeability and promotes NPE (Inobe et al., 2000).There are currently no effective interventions for NPE; however, the se-lective P2X purinoceptor 7 antagonist Brilliant Blue G has been used totreat NPE after SAH in a ratmodel (S. Chen et al., 2014), suggesting a po-tential clinical application.
5.2. Contribution of pulmonary dysfunction to stroke
Sleep-related breathing disorders are a risk factor for stroke andtransient ischemia (McArdle et al., 2003). Obstructive sleep apnea syn-drome (OSA) significantly increases the risk of stroke or death from anycause independently of other risk factors, including hypertension (Yaggiet al., 2005). The correlation between the OSA severity and plasmalevels of the procoagulant fibrinogen in stroke patients suggests a
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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 basallung functioning (Schanen et al., 2005). Asthma may directly cause ce-rebral hypoxemic episodes that can damage cerebral tissue if they areof sufficient duration and severity; indeed, stroke-like symptoms havebeen reported after severe asthma attacks (Morris et al., 1998). On theother hand, asthma can indirectly increase stroke risk by inducingblood hypertension, pulmonary hypertension, and AF (Salako andAjayi, 2000; Schanen et al., 2005).
Although impaired lung function due to chronic lung inflammationinduces a low-grade systemic inflammatory response that affectsblood vessels (Tamagawa and van Eeden, 2006), the mechanisms un-derlying the association between reduced lung function and ischemicstroke incidence are as yet unclear. It is therefore critical to identifymechanisms throughwhich lung impairment influences atherosclerosisand triggers acute vascular events such as stroke.
6. Brain and liver
The liver is responsible for the synthesis andmetabolismof blood co-agulation factors and fibrinolytic enzymes that play important roles inthe pathophysiology of stroke. The hypothalamus signals to peripheralorgans such as the liver by stimulating autonomic nerves and by releas-ing 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 asso-ciated with the activation of extracellular signal-regulated kinase, c-junN-terminal kinase, and caspase-3, as well as increases in tumor necrosisfactorα level and DNA fragmentation in rat striatum and liver, suggest-ing the activation of inflammatory and apoptotic responses (Ottaniet al., 2009). In addition, during the acute phase of stroke, the levels ofliver enzymes such as γ-glutamyl transpeptidase and glutamate-oxaloacetate transaminase (GOT) increase, while that of unconjugatedbilirubin decreases; these events are linked to inflammation (Muscariet al., 2014). Glutamate released from cerebral infarct tissue enters thecerebrospinalfluid and bloodstream(Castillo et al., 1996), and the resul-tant glutamate toxicity may trigger the synthesis of GOT (Muscari et al.,2014), a liver enzyme that exerts a protective function by metabolizingblood glutamate following stroke (Campos et al., 2011). Notably, de-creased serum GOT and increased glutamate levels are independentlyassociated with larger infarct volume and poor functional outcome at3 months (Campos et al., 2011; Muscari et al., 2014). Additional studiesare needed to clarify the link between cerebral infarct size and serumGOT levels.
6.2. Contribution of liver dysfunction to stroke
Liver dysfunction can affect stroke occurrence and prognosis. Earlyclinical studies have found that liver cirrhosis is a causal factor inspontaneous intracerebral hemorrhage (Niizuma et al., 1988b) and iscorrelated with ICH volume and re-bleeding (Niizuma et al., 1988a);moreover, the severity of liver cirrhosis is associated with ICH patientprognosis (Huang et al., 2008). On the contrary, a 9-year follow-upstudy revealed a trend of increased ICH incidence in patients withliver cirrhosis (Lai et al., 2011). Thus, there is controversy as to whetherICH incidence is associated with liver cirrhosis. Furthermore, it is un-clear why liver dysfunction is associated with a high risk for developingICH, but hemostatic dysregulation such as thrombocytopenia and coag-ulation disorders observed in these patients may play a significant role(Pluta et al., 2010). Antiplatelet therapy is an essential component of is-chemic stroke treatment and prevention (Jauch et al., 2013), while ab-normal liver function due to cirrhosis can induce a hemorrhagic state(Bianchini et al., 2014). Antiplatelet therapy is safe and effective for
Please cite this article as: Ma, S., et al., Peripheral to central: Organ interact10.1016/j.expneurol.2015.05.014
ischemic stroke prevention in patients with cirrhosis (Chen et al.,2012). Although a positive correlation has been observed betweenliver cirrhosis and intracerebral hemorrhaging, details of this interactionremain to be elucidated.
7. Brain and pancreas
The pancreas functions as a digestive organ and as part of the en-docrine system, and is innervated by automatic nerves. The brain–endocrine–pancreas axis secretes insulin to regulate blood glucoseconcentration (Uyama et al., 2004). Pancreatic dysfunction, includ-ing hypo- and hyperglycemia, can lead to metabolic disturbanceand cerebrovascular disease.
7.1. Pancreatic dysfunction induced by stroke
Stroke can alter the digestive functions of the pancreas. An earlyclinical study found that the levels of serum pancreatic enzymes, in-cluding amylase and lipase, were elevated in stroke patients (Pezzilliet al., 1997) possibly due to the action of the automatic nervous sys-tem (Larson et al., 1985). Acute stroke can also cause abnormal glucosemetabolism—known as stress hyperglycemia (SH) (Hafez et al., 2014;Kruyt et al., 2010)—which is usually resolved spontaneously after theacute phase of stroke (Dungan et al., 2009). SH during stroke is partlycaused by HPA axis activation, which leads to the release of catechol-amine that acts on theα2 receptor of pancreatic β cells, inhibiting insu-lin secretion (Dungan et al., 2009; Keahey et al., 1989). Increasedcatecholamine levels also cause insulin resistance (Dungan et al.,2009; Kruyt et al., 2010), which can exacerbate SH. These findings sug-gest that changes in serum pancreatic enzyme levels can have a non-pancreatic origin in stroke patients.
7.2. Contribution of pancreatic dysfunction to stroke
The risk of acute and recurrent ischemic stroke is higher in diabeticthan 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 ad-ministration of recombinant tissue plasminogen activator in patientswith large-vessel occlusion (Mandava et al., 2014); diabetes also in-creases the risk of long-term cognitive deficits, including post-strokedementia (Megherbi et al., 2003; Pendlebury and Rothwell, 2009).
Brain vasculature is severely compromised in diabetes (Elgebalyet al., 2011; Sima, 2010), which can impair autoregulation of cerebralblood flow—known as diabetic autonomic neuropathy (Mankovskyet al., 1996)—and thereby create a hypoxic environment that can triggercerebral neovascularization (Ergul et al., 2009; Kelly-Cobbs et al., 2012).Increased vascular endothelial growth factor and peroxynitrite forma-tion along with the downregulation of the guidance moleculeRoundabout-4 in diabetesmay contribute to perturbed cerebral neovas-cularization (Ergul et al., 2014). Additionally, matrix metalloproteinaseactivity is increased in a spontaneous type 2 diabetic rat model, whichleads to high vascular permeability and greater susceptibility to hemor-rhagic transformation after ischemia (Li et al., 2010; Prakash et al.,2012). These factors contribute to abnormal vascularization, which isassociated with increased risk and poor outcome in ischemic stroke pa-tients with diabetes or hyperglycemia. Although there is at present noconclusive evidence supporting the benefits of glucose-lowering treat-ment for stroke prevention in diabetes, reducing blood pressure in pa-tients 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 supplydeficiency in the ischemic penumbra—which reduce glucose and
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oxygen supplies—can contribute to brain damage after stroke. De-creasing glycemic variability may be associated with a better out-come in ischemic stroke (Gonzalez-Moreno et al., 2014). Whetherhyper- or hypoglycemia preconditioning can provide neuroprotec-tion during stroke requires further investigation.
8. Brain and the gastrointestinal (GI) system
The brain can modulate the GI system during stroke through auto-matic nervous system hyperactivation and systemic inflammation. Theintestinal immune system, consisting of Peyer's patches and individualimmune cells dispersed within the intestinal epithelium and the laminapropria, provides an immune barrier between gut microbiota and sys-temic circulation and is under the control of the sympathetic nervoussystem (Straub et al., 2006). The GI system undergoes various changesfollowing stroke, as detailed below.
8.1. GI dysfunction induced by stroke
Stroke disrupts communication between the central nervous andGI systems, leading to dysphagia, GI hemorrhage, delayed GI evacu-ation, and colorectal dysfunction (Schaller et al., 2006). Gastroduo-denal ulcers and GI bleeding are the most common complicationsin the acute and chronic stages of ischemic stroke and are associatedwith poor outcome (Camara-Lemarroy et al., 2014). A previous study
Please cite this article as: Ma, S., et al., Peripheral to central: Organ interact10.1016/j.expneurol.2015.05.014
found that the autonomic nervous and pituitary–adrenal systemshave 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 animalmodels, leading to diffuse edema in gastric mucosa, splinter hemor-rhage and erosion, endothelial cell necrosis, mucosal dissociation,and inflammatory cell infiltration (Feng et al., 2010). Cerebral ische-mia has variable effects on the cellularity of gut-associated lymphoidtissue, including a reduction in T and B cell counts in Peyer's patches(Schulte-Herbruggen et al., 2009). The loss of mucosal integrity andimmune cell dysfunction allows bacterial translocation (Tascilaret al., 2010). It has been suggested that a catecholamine-mediateddefect in early lymphocyte activation is a major cause of impairedantibacterial immune response after stroke in mice (Prass et al.,2003). Reduced gastric mucosal blood flow, stress, systemic inflamma-tion, and oxidative stressmay also contribute to post-stroke injury to GImucosa (Camara-Lemarroy et al., 2014; Hung, 2006; Kawakubo et al.,1996). Calcitonin gene-related peptide has been investigated for its po-tential function in protecting gastric mucosa after cerebral ischemia/re-perfusion (Feng et al., 2010).
8.2. Potential function of GI system on stroke
Helicobacter pylori is a Gram-negative bacterium that can causechronic gastritis, peptic ulcer disease, and gastric cancer (Correa,
on peripheral organs; blue arrows indicate the contribution of peripheral organs to stroke.mic nervous system; CKD, chronic kidney disease; CRP, C-reactive protein; γ-GT, gamma, hypothalamus–pituitary–adrenal; ICP, intracranial pressure; NPE, neurogenic pulmonaryg disorders; TTC, takotsubo cardiomyopathy.
ions in stroke pathophysiology, Exp. Neurol. (2015), http://dx.doi.org/
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1997; Marshall and Warren, 1984); it is detected in carotid athero-sclerotic lesions and is significantly associated with the incidenceof atherosclerotic ischemic stroke (Rozankovic et al., 2011). Therole of H. pylori in the pathogenesis of atherosclerosis may be relatedto an autoimmune mechanism that destabilizes carotid atheroscle-rotic plaques, leading to thrombosis and acute ischemic stroke(Rozankovic et al., 2011). H. pylori infection can induce the break-down of the blood–brain barrier via release of inflammatory media-tors, which may underlie the pathogenesis of various neuropathiesincluding stroke (Kountouras, 2009; Zhang et al., 2008), althoughthe link betweenH. pylori infection and ischemic stroke has been dis-puted by other studies (Heuschmann et al., 2001; Yu et al., 2014).H. pylori infection is treatable, which has important implications forstroke prevention and treatment if a physiological connection doesin fact exist.
9. Conclusion
This review described the interactions during stroke between thebrain and peripheral organs (Fig. 3), which are anatomically and func-tionally linked via the automatic nervous system by humoral regulationand direct innervation. The interaction between the brain and immunesystem is well-established and affects other organ systems and conse-quently, the outcome of stroke. Obviously, neuro-immunology plays adominant role in all the organ interactions discussed, especially inrenal dysfunction and stroke, splenic changes after stroke, and pulmo-nary diseases and stroke. In addition, arrhythmias, TTC, and AMI alsoserve as an important part in neurocardiology. Of notice, among theorgan interactions discussed, brain and pancreas crosstalk has receivedmore attention than the others due to the close relationship between di-abetes and stroke. The other manifestations after stroke that need to beconcerned include severe NPE, increased serum level of GOT and γ-GTrelated with liver damage. Moreover, gastrointestinal bleeding presentsas the common complication of stroke. Thus, understanding the molec-ular basis of these interactions is critical for stroke prevention and treat-ment. However, many outstanding questions remain. For instance, howthe interactions between central and peripheralmechanisms contributeto stroke progression and prognosis must be clarified. Themorbidity as-sociatedwith stroke is not fully understood, and there is a lack of exper-imental models that can recapitulate all of its aspects (Xi et al., 2014);this is exemplified by the variability in behavioral deficits and patternsof recovery after stroke among different rat strains (Kunze et al.,2014). Addressing these issues will lead to greater progress in our un-derstanding of stroke pathophysiology in the context of interactions be-tween the brain and peripheral organs and the development of moreeffective treatments.
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