Neuregulin-1 attenuates mortality associated with experimental cerebral malaria
- Wesley Solomon†1Email author,
- Nana O Wilson1,
- Leonard Anderson†2,
- Sidney Pitts†3,
- John Patrickson†3,
- Mingli Liu†1,
- Byron D Ford†4 and
- Jonathan K Stiles†1Email author
© Solomon et al.; licensee BioMed Central Ltd. 2014
Received: 20 September 2013
Accepted: 23 December 2013
Published: 17 January 2014
Cerebral Malaria (CM) is a diffuse encephalopathy caused by Plasmodium falciparum infection. Despite availability of antimalarial drugs, CM-associated mortality remains high at approximately 30% and a subset of survivors develop neurological and cognitive disabilities. While antimalarials are effective at clearing Plasmodium parasites they do little to protect against CM pathophysiology and parasite-induced brain inflammation that leads to seizures, coma and long-term neurological sequelae in CM patients. Thus, there is urgent need to explore therapeutics that can reduce or prevent CM pathogenesis and associated brain inflammation to improve survival. Neuregulin-1 (NRG-1) is a neurotrophic growth factor shown to protect against brain injury associated with acute ischemic stroke (AIS) and neurotoxin exposure. However, this drug has not been tested against CM-associated brain injury. Since CM-associated brain injuries and AIS share similar pathophysiological features, we hypothesized that NRG-1 will reduce or prevent neuroinflammation and brain damage as well as improve survival in mice with late-stage experimental cerebral malaria (ECM).
We tested the effects of NRG-1 on ECM-associated brain inflammation and mortality in P. berghei ANKA (PbA)-infected mice and compared to artemether (ARM) treatment; an antimalarial currently used in various combination therapies against malaria.
Treatment with ARM (25 mg/kg/day) effectively cleared parasites and reduced mortality in PbA-infected mice by 82%. Remarkably, NRG-1 therapy (1.25 ng/kg/day) significantly improved survival against ECM by 73% despite increase in parasite burden within NRG-1-treated mice. Additionally, NRG-1 therapy reduced systemic and brain pro-inflammatory factors TNFalpha, IL-6, IL-1alpha and CXCL10 and enhanced anti-inflammatory factors, IL-5 and IL-13 while decreasing leukocyte accumulation in brain microvessels.
This study suggests that NRG-1 attenuates ECM-associated brain inflammation and injuries and may represent a novel supportive therapy for the management of CM.
KeywordsNeuregulin-1 (NRG-1) Pro-inflammatory Anti-inflammatory Blood–brain barrier (BBB) Inflammation Plasmodium berghei ANKA (PbA) Adjunctive therapy Malaria Cerebral malaria (CM) Brain injury
Nearly 300 million persons each year are infected with Plasmodium falciparum (P. falciparum) infection, a subset of whom may develop severe anemia or a diffuse encephalopathy known as cerebral malaria (CM) . CM accounts for 110,000 deaths annually in children and one in four survivors develop neurological complications (cortical blindness, epilepsy, and monoparesis) and cognitive disability (speech deficits, working memory, and executive function disability) [2–8]. Despite appropriate antimalarial treatment, mortality associated with CM may be as high as 30% in adults and 20% in children [7, 9–11]. Thus, targeting parasite in acute disease is not sufficient to ameliorate persistent neurological sequelae and mortality associated with CM. Understanding immunopathogenic features such as brain inflammation and injury leading to fatal CM have led to the identification and development of small molecules or immunotherapeutics that may be used to stabilize the blood–brain barrier (BBB) and ameliorate CM-associated brain damage and mortality [12–14]. However, most of these interventions administered as prophylactics to prevent development of neurological signs failed to reverse CM-associated brain injuries or resulted in minimal therapeutic benefit, whereas others were deleterious [13, 14]. The use of prophylactic strategies may not be clinically relevant as most patients who present to clinics have neurological abnormalities or clinical signs of CM. It is therefore important for new therapeutic strategies to ameliorate complications associated with late stages of CM to improve clinical outcomes while reducing risk of neurological sequelae in surviving CM patients. Clinical studies in human CM and murine experimental CM (ECM) indicate an exaggerated activation and dysregulation of host inflammatory processes including brain endothelial activation, and disruption of the BBB during the pathogenesis of the disease [15–18]. In fact, extensive research has linked strong host pro-inflammatory response to malaria disease states [19–21] and genetic studies have identified several immune regulatory and effector loci that possess mutations associated with susceptibility and resistance to human severe (cerebral) malaria [22–24]. Efforts underway to identify candidate therapeutics against CM have produced promising candidates including artovastatin, a statin with strong anti-inflammatory effects that effectively attenuates ECM [25–27]. Thus, interventions aimed at modulating the deleterious hyper-inflammatory response to malaria infection while protecting against brain damage will potentially bolster therapeutics against severe malaria.
Neuregulin-1 (NRG-1) is a member of the neuregulin family of growth factors that promotes survival and function of neuronal cells [28–31]. Studies have shown that NRG-1 attenuates tissue damage and immunopathology in animal models of acute brain injury (ABI) such as acute ischemic stroke (AIS), traumatic brain injury (TBI), and nerve agent poisoning [32–37]. There are clear pathophysiological similarities between CM and AIS, including an exaggerated host expression of pro-inflammatory factors that lead to increased vascular endothelial activation with upregulation of adhesion molecules, glial activation, focal inflammation, activation of apoptotic pathways and eventually brain damage and death [38–40]. Exogenous treatment with NRG-1 has been shown to significantly alter or inactivate inflammatory pathways associated with tissue damage during ischemic episodes . Furthermore, NRG-1 reduces brain inflammation via inhibition of immune and oxidative stress mediators involved in the pathogenesis of focal ischemic brain damage . Although NRG-1 has been studied extensively in AIS it has yet to be studied as a potential intervention against cerebral malaria. Using the Plasmodium berghei (P. berghei) ANKA (PbA) model of ECM, we tested the hypothesis that NRG-1 will reduce or prevent ECM-associated inflammation and improve survival in mice with late stage ECM. We show here that NRG-1 (1.25 ng/kg/day) significantly reduces ECM-associated brain and systemic inflammation and improves survival in mice with late-stage ECM.
Infection of mice with P. bergheiANKA
Six- to eight-week-old C57BL/6 J mice (Charles Rivers Laboratories, Wilmington, MA, USA) were housed in groups of four per cage on a 12 hr light/12 hr dark cycle with access to food ad libitum and water. Mice were allowed to acclimatize to their new environment for 3 days before experimentation. All experimental procedures were reviewed and approved by the Morehouse School of Medicine Institutional Animal Care and Use Committee (Permit Number 09–06). Procedures were performed with strict adherence to national regulations on animal care and experimentation with the use of Care of Laboratory Animal Resources (CLAR) guidelines to minimize pain. PbA was obtained from MR4, Manassas, VA, USA (BEI Resources Repository, NIAID, NIH; MR4 number MRA-311, deposited by TF McCutchan). Parasites were propagated in C57BL/6 J mice and a fresh blood sample from a passage mouse was used for each experiment. Experimental groups of mice were infected via intraperitoneal (i.p.) injection of 106 PbA-infected red blood cells (pRBCs). Mice were sham-injected with 106 non-infected red blood cells (RBCs).
Clinical assessment of ECM
All animals were checked several times daily for mortality and ECM symptoms. For better estimation of the overall clinical status of mice during infection, simple behavioral tests (transfer arousal, locomotor activity, tail elevation, wire maneuver, contact righting reflex, and righting in arena) adapted from the SmithKline Beecham, Harwell, Imperial College, Royal London Hospital, phenotype assessment (SHIRPA) protocol [41–43] were used. Infected mice display signs of ECM by day 5 or 6 post infection . ECM is defined as the presentation of one or more signs of neurological deficit including ataxia, convulsions, limb paralysis, poor righting reflex, roll-over and coma . Presentation of these signs were evaluated and scored to better assess severity of ECM in mice .
Assessment of NRG-1 and artemether treatment in mice infected with or without PbA
Mice were selected and randomized into treatment groups after diagnosis with ECM on day 5 to 6 post infection. For survival experiments, 11 mice per group were used to obtain significant statistical data. To determine the therapeutic benefit of NRG-1 on ECM-associated brain damage and mortality and to compare NRG-1 with artemether (ARM) treatment, PbA-infected mice were treated daily via i.p. injection with 50-μl doses of NRG-1 (1.25 ng/kg/day, EGF-like domain, R & D Systems, Minneapolis, MN, USA) [NP_039250] or artemether prepared in coconut oil (25 mg/kg/day, Sigma-Aldrich, St Louis, MO, USA), from day 6 to day 9 post infection. PbA-infected mice treated daily with 50 μl saline solution (i.p.) from day 6 to day 9 post infection were used as the control. Mice were checked several times daily for mortality and signs of ECM neurological symptoms such as ataxia, loss of reflex and hemiplegia. All murine ECM experiments were terminated 19 days after PbA infection with animals euthanized accordingly. Parasite load was monitored periodically (beginning on day 5 post infection) by Giemsa staining of thin blood smears and assessed by counting the number of pRBCs per 1,000 erythrocytes.
Assessment of leukocyte accumulation in brain parenchymal vessels during murine ECM in PbA-infected mice by H&E staining
To determine the effect of NRG-1 and ARM treatment on leukocyte accumulation in brain parenchymal vessels during murine ECM pathogenesis, PbA-infected C57BL/6 J mice were anesthetized with isoflurane inhalation and euthanized on day 5 and day 11 post infection. Mice were perfused with 10 ml of cold sterile phosphate-buffered saline to clear vessels of blood prior to collection of brain tissue (three mice per time point per treatment group). Whole brains were stored in formalin for fixation, embedded in paraffin, and sectioned at 10 μm. Sagittal sections of the brain (day 5 and day 11 post infection) were fixed in 4% paraformaldehyde and blocked with horse serum for 30 minutes at room temperature. Sections were stained with H&E and leukocytes in the blood vessels were quantified using an ocular grid calibrated with a × 400 magnification in an Axioskop 2 Plus microscope (Carl Zeiss Microscopy, Thornwood, NY, USA). The whole area of each section was similarly quantified with the ocular grid calibrated at × 40 magnification. Digital photos were captured by a high-resolution AxioCam HRc camera (Carl Zeiss Microscopy).
Determination of the effect of NRG-1 on mRNA expression of factors involved in vascular endothelial activation and BBB integrity
Primer sequences used
Target gene or mRNA
Primer 5′ - 3′
The quantitative real-time PCR assay was performed using Bio-Rad C1000 thermal cycler (Bio-Rad Laboratories). Approximately 20 ng of cDNA was used in each 25 μl PCR reaction using the Bio-Rad iQ™ SYBR® Green Supermix (Bio-Rad Laboratories, Hercules, CA) and 50 μM of each primer. After a 15-minute incubation at 95°C, amplification was achieved by 39 cycles of a 15-s denaturation incubation at 95°C, followed by a 30-s annealing incubation at 55°C and 30-s extension incubation at 72°C. The identity and purity of the PCR product was confirmed by using dissociation curves and by checking the melting temperature of the PCR product, independently of the PCR reaction. To determine the relative amount of target cDNA present, the cycles to threshold (Ct) values of the target genes were compared with the basal expression of the housekeeping gene, hypoxanthine guanine phosphoribosyltransferase (HPRT). The average amount of HPRT present in each mouse group was used to normalized the quantity of target mRNA sequence against total RNA in each reaction. The differences in Ct values between HPRT and target gene of day 11 after infection of each group were compared with day 5 after infection-untreated control samples to determine the relative change in mRNA expression.
Assessment of NRG-1 effects on expression of immune determinants of CM severity
To determine the effect of NRG-1 and ARM treatment on cytokine/chemokine levels, serum collected from blood harvested via cardiac puncture at pre-treatment (day 0 and day 5) and post treatment (day 11) from anesthetized mice (three to four mice per treatment group per day; pooled) was measured for levels of TNFα, IL-1α, IL-6, chemokine (C-X-C motif) ligand 10 (CXCL10), granulocyte colony stimulating factor (G-CSF), IL-5, and IL-13. Pooled serum samples were evaluated using Milliplex MAP mouse Cytokine/Chemokine bead-based immunoassay (Millipore, Billerica, MA, USA) coupled with the Luminex 200™ system (Austin, TX, USA) according to the manufacturer’s protocol. Samples were tested at a 1:2 dilution using optimal concentrations of standards and antibodies according to the manufacturer’s protocol.
Results were expressed as means ± SD from at least three separate experiments performed in triplicate unless otherwise stated. Differences between means among the treatment groups were analyzed by using the Student t-test or one-way analysis of variance (ANOVA) with Holm-Sidak post-test methods where appropriate. Differences in survival among treatment groups were analyzed with Mantel-Cox log rank test. A P-value less than 0.05 was considered significant. Statistical analysis was performed with SigmaPlot (Version 10.0) with SigmaStat (Version 3.5) software for windows.
This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The Institutional Animal Care and Usage Committee (IACUC) of Morehouse School of Medicine (Permit Number 09–06) approved all protocols.
NRG-1 therapy attenuates ECM-associated mortality
NRG-1 effect on parasite load was assessed before and after treatment. Parasite load in saline-treated mice increased markedly from day 5 to day 11 post infection by which time all the mice had been euthanized (Figure 1A and B). ARM treatment significantly reduced parasite load in PbA-infected mice as expected from 21% on day 5 post infection to <5% by day 11 post infection when compared with saline-treated mice on day 11 post infection, P <0.001 (Figure 1B). NRG-1-treated mice demonstrated improved survival despite no significant difference in parasite load compared to saline-treated mice (Figure 1A and B) suggesting that NRG-1 mediated attenuation of ECM was not via the reduction of parasite burden.
NRG-1 treatment reduces leukocyte accumulation in brain microvasculature of PbA-infected mice
NRG-1 treatment decreases activation of brain vascular endothelium and promotes BBB stability in PbA-infected mice
Overproduction of pro-inflammatory factors promotes vascular endothelial activation and is deleterious to BBB integrity . To investigate the effect of NRG-1 on activation of brain vascular endothelium and BBB integrity during ECM, mRNA levels of specific protein markers (angiopoietin-1 and -2, CCAAT enhancer-binding protein (C/EBP)β, and intercellular adhesion molecule-1 (ICAM-1)) that mediate endothelial activation [47–49] and BBB breakdown [50, 51] were assessed.
C/EBPβ is a critical regulator of acute-phase pro-inflammatory genes involved in host response to infections [55, 56] and is implicated in the release of inflammatory and adhesion factors such as IL-6, TNFα, CD40, ICAM-1 and bioactive tachykinins responsible for neuroinflammation and tissue repair in the central nervous system [57–62]. C/EBPβ expression was significantly reduced in ARM-treated and NRG-1-treated mice compared to saline-treated mice, P <0.001 (Figure 3C). Expression of C/EBPβ increased significantly in the brains of saline-treated mice when compared to day 5 untreated mice, P <0.001 (Figure 3C). Expression of ICAM-1 which directly correlates with endothelial activation [47, 63, 64] was significantly reduced in brain of NRG-1 treated mice compared to saline-treated mice, P <0.001 (Figure 3D). ICAM-1 expression in NRG-1-treated mice was reduced to levels lower than that observed in day-5 untreated mice (Figure 3D). However, ICAM-1 expression increased significantly in saline-treated and ARM-treated mice compared to day-5 untreated controls, P <0.001 (Figure 3D).
NRG-1 treatment modulates immune determinants of CM severity
Despite prompt administration of optimal antimalarial treatment, mortality associated with CM remains unacceptably high, thus, prompting the development of adjunct therapeutics that can reduce or prevent CM pathology and associated mortalities [12, 13] Recent studies have shown that NRG-1 was effective in treating ABI such as AIS and acute neurotoxin exposure by preventing neuroinflammation and neuronal tissue death [35, 36], which are similar to those observed in CM. Furthermore, NRG-1 stabilizes the BBB and mediates inflammatory pathways to prevent tissue damage associated with brain injury [32, 33, 37]. Using a PbA ECM model that mimics significant features of human CM, we have demonstrated the effectiveness of NRG-1 therapy against ECM pathophysiology, and associated mortality.
Advances in drug therapies that eradicate malaria parasites are still unable to prevent mortality in up to 30% of CM patients. In humans, quinine and artemisinin derivatives (artesunate and artemether) are the mainstream drugs used to treat CM [81, 82]. ARM was selected for use in this study as previous research has demonstrated that ARM was more effective against murine ECM than quinine, artemisinin and artesunate . Despite anti-parasitic properties of ARM, mortality rates were as high as 18% in mice treated with ARM in the current study. However, no evidence of neurological dysfunction associated with ECM was observed in ARM-treated mice. This unacceptably high mortality in ARM-treated mice may be due to low efficacy of ARM against PbA that can lead to recrudescence and malarial anemia post treatment . Furthermore, therapies targeting parasite eradication without addressing secondary effects of parasite infection, such as tissue damage and neurological complications, are inadequate for preventing mortalities. Thus, there is great need for adjunct therapeutics that target CM pathology that in conjunction with parasite-eradicating antimalarial agents can prevent mortality associated with CM.
Permanent or reversible neurological sequelae such as coma, residual epilepsy and cognitive deficits, are common clinical outcomes in CM patients. These neurological outcomes are associated with inflammatory cascades initiated by pathogen toxins that lead to widespread endothelial activation and brain damage (petechial hemorrhage and neuronal cell death) and involves inflammation-induced sequestration of infected RBCs [83–85]. Similarly, accumulation of leukocytes occurs in brain microvessels of PbA-infected mice that leads to vascular congestion and contributes to brain damage. [86, 87]. Although parasitemia levels were high in PbA-infected mice treated with NRG-1, there was significant reduction in leukocyte accumulation in brain microvessels after NRG-1 treatment. This indicates that NRG-1 therapy effectively reduces brain inflammation associated with ECM pathogenesis even in the presence of high parasitemia.
Human CM and murine ECM are characterized by a dysregulated immune response leading to overexpression of pro-inflammatory cytokines including TNFα, IL-1α, IL-6, and CXCL10 [67–69, 74, 75]. These cytokines are secreted by T-cells, macrophages and endothelial cells in response to infection and play several roles that include promotion of acute immune response, leukocyte recruitment, BBB disruption and negative hypothalamic mediation during febrile illness [66, 70, 88–93]. Plasma and cerebrospinal fluid levels of TNFα, IL-1α and IL-6 are increased in children with CM [20, 68] suggesting their role in human CM. We previously reported that increased plasma and cerebrospinal fluid levels of CXCL10 predict fatal CM [72–74] and mice deficient in the CXCL10 gene are partially protected against murine ECM . NRG-1 therapy significantly reduced serum TNFα, IL-1α, IL-6, and CXCL10 levels while improving survival against ECM. High serum levels of the growth factor G-CSF have been shown to correlate with fatal CM in humans . However, NRG-1 reduced G-CSF, suggesting amelioration of pathogenic pathways that leads to induction of G-CSF observed in fatal CM [20, 80]. Thus, further study is warranted to determine the role of G-CSF in severe disease and the NRG-1 protective effect in reducing G-CSF production. Furthermore, there is growing evidence of the role for anti-inflammatory factors, IL-5 and IL-13 in protection against malarial disease. In a population of south Asian malaria patients, increased levels of IL-5 was associated with reduced severity of disease . Genetic studies in African and south-east Asian populations have linked IL-13 to protection against cerebral malaria and show that polymorphisms that alter IL-13 production may increase risk of severe malaria [76–78]. In the present study, NRG-1 enhanced production of IL-5 and IL-13, and suggests NRG-1 promotes anti-inflammatory factors while dampening pro-inflammatory factors to ameliorate CM pathogenesis.
Angiopoietin-1 (a biomarker of endothelium quiescience and stability) and vascular permeability factor angiopoietin-2 (marker of vascular barrier breakdown) are potent modulators of vascular inflammation, endothelial activation and BBB function [49, 94–96]. Angiopoietin-1 stabilizes the vascular endothelium barrier  and regulates the activity of BBB permeability factors such as platelet-activating factor (PAF), vascular epithelial growth factor (VEGF), ELAM-1, bradykinin, thrombin and histamine [98–101]. Increased activity of angiopoietin-1 promotes endothelial survival [102, 103], modulates plasma leakage [100, 104, 105] and reduces vascular inflammation by inhibiting ICAM-1, vascular cell adhesion molecule-1 (VCAM-1) and E-selectin expression . Conversely, pro-inflammatory cytokines TNF-α, IL-1β and vascular permeability factor, VEGF, mediate the release of angiopoietin-2, an antagonist to angiopoietin-1 [48, 107], that promotes increased vascular inflammation , disruption of angiogenesis , endothelial cell death  and vascular regression [110, 111]. Moreover, angiopoietin-2 expression is elevated in response to endothelial activation, hypoxia and ischemia [107, 112–114]. In human CM, high levels of angiopoietin-2 and low levels of angiopoietin-1 are linked to CM severity and studies suggest these angiogenic factors function as prognostic biomarkers that can discriminate severe CM from mild malaria and predict fatal CM outcome [53, 54]. Nakaoka et al. show that NRG-1 stimulates expression of angiopoietin-1  and increased expression of angiopoietin-1 inhibits release or activity of angiopoietin-2 [107, 116]. In the present study, NRG-1 treatment increased expression of angiopoietin-1, thus promoting endothelial barrier function and integrity during ECM, while modulating angiopoietin-2 expression in the brains of PbA-infected mice.
Parasite sequestration and activation of endothelial cells by infected erythrocytes and pro-inflammatory cytokines are hallmark events in the brain pathology of pediatric CM patients [64, 117, 118]. Parasite sequestration and endothelial activation correlate with an increase in adhesion molecules such as ICAM-1 and VCAM-1 that bind infected erythrocytes, influence leukocyte migration and promote further release of pro-inflammatory cytokines [119–121]. ICAM-1 is a marker of endothelial activation whose expression is upregulated on the vascular endothelium in the brain in murine and human CM [64, 122–124]. ICAM expression is induced by pro-inflammatory cytokines such as TNF-α, IFN-γ and VEGF [47, 125, 126]. In human CM, increased ICAM-1 levels are associated with disease severity [63, 119, 127]. Furthermore, murine ECM studies show increased expression of ICAM-1 contributes to the development of ECM [47, 128, 129]. Previous studies indicate NRG-1 reduces the expression of ICAM-1 following ischemic stroke . NRG-1 increases activity of PI3-kinase [130, 131] which suppresses VEGF-mediated expression of ICAM-1 on endothelial cells [106, 126]. Additionally, C/EBPβ is a critical regulator of acute host-response to infections and neuroinflammation [55–58, 60] that stimulates release of inflammatory and adhesion factors such as IL-6, TNFα, CD40 and ICAM-1, thus contributing to ECM development [56–59, 61]. In this study, NRG-1 treatment of murine ECM demonstrated inhibition of ICAM-1 and C/EBPβ in the ECM brain while reducing leukocyte adhesiveness and accumulation in brain microvessels.
NRG-1 was recently used as a treatment for heart failure and showed significant efficacy for improving cardiac function in a phase-II patient study [132–134]. In this study, patients received placebo or NRG-1 at a dose of 0.3 to 1.2 μg/kg/day intravenously for 10 days, in addition to standard drug therapies. During a follow-up period 11 to 90 days after study initiation, NRG-1 significantly improved heart function in patients and the effective doses were shown to be safe and tolerable. Two additional clinical trials to determine the ability of NRG-1 to improve cardiac function after heart failure have been initiated in the US (ClinicalTrails.gov identifiers NCT01258387 and NCT01541202). During the period of study, no severe events were observed in either healthy or impaired patients.
The use of recombinant human NRG-1 against acute brain injury is being tested in experimental models [32, 34–36, 135, 136]. Recent and ongoing clinical trials provide evidence indicating efficacy and safety of recombinant human NRG-1 against chronic heart failure and vascular remodeling [132–134]. The efficacy of NRG-1 treatment against murine ECM provides compelling evidence for developing NRG-1 and NRG-like drugs for the treatment and management of CM patients. By inhibiting systemic and brain inflammation resulting from ECM pathogenesis, NRG-1 therapy improved survival in mice with late-stage ECM. The ability of NRG-1 to affect a range of functionally related CM inflammatory mediators increases the likelihood that such an effect will translate to human CM to protect against human CM pathologies. We propose further investigation of NRG-1 as a supportive therapy alongside current antimalarial agents in the management of CM.
Acute brain injury
Acute ischemic stroke
Analysis of variance
CCAAT enhancer-binding protein
Cycles to threshold
Chemokine (C-X-C motif) ligand
Experimental cerebral malaria
Granulocyte colony stimulating factor
Hematoxylin and eosin
Intercellular adhesion molecule-1
Plasmodium berghei ANKA
PbA-infected red blood cell
Red blood cell
Traumatic brain injury
Tumor necrosis factor
Vascular epithelial growth factor
Vascular cell adhesion molecule-1.
We thank Morehouse School of Medicine (MSM) Center for Laboratory Animal Resources staff for technical assistance in animal experiments. This work was financially supported by the National Institutes of Health grant numbers NIH-FIC (1T90-HG004151-01) for postdoctoral training in Genomics and Hemoglobinopathies, NIH/FIC/NINDS R21, NIH/NIMHD/8G12 MD007602, NHI-U01 NS 057993, NIH-U54 NS060659 and the CounterACT Program, NIH/NINDS/U01 NS 057993.
- World Health Organization: World Malaria Report 2011. http://www.who.int/malaria/world_malaria_report_2011/WMR2011_noprofiles_lowres.pdf.
- Bondi FS: The incidence and outcome of neurological abnormalities in childhood cerebral malaria: a long-term follow-up of 62 survivors. Trans R Soc Trop Med Hyg. 1992, 86: 17-19. 10.1016/0035-9203(92)90420-H.PubMedGoogle Scholar
- Brewster DR, Kwiatkowski D, White NJ: Neurological sequelae of cerebral malaria in children. Lancet. 1990, 336: 1039-1043. 10.1016/0140-6736(90)92498-7.PubMedGoogle Scholar
- Holding PA, Stevenson J, Peshu N, Marsh K: Cognitive sequelae of severe malaria with impaired consciousness. Trans R Soc Trop Med Hyg. 1999, 93: 529-534. 10.1016/S0035-9203(99)90368-1.PubMedGoogle Scholar
- Idro R, Kakooza-Mwesige A, Balyejjussa S, Mirembe G, Mugasha C, Tugumisirize J, Byarugaba J: Severe neurological sequelae and behaviour problems after cerebral malaria in Ugandan children. BMC Res Notes. 2010, 3: 104-10.1186/1756-0500-3-104.PubMedGoogle Scholar
- Boivin MJ, Bangirana P, Byarugaba J, Opoka RO, Idro R, Jurek AM, John CC: Cognitive impairment after cerebral malaria in children: a prospective study. Pediatrics. 2007, 119: e360-e366. 10.1542/peds.2006-2027.PubMedGoogle Scholar
- Murphy SC, Breman JG: Gaps in the childhood malaria burden in Africa: cerebral malaria, neurological sequelae, anemia, respiratory distress, hypoglycemia, and complications of pregnancy. Am J Trop Med Hyg. 2001, 64 (Suppl 1–2): 57-67.PubMedGoogle Scholar
- Meremikwu MM, Asindi AA, Ezedinachi E: The pattern of neurological sequelae of childhood cerebral malaria among survivors in Calabar, Nigeria. Cent Afr J Med. 1997, 43: 231-234.PubMedGoogle Scholar
- Idro R, Marsh K, John CC, Newton CR: Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome. Pediatr Res. 2010, 68: 267-274.PubMedGoogle Scholar
- Newton CR, Krishna S: Severe falciparum malaria in children: current understanding of pathophysiology and supportive treatment. Pharmacol Ther. 1998, 79: 1-53. 10.1016/S0163-7258(98)00008-4.PubMedGoogle Scholar
- Dondorp A, Nosten F, Stepniewska K, Day N, White N: Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet. 2005, 366: 717-725.PubMedGoogle Scholar
- Mishra SK, Wiese L: Advances in the management of cerebral malaria in adults. Curr Opin Neurol. 2009, 22: 302-307. 10.1097/WCO.0b013e32832a323d.PubMedGoogle Scholar
- Mohanty S, Patel DK, Pati SS, Mishra SK: Adjuvant therapy in cerebral malaria. Indian J Med Res. 2006, 124: 245-260.PubMedGoogle Scholar
- John CC, Kutamba E, Mugarura K, Opoka RO: Adjunctive therapy for cerebral malaria and other severe forms of Plasmodium falciparum malaria. Expert Rev Anti Infect Ther. 2010, 8: 997-1008. 10.1586/eri.10.90.PubMedGoogle Scholar
- Day NP, Hien TT, Schollaardt T, Loc PP, Chuong LV, Chau TT, Mai NT, Phu NH, Sinh DX, White NJ, Ho M: The prognostic and pathophysiologic role of pro- and antiinflammatory cytokines in severe malaria. J Infect Dis. 1999, 180: 1288-1297. 10.1086/315016.PubMedGoogle Scholar
- Brown H, Turner G, Rogerson S, Tembo M, Mwenechanya J, Molyneux M, Taylor T: Cytokine expression in the brain in human cerebral malaria. J Infect Dis. 1999, 180: 1742-1746. 10.1086/315078.PubMedGoogle Scholar
- Hansen DS: Inflammatory responses associated with the induction of cerebral malaria: lessons from experimental murine models. PLoS Pathog. 2012, 8: e1003045-10.1371/journal.ppat.1003045.PubMedGoogle Scholar
- Nacer A, Movila A, Baer K, Mikolajczak SA, Kappe SH, Frevert U: Neuroimmunological blood brain barrier opening in experimental cerebral malaria. PLoS Pathog. 2012, 8: e1002982-10.1371/journal.ppat.1002982.PubMedGoogle Scholar
- Hunt NH, Grau GE: Cytokines: accelerators and brakes in the pathogenesis of cerebral malaria. Trends Immunol. 2003, 24: 491-499. 10.1016/S1471-4906(03)00229-1.PubMedGoogle Scholar
- John CC, Panoskaltsis-Mortari A, Opoka RO, Park GS, Orchard PJ, Jurek AM, Idro R, Byarugaba J, Boivin MJ: Cerebrospinal fluid cytokine levels and cognitive impairment in cerebral malaria. Am J Trop Med Hyg. 2008, 78: 198-205.PubMedGoogle Scholar
- Schofield L, Grau GE: Immunological processes in malaria pathogenesis. Nat Rev Immunol. 2005, 5: 722-735. 10.1038/nri1686.PubMedGoogle Scholar
- Verra F, Mangano VD, Modiano D: Genetics of susceptibility to Plasmodium falciparum: from classical malaria resistance genes towards genome-wide association studies. Parasite Immunol. 2009, 31: 234-253. 10.1111/j.1365-3024.2009.01106.x.PubMedGoogle Scholar
- Driss A, Hibbert JM, Wilson NO, Iqbal SA, Adamkiewicz TV, Stiles JK: Genetic polymorphisms linked to susceptibility to malaria. Malar J. 2011, 10: 271.PubMedGoogle Scholar
- Hill AV: The immunogenetics of resistance to malaria. Proc Assoc Am Physicians. 1999, 111: 272-277. 10.1046/j.1525-1381.1999.99234.x.PubMedGoogle Scholar
- Taoufiq Z, Pino P, N’Dilimabaka N, Arrouss I, Assi S, Soubrier F, Rebollo A, Mazier D: Atorvastatin prevents Plasmodium falciparum cytoadherence and endothelial damage. Malar J. 2011, 10: 52.PubMedGoogle Scholar
- Wilson NO, Solomon W, Anderson L, Patrickson J, Pitts S, Bond V, Liu M, Stiles JK: Pharmacologic inhibition of CXCL10 in combination with anti-malarial therapy eliminates mortality associated with murine model of cerebral malaria. PLoS One. 2013, 8: e60898-10.1371/journal.pone.0060898.PubMedGoogle Scholar
- Achtman AH, Pilat S, Law CW, Lynn DJ, Janot L, Mayer ML, Ma S, Kindrachuk J, Finlay BB, Brinkman FS, Smyth GK, Hancock RE, Schofield L: Effective adjunctive therapy by an innate defense regulatory peptide in a preclinical model of severe malaria. Sci Transl Med. 2012, 4: 135-164.Google Scholar
- Li Y, Tennekoon GI, Birnbaum M, Marchionni MA, Rutkowski JL: Neuregulin signaling through a PI3K/Akt/Bad pathway in Schwann cell survival. Mol Cell Neurosci. 2001, 17: 761-767. 10.1006/mcne.2000.0967.PubMedGoogle Scholar
- Falls DL: Neuregulins: functions, forms, and signaling strategies. Exp Cell Res. 2003, 284: 14-30. 10.1016/S0014-4827(02)00102-7.PubMedGoogle Scholar
- Talmage DA: Mechanisms of neuregulin action. Novartis Found Symp. 2008, 289: 74-84. discussion 84–93PubMedGoogle Scholar
- Buonanno A, Fischbach GD: Neuregulin and ErbB receptor signaling pathways in the nervous system. Curr Opin Neurobiol. 2001, 11: 287-296. 10.1016/S0959-4388(00)00210-5.PubMedGoogle Scholar
- Xu Z, Ford GD, Croslan DR, Jiang J, Gates A, Allen R, Ford BD: Neuroprotection by neuregulin-1 following focal stroke is associated with the attenuation of ischemia-induced pro-inflammatory and stress gene expression. Neurobiol Dis. 2005, 19: 461-470. 10.1016/j.nbd.2005.01.027.PubMedGoogle Scholar
- Xu Z, Jiang J, Ford G, Ford BD: Neuregulin-1 is neuroprotective and attenuates inflammatory responses induced by ischemic stroke. Biochem Biophys Res Commun. 2004, 322: 440-446. 10.1016/j.bbrc.2004.07.149.PubMedGoogle Scholar
- Li Y, Xu Z, Ford GD, Croslan DR, Cairobe T, Li Z, Ford BD: Neuroprotection by neuregulin-1 in a rat model of permanent focal cerebral ischemia. Brain Res. 2007, 1184: 277-283.PubMedGoogle Scholar
- Li Y, Lein PJ, Liu C, Bruun DA, Giulivi C, Ford GD, Tewolde T, Ross-Inta C, Ford BD: Neuregulin-1 is neuroprotective in a rat model of organophosphate-induced delayed neuronal injury. Toxicol Appl Pharmacol. 2012, 262: 194-204. 10.1016/j.taap.2012.05.001.PubMedGoogle Scholar
- Xu Z, Croslan DR, Harris AE, Ford GD, Ford BD: Extended therapeutic window and functional recovery after intraarterial administration of neuregulin-1 after focal ischemic stroke. J Cereb Blood Flow Metab. 2006, 26: 527-535. 10.1038/sj.jcbfm.9600212.PubMedGoogle Scholar
- Lok J, Zhao S, Leung W, Seo JH, Navaratna D, Wang X, Whalen MJ, Lo EH: Neuregulin-1 effects on endothelial and blood–brain-barrier permeability after experimental injury. Transl Stroke Res. 2012, 3: S119-S124. 10.1007/s12975-012-0157-x.PubMedGoogle Scholar
- Stanimirovic D, Satoh K: Inflammatory mediators of cerebral endothelium: a role in ischemic brain inflammation. Brain Pathol. 2000, 10: 113-126.PubMedGoogle Scholar
- Kim JS, Chopp M, Chen H, Levine SR, Carey JL, Welch KM: Adhesive glycoproteins CD11a and CD18 are upregulated in the leukocytes from patients with ischemic stroke and transient ischemic attacks. J Neurol Sci. 1995, 128: 45-50. 10.1016/0022-510X(94)00203-Z.PubMedGoogle Scholar
- Stoll G, Jander S, Schroeter M: Inflammation and glial responses in ischemic brain lesions. Prog Neurobiol. 1998, 56: 149-171. 10.1016/S0301-0082(98)00034-3.PubMedGoogle Scholar
- Clemmer L, Martins YC, Zanini GM, Frangos JA, Carvalho LJ: Artemether and artesunate show the highest efficacies in rescuing mice with late-stage cerebral malaria and rapidly decrease leukocyte accumulation in the brain. Antimicrob Agents Chemother. 2011, 55: 1383-1390. 10.1128/AAC.01277-10.PubMedGoogle Scholar
- Lackner P, Beer R, Heussler V, Goebel G, Rudzki D, Helbok R, Tannich E, Schmutzhard E: Behavioural and histopathological alterations in mice with cerebral malaria. Neuropathol Appl Neurobiol. 2006, 32: 177-188. 10.1111/j.1365-2990.2006.00706.x.PubMedGoogle Scholar
- Martins YC, Werneck GL, Carvalho LJ, Silva BP, Andrade BG, Souza TM, Souza DO, Daniel-Ribeiro CT: Algorithms to predict cerebral malaria in murine models using the SHIRPA protocol. Malar J. 2010, 9: 85.PubMedGoogle Scholar
- Waknine-Grinberg JH, Hunt N, Bentura-Marciano A, McQuillan JA, Chan HW, Chan WC, Barenholz Y, Haynes RK, Golenser J: Artemisone effective against murine cerebral malaria. Malar J. 2010, 9: 227.PubMedGoogle Scholar
- Belnoue E, Kayibanda M, Vigario AM, Deschemin JC, Van Rooijen N, Viguier M, Snounou G, Renia L: On the pathogenic role of brain-sequestered alphabeta CD8+ T cells in experimental cerebral malaria. J Immunol. 2002, 169: 6369-6375.PubMedGoogle Scholar
- Faille D, El-Assaad F, Alessi MC, Fusai T, Combes V, Grau GE: Platelet-endothelial cell interactions in cerebral malaria: the end of a cordial understanding. Thromb Haemost. 2009, 102: 1093-1102.PubMedGoogle Scholar
- Favre N, Da Laperousaz C, Ryffel B, Weiss NA, Imhof BA, Rudin W, Lucas R, Piguet PF: Role of ICAM-1 (CD54) in the development of murine cerebral malaria. Microbes Infect. 1999, 1: 961-968. 10.1016/S1286-4579(99)80513-9.PubMedGoogle Scholar
- Fiedler U, Augustin HG: Angiopoietins: a link between angiogenesis and inflammation. Trends Immunol. 2006, 27 (12): 552-558. 10.1016/j.it.2006.10.004.PubMedGoogle Scholar
- Fiedler U, Reiss Y, Scharpfenecker M, Grunow V, Koidl S, Thurston G, Gale NW, Witzenrath M, Rosseau S, Suttorp N, Sobke A, Herrmann M, Preissner KT, Vajkoczy P, Augustin HG: Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med. 2006, 12: 235-239. 10.1038/nm1351.PubMedGoogle Scholar
- Nag S, Papneja T, Venugopalan R, Stewart DJ: Increased angiopoietin2 expression is associated with endothelial apoptosis and blood–brain barrier breakdown. Lab Invest. 2005, 85 (10): 1189-1198. 10.1038/labinvest.3700325.PubMedGoogle Scholar
- Pino P, Taoufiq Z, Nitcheu J, Vouldoukis I, Mazier D: Blood–brain barrier breakdown during cerebral malaria: suicide or murder?. Thromb Haemost. 2005, 94 (2): 336-340.PubMedGoogle Scholar
- Conroy AL, Lafferty EI, Lovegrove FE, Krudsood S, Tangpukdee N, Liles WC, Kain KC: Whole blood angiopoietin-1 and -2 levels discriminate cerebral and severe (non-cerebral) malaria from uncomplicated malaria. Malar J. 2009, 8: 295.PubMedGoogle Scholar
- Lovegrove FE, Tangpukdee N, Opoka RO, Lafferty EI, Rajwans N, Hawkes M, Krudsood S, Looareesuwan S, John CC, Liles WC, Kain KC: Serum angiopoietin-1 and -2 levels discriminate cerebral malaria from uncomplicated malaria and predict clinical outcome in African children. PLoS One. 2009, 4: e4912-10.1371/journal.pone.0004912.PubMedGoogle Scholar
- Jain V, Lucchi NW, Wilson NO, Blackstock AJ, Nagpal AC, Joel PK, Singh MP, Udhayakumar V, Stiles JK, Singh N: Plasma levels of angiopoietin-1 and -2 predict cerebral malaria outcome in Central India. Malar J. 2011, 10: 383.PubMedGoogle Scholar
- Alam T, An MR, Papaconstantinou J: Differential expression of three C/EBP isoforms in multiple tissues during the acute phase response. J Biol Chem. 1992, 267: 5021-5024.PubMedGoogle Scholar
- Baumann H, Morella KK, Campos SP, Cao Z, Jahreis GP: Role of CAAT-enhancer binding protein isoforms in the cytokine regulation of acute-phase plasma protein genes. J Biol Chem. 1992, 267: 19744-19751.PubMedGoogle Scholar
- Poli V: The role of C/EBP isoforms in the control of inflammatory and native immunity functions. J Biol Chem. 1998, 273: 29279-29282. 10.1074/jbc.273.45.29279.PubMedGoogle Scholar
- Fields J, Ghorpade A: C/EBPbeta regulates multiple IL-1beta-induced human astrocyte inflammatory genes. J Neuroinflammation. 2012, 9: 177-10.1186/1742-2094-9-177.PubMedGoogle Scholar
- Natsuka S, Akira S, Nishio Y, Hashimoto S, Sugita T, Isshiki H, Kishimoto T: Macrophage differentiation-specific expression of NF-IL6, a transcription factor for interleukin-6. Blood. 1992, 79: 460-466.PubMedGoogle Scholar
- Kovacs KA, Steinmann M, Magistretti PJ, Halfon O, Cardinaux JR: C/EBPbeta couples dopamine signalling to substance P precursor gene expression in striatal neurones. J Neurochem. 2006, 98: 1390-1399. 10.1111/j.1471-4159.2006.03957.x.PubMedGoogle Scholar
- Greenwel P, Tanaka S, Penkov D, Zhang W, Olive M, Moll J, Vinson C, Di Liberto M, Ramirez F: Tumor necrosis factor alpha inhibits type I collagen synthesis through repressive CCAAT/enhancer-binding proteins. Mol Cell Biol. 2000, 20: 912-918. 10.1128/MCB.20.3.912-918.2000.PubMedGoogle Scholar
- Maggi CA: The effects of tachykinins on inflammatory and immune cells. Regul Pept. 1997, 70: 75-90. 10.1016/S0167-0115(97)00029-3.PubMedGoogle Scholar
- Armah H, Wired EK, Dodoo AK, Adjei AA, Tettey Y, Gyasi R: Cytokines and adhesion molecules expression in the brain in human cerebral malaria. Int J Environ Res Public Health. 2005, 2: 123-131. 10.3390/ijerph2005010123.PubMedGoogle Scholar
- Turner GD, Morrison H, Jones M, Davis TM, Looareesuwan S, Buley ID, Gatter KC, Newbold CI, Pukritayakamee S, Nagachinta B, White NJ, Berendt AR: An immunohistochemical study of the pathology of fatal malaria. Evidence for widespread endothelial activation and a potential role for intercellular adhesion molecule-1 in cerebral sequestration. Am J Pathol. 1994, 145: 1057-1069.PubMedGoogle Scholar
- De Kossodo S, Grau GE: Role of cytokines and adhesion molecules in malaria immunopathology. Stem Cells. 1993, 11: 41-48. 10.1002/stem.5530110108.PubMedGoogle Scholar
- De Vries HE, Blom-Roosemalen MC, Van Oosten M, De Boer AG, Van Berkel TJ, Breimer DD, Kuiper J: The influence of cytokines on the integrity of the blood–brain barrier in vitro. J Neuroimmunol. 1996, 64: 37-43. 10.1016/0165-5728(95)00148-4.PubMedGoogle Scholar
- Jakobsen PH, McKay V, Morris-Jones SD, McGuire W, Van Hensbroek MB, Meisner S, Bendtzen K, Schousboe I, Bygbjerg IC, Greenwood BM: Increased concentrations of interleukin-6 and interleukin-1 receptor antagonist and decreased concentrations of beta-2-glycoprotein I in Gambian children with cerebral malaria. Infect Immun. 1994, 62: 4374-4379.PubMedGoogle Scholar
- Kwiatkowski D, Hill AV, Sambou I, Twumasi P, Castracane J, Manogue KR, Cerami A, Brewster DR, Greenwood BM: TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria. Lancet. 1990, 336: 1201-1204. 10.1016/0140-6736(90)92827-5.PubMedGoogle Scholar
- Lyke KE, Burges R, Cissoko Y, Sangare L, Dao M, Diarra I, Kone A, Harley R, Plowe CV, Doumbo OK, Sztein MB: Serum levels of the proinflammatory cytokines interleukin-1 beta (IL-1beta), IL-6, IL-8, IL-10, tumor necrosis factor alpha, and IL-12(p70) in Malian children with severe Plasmodium falciparum malaria and matched uncomplicated malaria or healthy controls. Infect Immun. 2004, 72: 5630-5637. 10.1128/IAI.72.10.5630-5637.2004.PubMedGoogle Scholar
- Netea MG, Kullberg BJ, Van der Meer JW: Circulating cytokines as mediators of fever. Clin Infect Dis. 2000, 31 (Suppl 5): S178-S184.PubMedGoogle Scholar
- Thornton P, McColl BW, Greenhalgh A, Denes A, Allan SM, Rothwell NJ: Platelet interleukin-1alpha drives cerebrovascular inflammation. Blood. 2010, 115: 3632-3639. 10.1182/blood-2009-11-252643.PubMedGoogle Scholar
- Armah HB, Wilson NO, Sarfo BY, Powell MD, Bond VC, Anderson W, Adjei AA, Gyasi RK, Tettey Y, Wiredu EK, Tongren JE, Udhayakumar V, Stiles JK: Cerebrospinal fluid and serum biomarkers of cerebral malaria mortality in Ghanaian children. Malar J. 2007, 6: 147.PubMedGoogle Scholar
- Jain V, Armah HB, Tongren JE, Ned RM, Wilson NO, Crawford S, Joel PK, Singh MP, Nagpal AC, Dash AP, Udhayakumar V, Singh N, Stiles JK: Plasma IP-10, apoptotic and angiogenic factors associated with fatal cerebral malaria in India. Malar J. 2008, 7: 83.PubMedGoogle Scholar
- Wilson NO, Jain V, Roberts CE, Lucchi N, Joel PK, Singh MP, Nagpal AC, Dash AP, Udhayakumar V, Singh N, Stiles JK: CXCL4 and CXCL10 predict risk of fatal cerebral malaria. Dis Markers. 2011, 30: 39-49. 10.1155/2011/828256.PubMedGoogle Scholar
- Campanella GS, Tager AM, El Khoury JK, Thomas SY, Abrazinski TA, Manice LA, Colvin RA, Luster AD: Chemokine receptor CXCR3 and its ligands CXCL9 and CXCL10 are required for the development of murine cerebral malaria. Proc Natl Acad Sci USA. 2008, 105: 4814-4819. 10.1073/pnas.0801544105.PubMedGoogle Scholar
- Manjurano A, Clark TG, Nadjm B, Mtove G, Wangai H, Sepulveda N, Campino SG, Maxwell C, Olomi R, Rockett KR, Jeffreys A, Riley EM, Reyburn H, Drakeley C, MalariaGen Consortium: Candidate human genetic polymorphisms and severe malaria in a Tanzanian population. PLoS One. 2012, 7: e47463-10.1371/journal.pone.0047463.PubMedGoogle Scholar
- Naka I, Nishida N, Patarapotikul J, Nuchnoi P, Tokunaga K, Hananantachai H, Tsuchiya N, Ohashi J: Identification of a haplotype block in the 5q31 cytokine gene cluster associated with the susceptibility to severe malaria. Malar J. 2009, 8: 232.PubMedGoogle Scholar
- Ohashi J, Naka I, Patarapotikul J, Hananantachai H, Looareesuwan S, Tokunaga K: A single-nucleotide substitution from C to T at position -1055 in the IL-13 promoter is associated with protection from severe malaria in Thailand. Genes Immun. 2003, 4: 528-531. 10.1038/sj.gene.6364010.PubMedGoogle Scholar
- Prakash D, Fesel C, Jain R, Cazenave PA, Mishra GC, Pied S: Clusters of cytokines determine malaria severity in Plasmodium falciparum-infected patients from endemic areas of Central India. J Infect Dis. 2006, 194: 198-207. 10.1086/504720.PubMedGoogle Scholar
- John CC, Park GS, Sam-Agudu N, Opoka RO, Boivin MJ: Elevated serum levels of IL-1ra in children with Plasmodium falciparum malaria are associated with increased severity of disease. Cytokine. 2008, 41: 204-208. 10.1016/j.cyto.2007.12.008.PubMedGoogle Scholar
- Pasvol G: The treatment of complicated and severe malaria. Br Med Bull. 2005, 75–76: 29-47.PubMedGoogle Scholar
- World Health Organization: Guidelines for the treatment of malaria, second edition. http://whqlibdoc.who.int/publications/2010/9789241547925_eng.pdf.
- Aikawa M, Iseki M, Barnwell JW, Taylor D, Oo MM, Howard RJ: The pathology of human cerebral malaria. Am J Trop Med Hyg. 1990, 43 (2 Pt 2): 30-37.PubMedGoogle Scholar
- Angulo I, Fresno M: Cytokines in the pathogenesis of and protection against malaria. Clin Diagn Lab Immunol. 2002, 9: 1145-1152.PubMedGoogle Scholar
- Idro R, Jenkins NE, Newton CR: Pathogenesis, clinical features, and neurological outcome of cerebral malaria. Lancet Neurol. 2005, 4: 827-840. 10.1016/S1474-4422(05)70247-7.PubMedGoogle Scholar
- Hearn J, Rayment N, Landon DN, Katz DR, De Souza JB: Immunopathology of cerebral malaria: morphological evidence of parasite sequestration in murine brain microvasculature. Infect Immun. 2000, 68: 5364-5376. 10.1128/IAI.68.9.5364-5376.2000.PubMedGoogle Scholar
- Baptista FG, Pamplona A, Pena AC, Mota MM, Pied S, Vigario AM: Accumulation of Plasmodium berghei-infected red blood cells in the brain is crucial for the development of cerebral malaria in mice. Infect Immun. 2010, 78: 4033-4039. 10.1128/IAI.00079-10.PubMedGoogle Scholar
- Castell JV, Gomez-Lechon MJ, David M, Andus T, Geiger T, Trullenque R, Fabra R, Heinrich PC: Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes. FEBS Lett. 1989, 242: 237-239. 10.1016/0014-5793(89)80476-4.PubMedGoogle Scholar
- Heinrich PC, Castell JV, Andus T: Interleukin-6 and the acute phase response. Biochem J. 1990, 265: 621-636.PubMedGoogle Scholar
- Campbell IL, Abraham CR, Masliah E, Kemper P, Inglis JD, Oldstone MB, Mucke L: Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc Natl Acad Sci USA. 1993, 90: 10061-10065. 10.1073/pnas.90.21.10061.PubMedGoogle Scholar
- Issekutz AC, Issekutz TB: Quantitation and kinetics of blood monocyte migration to acute inflammatory reactions, and IL-1 alpha, tumor necrosis factor-alpha, and IFN-gamma. J Immunol. 1993, 151: 2105-2115.PubMedGoogle Scholar
- Issekutz AC, Lopes N, Issekutz TB: Role of interleukin-1 and tumour necrosis factor in leukocyte recruitment to acute dermal inflammation. Mediators Inflamm. 1992, 1: 347-353. 10.1155/S0962935192000528.PubMedGoogle Scholar
- Miu J, Mitchell AJ, Muller M, Carter SL, Manders PM, McQuillan JA, Saunders BM, Ball HJ, Lu B, Campbell IL, Hunt NH: Chemokine gene expression during fatal murine cerebral malaria and protection due to CXCR3 deficiency. J Immunol. 2008, 180: 1217-1230.PubMedGoogle Scholar
- Minhas N, Xue M, Fukudome K, Jackson CJ: Activated protein C utilizes the angiopoietin/Tie2 axis to promote endothelial barrier function. Faseb J. 2010, 24: 873-881. 10.1096/fj.09-134445.PubMedGoogle Scholar
- Fagiani E, Christofori G: Angiopoietins in angiogenesis. Cancer Lett. 2013, 328: 18-26. 10.1016/j.canlet.2012.08.018.PubMedGoogle Scholar
- Tsigkos S, Koutsilieris M, Papapetropoulos A: Angiopoietins in angiogenesis and beyond. Expert Opin Investig Drugs. 2003, 12: 933-941. 10.1517/135437184.108.40.2063.PubMedGoogle Scholar
- Jeansson M, Gawlik A, Anderson G, Li C, Kerjaschki D, Henkelman M, Quaggin SE: Angiopoietin-1 is essential in mouse vasculature during development and in response to injury. J Clin Invest. 2011, 121: 2278-2289. 10.1172/JCI46322.PubMedGoogle Scholar
- Gamble JR, Drew J, Trezise L, Underwood A, Parsons M, Kasminkas L, Rudge J, Yancopoulos G, Vadas MA: Angiopoietin-1 is an antipermeability and anti-inflammatory agent in vitro and targets cell junctions. Circ Res. 2000, 87: 603-607. 10.1161/01.RES.87.7.603.PubMedGoogle Scholar
- Gavard J, Patel V, Gutkind JS: Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia. Dev Cell. 2008, 14: 25-36. 10.1016/j.devcel.2007.10.019.PubMedGoogle Scholar
- Pizurki L, Zhou Z, Glynos K, Roussos C, Papapetropoulos A: Angiopoietin-1 inhibits endothelial permeability, neutrophil adherence and IL-8 production. Br J Pharmacol. 2003, 139: 329-336. 10.1038/sj.bjp.0705259.PubMedGoogle Scholar
- Jho D, Mehta D, Ahmmed G, Gao XP, Tiruppathi C, Broman M, Malik AB: Angiopoietin-1 opposes VEGF-induced increase in endothelial permeability by inhibiting TRPC1-dependent Ca2 influx. Circ Res. 2005, 96: 1282-1290. 10.1161/01.RES.0000171894.03801.03.PubMedGoogle Scholar
- Jones N, Iljin K, Dumont DJ, Alitalo K: Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nat Rev Mol Cell Biol. 2001, 2: 257-267. 10.1038/35067005.PubMedGoogle Scholar
- Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD: Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell. 1996, 87: 1171-1180. 10.1016/S0092-8674(00)81813-9.PubMedGoogle Scholar
- Thurston G, Rudge JS, Ioffe E, Zhou H, Ross L, Croll SD, Glazer N, Holash J, McDonald DM, Yancopoulos GD: Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med. 2000, 6: 460-463. 10.1038/74725.PubMedGoogle Scholar
- Uemura A, Ogawa M, Hirashima M, Fujiwara T, Koyama S, Takagi H, Honda Y, Wiegand SJ, Yancopoulos GD, Nishikawa S: Recombinant angiopoietin-1 restores higher-order architecture of growing blood vessels in mice in the absence of mural cells. J Clin Invest. 2002, 110: 1619-1628.PubMedGoogle Scholar
- Kim I, Moon SO, Park SK, Chae SW, Koh GY: Angiopoietin-1 reduces VEGF-stimulated leukocyte adhesion to endothelial cells by reducing ICAM-1, VCAM-1, and E-selectin expression. Circ Res. 2001, 89: 477-479. 10.1161/hh1801.097034.PubMedGoogle Scholar
- Mandriota SJ, Pepper MS: Regulation of angiopoietin-2 mRNA levels in bovine microvascular endothelial cells by cytokines and hypoxia. Circ Res. 1998, 83: 852-859. 10.1161/01.RES.83.8.852.PubMedGoogle Scholar
- Roviezzo F, Tsigkos S, Kotanidou A, Bucci M, Brancaleone V, Cirino G, Papapetropoulos A: Angiopoietin-2 causes inflammation in vivo by promoting vascular leakage. J Pharmacol Exp Ther. 2005, 314: 738-744. 10.1124/jpet.105.086553.PubMedGoogle Scholar
- Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD: Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997, 277: 55-60. 10.1126/science.277.5322.55.PubMedGoogle Scholar
- Lobov IB, Brooks PC, Lang RA: Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci USA. 2002, 99: 11205-11210. 10.1073/pnas.172161899.PubMedGoogle Scholar
- Cao Y, Sonveaux P, Liu S, Zhao Y, Mi J, Clary BM, Li CY, Kontos CD, Dewhirst MW: Systemic overexpression of angiopoietin-2 promotes tumor microvessel regression and inhibits angiogenesis and tumor growth. Cancer Res. 2007, 67: 3835-3844. 10.1158/0008-5472.CAN-06-4056.PubMedGoogle Scholar
- Mandriota SJ, Pyke C, Di Sanza C, Quinodoz P, Pittet B, Pepper MS: Hypoxia-inducible angiopoietin-2 expression is mimicked by iodonium compounds and occurs in the rat brain and skin in response to systemic hypoxia and tissue ischemia. Am J Pathol. 2000, 156: 2077-2089. 10.1016/S0002-9440(10)65079-1.PubMedGoogle Scholar
- Oh H, Takagi H, Suzuma K, Otani A, Matsumura M, Honda Y: Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells. J Biol Chem. 1999, 274: 15732-15739. 10.1074/jbc.274.22.15732.PubMedGoogle Scholar
- Takagi H, Koyama S, Seike H, Oh H, Otani A, Matsumura M, Honda Y: Potential role of the angiopoietin/tie2 system in ischemia-induced retinal neovascularization. Invest Ophthalmol Vis Sci. 2003, 44: 393-402. 10.1167/iovs.02-0276.PubMedGoogle Scholar
- Nakaoka Y, Nishida K, Narimatsu M, Kamiya A, Minami T, Sawa H, Okawa K, Fujio Y, Koyama T, Maeda M, Sone M, Yamasaki S, Arai Y, Koh GY, Kodama T, Hirota H, Otsu K, Hirano T, Mochizuki N: Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling. J Clin Invest. 2007, 117: 1771-1781. 10.1172/JCI30651.PubMedGoogle Scholar
- Korff T, Ernst E, Nobiling R, Feldner A, Reiss Y, Plate KH, Fiedler U, Augustin HG, Hecker M: Angiopoietin-1 mediates inhibition of hypertension-induced release of angiopoietin-2 from endothelial cells. Cardiovasc Res. 2012, 94: 510-518. 10.1093/cvr/cvs124.PubMedGoogle Scholar
- Adams S, Brown H, Turner G: Breaking down the blood–brain barrier: signaling a path to cerebral malaria?. Trends Parasitol. 2002, 18: 360-366. 10.1016/S1471-4922(02)02353-X.PubMedGoogle Scholar
- Turner G: Cerebral malaria. Brain Pathol. 1997, 7: 569-582. 10.1111/j.1750-3639.1997.tb01075.x.PubMedGoogle Scholar
- Erdman LK, Dhabangi A, Musoke C, Conroy AL, Hawkes M, Higgins S, Rajwans N, Wolofsky KT, Streiner DL, Liles WC, Cserti-Gazdewich CM, Kain KC: Combinations of host biomarkers predict mortality among Ugandan children with severe malaria: a retrospective case–control study. PLoS One. 2011, 6: e17440-10.1371/journal.pone.0017440.PubMedGoogle Scholar
- Jenkins N, Wu Y, Chakravorty S, Kai O, Marsh K, Craig A: Plasmodium falciparum intercellular adhesion molecule-1-based cytoadherence-related signaling in human endothelial cells. J Infect Dis. 2007, 196: 321-327. 10.1086/518795.PubMedGoogle Scholar
- Turner GD, Ly VC, Nguyen TH, Tran TH, Nguyen HP, Bethell D, Wyllie S, Louwrier K, Fox SB, Gatter KC, Day NP, Tran TH, White NJ, Berendt AR: Systemic endothelial activation occurs in both mild and severe malaria. Correlating dermal microvascular endothelial cell phenotype and soluble cell adhesion molecules with disease severity. Am J Pathol. 1998, 152: 1477-1487.PubMedGoogle Scholar
- Porta J, Carota A, Pizzolato GP, Wildi E, Widmer MC, Margairaz C, Grau GE: Immunopathological changes in human cerebral malaria. Clin Neuropathol. 1993, 12: 142-146.PubMedGoogle Scholar
- Grau GE, Pointaire P, Piguet PF, Vesin C, Rosen H, Stamenkovic I, Takei F, Vassalli P: Late administration of monoclonal antibody to leukocyte function-antigen 1 abrogates incipient murine cerebral malaria. Eur J Immunol. 1991, 21: 2265-2267. 10.1002/eji.1830210939.PubMedGoogle Scholar
- Grau GE, Tacchini-Cottier F, Vesin C, Milon G, Lou JN, Piguet PF, Juillard P: TNF-induced microvascular pathology: active role for platelets and importance of the LFA-1/ICAM-1 interaction. Eur Cytokine Netw. 1993, 4: 415-419.PubMedGoogle Scholar
- Lucas R, Lou JN, Juillard P, Moore M, Bluethmann H, Grau GE: Respective role of TNF receptors in the development of experimental cerebral malaria. J Neuroimmunol. 1997, 72: 143-148. 10.1016/S0165-5728(96)00185-3.PubMedGoogle Scholar
- Kim I: Vascular Endothelial Growth Factor Expression of Intercellular Adhesion Molecule 1(ICAM-1), Vascular Cell Adhesion Molecule 1 (VCAM-1) and E-Selectin through Nuclear Factor -κB Activation in Endothelial Cells. J Biol Chem. 2001, 276: 7614-7620. 10.1074/jbc.M009705200.PubMedGoogle Scholar
- Conroy AL, Phiri H, Hawkes M, Glover S, Mallewa M, Seydel KB, Taylor TE, Molyneux ME, Kain KC: Endothelium-based biomarkers are associated with cerebral malaria in Malawian children: a retrospective case–control study. PLoS One. 2010, 5: e15291-10.1371/journal.pone.0015291.PubMedGoogle Scholar
- Li J, Chang WL, Sun G, Chen HL, Specian RD, Berney SM, Kimpel D, Granger DN, Van der Heyde HC: Intercellular adhesion molecule 1 is important for the development of severe experimental malaria but is not required for leukocyte adhesion in the brain. J Investig Med. 2003, 51: 128-140.PubMedGoogle Scholar
- Sun G, Chang WL, Li J, Berney SM, Kimpel D, Van der Heyde HC: Inhibition of platelet adherence to brain microvasculature protects against severe Plasmodium berghei malaria. Infect Immun. 2003, 71: 6553-6561. 10.1128/IAI.71.11.6553-6561.2003.PubMedGoogle Scholar
- Guo WP, Fu XG, Jiang SM, Wu JZ: Neuregulin-1 regulates the expression of Akt, Bcl-2, and Bad signaling after focal cerebral ischemia in rats. Biochem Cell Biol. 2010, 88: 649-654. 10.1139/O09-189.PubMedGoogle Scholar
- Xiao J, Li B, Zheng Z, Wang M, Peng J, Li Y, Li Z: Therapeutic effects of neuregulin-1 gene transduction in rats with myocardial infarction. Coron Artery Dis. 2012, 23: 460-468. 10.1097/MCA.0b013e32835877da.PubMedGoogle Scholar
- Gao R, Zhang J, Cheng L, Wu X, Dong W, Yang X, Li T, Liu X, Xu Y, Li X, Zhou M: A Phase II, randomized, double-blind, multicenter, based on standard therapy, placebo-controlled study of the efficacy and safety of recombinant human neuregulin-1 in patients with chronic heart failure. J Am Coll Cardiol. 2010, 55: 1907-1914. 10.1016/j.jacc.2009.12.044.PubMedGoogle Scholar
- Jabbour A, Hayward CS, Keogh AM, Kotlyar E, McCrohon JA, England JF, Amor R, Liu X, Li XY, Zhou MD, Graham RM, Macdonald PS: Parenteral administration of recombinant human neuregulin-1 to patients with stable chronic heart failure produces favourable acute and chronic haemodynamic responses. Eur J Heart Fail. 2011, 13: 83-92. 10.1093/eurjhf/hfq152.PubMedGoogle Scholar
- Xu Y, Li X, Liu X, Zhou M: Neuregulin-1/ErbB signaling and chronic heart failure. Adv Pharmacol. 2010, 59: 31-51.PubMedGoogle Scholar
- Guo WP, Wang J, Li RX, Peng YW: Neuroprotective effects of neuregulin-1 in rat models of focal cerebral ischemia. Brain Res. 2006, 1087: 180-185. 10.1016/j.brainres.2006.03.007.PubMedGoogle Scholar
- Shyu WC, Lin SZ, Chiang MF, Yang HI, Thajeb P, Li H: Neuregulin-1 reduces ischemia-induced brain damage in rats. Neurobiol Aging. 2004, 25: 935-944. 10.1016/j.neurobiolaging.2003.10.012.PubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.