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01.12.2014 | Research | Ausgabe 1/2014 Open Access

Journal of Neuroinflammation 1/2014

Neuregulin-1 attenuates mortality associated with experimental cerebral malaria

Journal of Neuroinflammation > Ausgabe 1/2014
Wesley Solomon, Nana O Wilson, Leonard Anderson, Sidney Pitts, John Patrickson, Mingli Liu, Byron D Ford, Jonathan K Stiles
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1742-2094-11-9) contains supplementary material, which is available to authorized users.
Wesley Solomon, Leonard Anderson, Sidney Pitts, John Patrickson, Mingli Liu, Byron D Ford and Jonathan K Stiles contributed equally to this work.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

WS designed and performed experiments, analyzed data and wrote the paper. NW performed experiments, analyzed data and wrote the paper. LA designed and performed experiments. SP designed and performed experiments. JP designed experiments and analyzed data. ML designed and performed experiments and analyzed data. BF designed experiments, analyzed data and assisted in the drafting this manuscript. JS conceived the study, designed and supervised experiments and assisted in the drafting this manuscript. All authors read and approved the final manuscript.



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.
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