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Open Access Research

Neuregulin-1 attenuates mortality associated with experimental cerebral malaria

Wesley Solomon1*, Nana O Wilson1, Leonard Anderson2, Sidney Pitts3, John Patrickson3, Mingli Liu1, Byron D Ford4 and Jonathan K Stiles1*

Author Affiliations

1 Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, USA

2 Cardiovascular Research Institute Morehouse School of Medicine, Atlanta, GA, USA

3 Department of Pathology Morehouse School of Medicine, Atlanta, GA, USA

4 Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USA

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Journal of Neuroinflammation 2014, 11:9  doi:10.1186/1742-2094-11-9

Published: 17 January 2014

Abstract

Background

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).

Methods

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.

Results

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.

Conclusions

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.

Keywords:
Neuregulin-1 (NRG-1); Pro-inflammatory; Anti-inflammatory; Blood–brain barrier (BBB); Inflammation; Plasmodium berghei ANKA (PbA); Adjunctive therapy; Malaria; Cerebral malaria (CM); Brain injury