A recent study published in the Journal of Stroke and Cerebrovascular Diseases reveals that neuregulin-1b (NRG-1), an endogenous neuroprotective polypeptide, is elevated in the conditions of chronic hemolysis and reduced cerebrovascular perfusion associated with sickle cell disease (SCD) and suggests that the substance might hold therapeutic benefits for patients with SCD.

The main objective of the study was to determine if the expression of NRG-1 was increased in SCD or experimental conditions mimicking the SCD as well as reveal if treatment with exogenous NRG-1 could reduce markers of cerebrovascular inflammation.

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In order to gain insight into the expression of NRG-1 in SCD, the researchers first measured circulating plasma and brain-specific NRG-1 levels in Townes sickle cell mouse model.

Next, they wanted to investigate if cells that are part of the blood-brain barrier react to conditions used to mimic chronic hemolysis and reduced cerebrovascular perfusion in SCD by increasing NRG-1 production. They cultivated human brain microvascular cells and astrocytes and exposed them to excess heme, ischemia, or a combination of the two in order to analyze endogenous gene expression of NRG-1 and its ERBB4 receptor.

With hopes of NRG-1 being potentially beneficial for people with SCD, the researchers also evaluated the markers of cerebrovascular inflammation in human brain microvascular endothelial cells and astrocytes after pre-treatment with NRG-1. The human astrocytes and brain microvascular endothelial cells were cultured in the same SCD-mimicking conditions as before, but with the addition of exogenous NRG-1.

The laboratory analyses showed an increase of plasma and brain-specific NRG-1 in transgenic SCD mice compared with healthy mice controls. The expression of NRG-1 in cultured human microvascular cells and astrocytes exposed to excess heme and ischemia was elevated compared with positive controls used to confirm experimental conditions.

Results also showcased a reduction of inflammatory chemokine (CXCL-1 and CXCL-10) and adhesion molecule (ICAM-1 and VCAM-1) expression after pre-treatment with NRG-1. Simultaneously, pro-angiogenic factors (VEGF-A) in microvascular cells and astrocytes exposed to excess heme and ischemia were increased. 

“Recombinant human NRG-1b has already passed safety and efficacy testing to be administered intravenously to humans,” Chambliss and colleagues noted. “Neuregulin-1b is also slated to begin clinical trials for treatment of post-ischemic injury for non-SCA stroke. Our findings strongly support the NRG-1/ERBB4 pathway as a potential therapeutic target for preventing or treating SCD cerebrovascular disease.”

Cerebrovascular complications remain highly common in people with SCD. Research shows that 11% of children with SCD experience a stroke before the age of 20 in the absence of an effective preventive treatment.

Reference

Chambliss C, Stiles JK, Gee BE. Neuregulin-1 attenuates hemolysis- and ischemia induced-cerebrovascular inflammation associated with sickle cell diseaseJ Stroke Cerebrovasc Dis. Published online on December 3, 2022. doi:10.1016/j.jstrokecerebrovasdis.2022.106912