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

Gao, Runlin; Zhang, Jiän; Cheng, Liuquan; Wu, Xue-si; Dong, Wei; Yang, Xinchun; Li, Tianchang; Liu, Xifu; Xu, Yecheng; Li, Xinyan; Zhou, Meijuan

doi:10.1016/j.jacc.2009.12.044

Cited by 252 publications

(227 citation statements)

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“…Therefore, our present results suggest a complex action of NRG1 whereby food intakes and weight gain are both decreased possibly through an increase in leptin, while physical activity and energy expenditure are limited through unknown pathways. However, the possibility of a side-effect induced by NRG1 treatment that might promote a decrease in mouse locomotion cannot be ruled out, although human studies using comparable dose ranges have shown no such significant side-effect induced by chronic NRG1 treatment [15,16]. More studies are now needed to elucidate the origin of the NRG1-induced increase in circulating leptin and the contribution of increased circulating leptin to altered food intakes and weight gain.…”

Section: Discussionmentioning

confidence: 99%

Neuregulin 1 affects leptin levels, food intake and weight gain in normal-weight, but not obese, db/db mice

Ennequin

Caillaud

Chavanelle

et al. 2015

Diabetes & Metabolism

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Aim. -Studies in vitro have highlighted the potential involvement of neuregulin 1 (NRG1) in the regulation of energy metabolism. This effect has also been suggested in vivo, as intracerebroventricular injection of NRG1 reduces food intakes and weight gain in rodents. Thus, it was hypothesised that NRG1 might affect serum leptin levels in mice.Methods. -Weight, food intakes, energy expenditure, spontaneous physical activity and serum leptin levels were evaluated in normal-weight C57BL/6JRJ mice following intraperitoneal administration of NRG1 (50 g/kg, three times/week) or saline for 8 weeks. Based on the results of this first experiment, leptin-resistant obese db/db mice were then given NRG1 for 8 weeks.Results. -Leptin serum concentrations were six times higher in C57BL/6JRJ mice treated with NRG1 than in the animals given saline. NRG1 treatment also reduced weight gain by 10% and food intakes by 15% compared with saline treatment, while energy expenditure remained unchanged. In db/db mice, serum leptin concentrations, weight gain, food intakes, energy expenditure and spontaneous physical activity were not altered by NRG1 treatment.Conclusion. -The decrease in food intakes and weight gain associated with NRG1 treatment in C57BL/6JRJ mice may be partly explained by increased leptin levels, whereas db/db mice were not affected by the treatment, suggesting resistance to NRG1 in this pathological state.

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Section: Discussionmentioning

confidence: 99%

Neuregulin 1 affects leptin levels, food intake and weight gain in normal-weight, but not obese, db/db mice

Ennequin

Caillaud

Chavanelle

et al. 2015

Diabetes & Metabolism

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“…NRG1 also has a role in cardiac maintenance and indeed clinical trials are underway for its use in heart failure [95]. The potential mechanisms of how NRG1 signaling may modulate nerve repair have not been extensively studied; these will be discussed in more detail later.…”

Section: Treatment With Nrg1 Can Promote Nerve Repairmentioning

confidence: 99%

The Role of Neuregulin-1 In the Response To Nerve Injury

Fricker

Bennett

2011

Future Neurol.

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Axons and Schwann cells exist in a highly interdependent relationship: damage to one cell type invariably leads to pathophysiological changes in the other. Greater understanding of communication between these cell types will not only give insight into peripheral nerve development, but also the reaction to and recovery from peripheral nerve injury. The type III isoform of neuregulin-1 (NRG1) has emerged as a key signaling factor that is expressed on axons and, through binding to erbB2/3 receptors on Schwann cells, regulates multiple phases of their development. In adulthood, NRG1 is dispensable for the maintenance of the myelin sheath; however, this factor is required for both axon regeneration and remyelination following nerve injury. The outcome of NRG1 signaling depends on interactions with other pathways within Schwann cells such as Notch, integrin and cAMP signaling. In certain circumstances, this signaling pathway may be maladaptive; for instance, direct binding of Mycobacterium leprae onto erbB2 receptors produces excessive activation and can actually promote demyelination. Attempts to modulate this pathway in order to promote nerve repair will therefore need to give consideration to the exact isoform used, as well as how it is processed and the context in which it is presented to the Schwann cell. Keywordsneuregulin-1; neuropathy; peripheral nerve injury; regeneration; remyelination; repair; Schwann cell Peripheral nerve injury causes significant morbidity and reduced quality of life as a consequence of weakness, sensory loss and neuropathic pain. In total, 6% of the elderly population suffer from peripheral neuropathy [1], which can be caused by metabolic diseases such as diabetes, inherited genetic disorders such as Charcot-Marie-Tooth disease, infectious and inflammatory disorders including Guillan-Barré syndrome and traumatic injury to the nerve (which alone effects up to 300,000 people in Europe per year [1,2]). In contrast to the CNS, peripheral nerves have a significant regenerative capacity [3]; however, in patients, regeneration and the clinical outcome are often poor. Axons regenerate at a rate of approximately 1 mm per day, depending on the site of the lesion. There may be a delay of months if not years before the target zone is re-innervated, and by this time, the target organ and supporting cells may have irreversibly changed, becoming much less receptive to reinnervation. The current approaches to peripheral nerve repair following nerve transection are either to surgically suture the nerve or to bridge the gap between the two cut ends. Financial & competing interests disclosureThe authors have no other rel evant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Europe PMC Funders Group NRGs & the PNSNRGs Neuregulins are a family of growth factors en...

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“…In fact, several studies using animal models of heart failure have demonstrated the therapeutic benefits of neuregulins, which improved cardiac performance, attenuated disease markers, and prolonged animal survival [24,25]. Furthermore, phase I and II clinical trials for chronic heart failure in humans confirmed the favorable effects mediated by neuregulins [26,27], highlighting the therapeutic potential of these growth factors in cardiac repair. In this study, we have examined the efficacy of novel MP-based delivery of NRG1 and FGF1 in a rat model of MI.…”

Section: Introductionmentioning

confidence: 99%

Controlled delivery of fibroblast growth factor-1 and neuregulin-1 from biodegradable microparticles promotes cardiac repair in a rat myocardial infarction model through activation of endogenous regeneration

Formiga

Pelacho

Garbayo

et al. 2014

Journal of Controlled Release

102

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Acidic fibroblast growth factor (FGF1) and neuregulin-1 (NRG1) are growth factors involved in cardiac development and regeneration. Microparticles (MPs) mediate cytokine sustained release, and can be utilized to overcome issues related to the limited therapeutic protein stability during systemic administration. We sought to examine whether the administration of microparticles (MPs) containing FGF1 and NRG1 could promote cardiac regeneration in a myocardial infarction (MI) rat model. We investigated the possible underlying mechanisms contributing to the beneficial effects of this therapy, especially those linked to endogenous regeneration. FGF1-and NRG1-loaded MPs were prepared using a multiple emulsion solvent evaporation technique. Seventy-three female Sprague-Dawley rats underwent permanent left anterior descending coronary artery occlusion, and MPs were intramyocardially injected in the peri-infarcted zone four days later. Cardiac function, heart tissue remodeling, revascularization, apoptosis, cardiomyocyte proliferation, and stem cell homing were evaluated one week and three months after treatment. MPs were shown to efficiently encapsulate FGF1 and NRG1, releasing the bioactive proteins in a sustained manner. Three months after treatment, a statistically significant improvement in cardiac function was detected in rats treated with growth factor-loaded MPs (FGF1, NRG1, or FGF1/NRG1). The therapy led to inhibition of cardiac remodeling with smaller infarct size, a lower fibrosis degree and induction of tissue revascularization. Cardiomyocyte proliferation and progenitor cell recruitment was detected. Our data support the therapeutic benefit of NRG1 and FGF1 when combined with protein delivery systems for cardiac regeneration. This approach could be scaled up for use in preclinical and clinical studies.

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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

Cited by 252 publications

References 10 publications

Neuregulin 1 affects leptin levels, food intake and weight gain in normal-weight, but not obese, db/db mice

Neuregulin 1 affects leptin levels, food intake and weight gain in normal-weight, but not obese, db/db mice

The Role of Neuregulin-1 In the Response To Nerve Injury

Controlled delivery of fibroblast growth factor-1 and neuregulin-1 from biodegradable microparticles promotes cardiac repair in a rat myocardial infarction model through activation of endogenous regeneration

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