Therapeutic effects of nonerythropoietic erythropoietin analog ARA290 in experimental autoimmune encephalomyelitis rat

Hong, Chen; Luo, Bangwei; Yang, Xiaofeng; Xiong, Jian; Liu, Zongwei; Jiang, Man; Shi, Rongchen; Yan, Chuansheng; Wu, Yuzhang; Zhang, Zhiren

doi:10.1016/j.jneuroim.2014.01.006

Cited by 20 publications

(20 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other EPO derivatives based on the same desire to eliminate undesired hematopoiesis have been studied for their use in brain injury, including HBSP and a pHBSP (also known as ARA290) [16]. HBSP and its analog pHBSP have been found to be tissue protective in models of stroke [18], cardiovascular disease [19,20], experimental autoimmune encephalomyelitis (EAE) [21], and TBI [15]. In our investigation, JM4 also significantly limited the size of the lesion in injured brains following TBI (Fig.…”

Section: Discussionmentioning

confidence: 99%

Beneficial Effect of Erythropoietin Short Peptide on Acute Traumatic Brain Injury

et al. 2016

View full text Add to dashboard Cite

There is currently no effective medical treatment for traumatic brain injury (TBI). Beyond the immediate physical damage caused by the initial impact, additional damage evolves due to the inflammatory response that follows brain injury. Here we show that therapy with JM4, a low molecular weight 19-amino acid nonhematopoietic erythropoietin (EPO) peptidyl fragment, containing amino acids 28-46 derived from the first loop of EPO, markedly reduces acute brain injury. Mice underwent controlled cortical injury and received either whole molecule EPO, JM4, or sham-treatment with phosphate-buffered saline. Animals treated with JM4 peptide exhibited a large decrease in number of dead neural cells and a marked reduction in lesion size at both 3 and 8 days postinjury. Therapy with JM4 also led to improved functional recovery and we observed a treatment window for JM4 peptide that remained open for at least 9 h postinjury. The fulllength EPO molecule was divided into a series of 6 contiguous peptide segments; the JM4-containing segment and the adjoining downstream region contained the bulk of the death attenuating effects seen with intact EPO molecule following TBI. These findings indicate that the JM4 molecule substantially blocks cell death and brain injury following acute brain trauma and, as such, presents an excellent opportunity to explore the therapeutic potential of a small-peptide EPO derivative in the medical treatment of TBI.

show abstract

Section: Discussionmentioning

confidence: 99%

Beneficial Effect of Erythropoietin Short Peptide on Acute Traumatic Brain Injury

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Finally, pHBSP has also been reported to alter T cell polarization and differentiation, but not proliferation (Chen et al, 2014;Cravedi et al, 2014). However, the exact mechanism of pHBSP-derived immunomodulation remains uncertain.…”

Section: Molecular Mechanisms Of Tissue-protective Effectsmentioning

confidence: 99%

“…There are also convincing data on the neuroprotective effects of pHBSP, as shown using the experimental models of autoimmune encephalomyelitis and autoimmune neuritis, which mimic the human multiple sclerosis and the Guillain-Barré Syndrome, respectively. Therapeutic administration of pHBSP to rats reduced severity and shortened duration of the experimental autoimmune encephalomyelitis, probably by inhibiting the expression of inflammatory cytokines in the spinal cord, suppressing lymphocyte proliferation and altering T helper cell differentiation (Chen et al, 2014). Similarly, pHBSP greatly decreased the severity of the neurological symptoms and shortened the recovery time and total duration of the experimental autoimmune neuritis, by decreasing the incidence of perivascular inflammatory cell infiltration in peripheral nerves and exerting direct cyto-protective and anti-inflammatory effects on Schwann cells, which are critical for the remyelination of the injured nerves .…”

Section: Preclinical Studiesmentioning

confidence: 99%

Flipping the molecular switch for innate protection and repair of tissues: Long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin

Collino

Thiemermann

Cerami

et al. 2015

Pharmacology & Therapeutics

View full text Add to dashboard Cite

Many disease processes activate a cellular stress response that initiates a cascade of inflammation and damage. However, this process also triggers a tissue protection and repair system mediated by locally-produced hyposialated erythropoietin (hsEPO). Although recombinant EPO is used widely for treating anemia, potential use of recombinant EPO for tissue-protection is limited by rises in hematocrit, platelet activation, and selectin expression resulting in a high risk of thrombosis. Importantly, the erythropoietic and tissue-protective effects of EPO are mediated by different receptors. Whereas EPO stimulates red cell progenitors by binding to an EPO receptor (EPOR) homodimer, a heterodimer receptor complex composed of EPOR and β common receptor (βcR) subunits, termed the innate repair receptor (IRR), activates tissue protection and repair. The IRR is typically not expressed by normal tissues, but instead is rapidly induced by injury or inflammation. Based on this understanding, EPO derivatives have been developed which selectively activate the IRR without interacting with the EPOR homodimer. The latest generation of specific ligands of the IRR includes an 11 amino acid peptide modeled from the three dimensional structure of the EPO in the region of helix B called pyroglutamate helix B surface peptide (pHBSP; ARA-290). Despite a short plasma half-life (~2min), pHBSP activates a molecular switch that triggers sustained biological effects that have been observed in a number of experimental animal models of disease and in clinical trials. This review summarizes pharmacokinetic and pharmacodynamic data and discusses the molecular mechanisms underlying the long-lasting effects of this short-lived peptide.

show abstract

“…In the study on the therapeutic effects of HBSP in experimental autoimmune encephalomyelitis (EAE), the administration of HBSP to EAE rats significantly reduced the severity and shortened the duration of injury, reduced the infiltration of proinflammatory cells and suppressed expression of pro-inflammatory cytokines such as IL-1β, IL-17, TNF-α, IFN-γ. The expression of inducible NO synthase and transcription factor T-bet at mRNA level was also reduced in spinal cords following HBSP treatment [50]. In the in vitro study, HBSP inhibited antigen-specific and non-specific lymphocyte proliferation and promoted the polarization of Th2 and regulatory T cells (Treg) while suppressed the polarization of Th1 and Th17 cells in EAE lymph nodes [50].…”

Section: In Nervous Systemmentioning

confidence: 98%

The Role of Erythropoietin-Derived Peptides in Tissue Protection

Zhang¹,

Yang²

2018

Polypeptide - New Insight Into Drug Discovery and Development

View full text Add to dashboard Cite

Erythropoietin (EPO), recognized as a tissue protective agent, can trigger anti-inflammatory and anti-apoptotic processes to delimit injury and promote repair by the binding tissueprotective receptor. However, only at a high dosage can EPO exert tissue protective effects, which simultaneously elicits some severe erythropoiesis-related side effects. Thus, the structural modification of EPO for the prevention of side effects is undoubtedly required. This chapter reviewed the development from EPO to its peptide derivatives with tissue protective efficacy. We also discussed are the therapeutic effects and limitations of each peptide, signaling pathways involved and the benefits for translation.

show abstract

Therapeutic effects of nonerythropoietic erythropoietin analog ARA290 in experimental autoimmune encephalomyelitis rat

Cited by 20 publications

References 46 publications

Beneficial Effect of Erythropoietin Short Peptide on Acute Traumatic Brain Injury

Beneficial Effect of Erythropoietin Short Peptide on Acute Traumatic Brain Injury

Flipping the molecular switch for innate protection and repair of tissues: Long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin

The Role of Erythropoietin-Derived Peptides in Tissue Protection

Contact Info

Product

Resources

About