Treatment of Mild Traumatic Brain Injury with an Erythropoietin-Mimetic Peptide

Abstract

Mild traumatic brain injury (mTBI) results in an estimated 75-90% of the 1.7 million TBI-related emergency room visits each year. Post-concussion symptoms, which can include impaired memory problems, may persist for prolonged periods of time in a fraction of these cases. The purpose of this study was to determine if an erythropoietin-mimetic peptide, pyroglutamate helix B surface peptide (pHBSP), would improve neurological outcomes following mTBI. Sixty-four rats were randomly assigned to pHBSP or control (inactive peptide) 30 lg/kg IP every 12 h for 3 days, starting at either 1 hour (early treatment) or 24 h (delayed treatment), after mTBI (cortical impact injury 3 m/sec, 2.5 mm deformation). Treatment with pHBSP resulted in significantly improved performance on the Morris water maze task. Rats that received pHBSP required 22.3 -1.3 sec to find the platform, compared to 26.3 -1.3 sec in control rats ( p = 0.022). The rats that received pHBSP also traveled a significantly shorter distance to get to the platform, 5.0 -0.3 meters, compared to 6.1 -0.3 meters in control rats ( p = 0.019). Motor tasks were only transiently impaired in this mTBI model, and no treatment effect on motor performance was observed with pHBSP. Despite the minimal tissue injury with this mTBI model, there was significant activation of inflammatory cells identified by labeling with CD68, which was reduced in the pHBSP-treated animals. The results suggest that pHBSP may improve cognitive function following mTBI.

The Many Facets of Erythropoietin Physiologic and Metabolic Response

“…Erythropoietin derivatives that can promote nonhematopoietic tissue protective effects, especially neuroprotection and cardioprotection, without stimulating erythropoiesis, have been proposed to bind alternate EPO receptors such as the EPOR/βc receptor heterodimer. These include asialoerythropoietin, carbamylated EPO, ARA 290 [cibinetide; helix B surface peptide (11 amino acid peptide derived from the EPO sequence)], and recombinant EV-3 (an EPO derived a spliced variant with exon 3 deleted) (Erbayraktar et al, 2003;Brines et al, 2004Brines et al, , 2008Fiordaliso et al, 2005;Robertson et al, 2013;Bonnas et al, 2017). Clinical studies explored the safety and use of EPO and carbamylated EPO to increase frataxin levels for treatment of Friedreich's Ataxia (Boesch et al, 2014;Egger et al, 2014;Santner et al, 2014).…”

ARA 290, a Nonerythropoietic Peptide Engineered from Erythropoietin, Improves Metabolic Control and Neuropathic Symptoms in Patients with Type 2 Diabetes

“…One promising candidate is ARA 290, which is an 11-amino acid peptide modeled from the three dimensional structure of helix B of the EPO molecule that interacts with the IRR (8). ARA 290 has been evaluated extensively in a wide spectrum of preclinical models, including diet-induced insulin resistance (10), diabetic retinopathy (11), diabetic autonomic neuropathy (12), myocardial infarction (13), chronic heart failure (14), burns (15), traumatic brain injury (16,17) and shock-induced multi-organ failure (18), among others. The results of these studies show that ARA 290 prevents tissue injury, reduces inflammation and activates healing.…”

Changes in Brain Tissue Oxygenation After Treatment of Diffuse Traumatic Brain Injury by Erythropoietin*

“…Post-traumatic administration of recombinant human erythropoietin (rhEPO) was found to induce a significant reduction of inflammation and cell apoptosis, together with improved functional recovery after focal TBI in mice (17). Improved cognitive function was found in rats treated with erythropoietin-mimetic peptide after mild TBI (18). Using the impact-acceleration model to induce diffuse TBI in rats, we found that rhEPO and carbamylated erythropoietin, a modified erythropoietin lacking erythropoietic activity, blocked the development of posttraumatic cellular edema as early as 1 hour after the insult (19,20).…”