Beneficial Effect of Erythropoietin Short Peptide on Acute Traumatic Brain Injury

Abstract

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.

Erythropoietin prevents the effect of chronic restraint stress on the number of hippocampal CA3c dendritic terminals—relation to expression of genes involved in synaptic plasticity, angiogenesis, inflammation, and oxidative stress in male rats

“…Although the effect of EPO treatment on tissues outside the bone marrow has been found to be not entirely dependent on hematopoiesis (Leist et al, 2004;Wang et al, 2016), we do not know if the effects of EPO treatment observed in the current study are caused by an increase in hematocrit, because hematocrit was not measured. EPO treatment of mice every other day for 3 weeks at the same dosage as used in the current study, 5,000 IU/kg, has been shown to cause an increase in hematocrit that was still detectable 1 week after the secession of treatment, but had abated at 3 weeks (Adamcio et al, 2008).…”

Anti-inflammatory efficiency of erythropoietin in sciatic nerve damage

“…Wang et al showed that EPO improved neurological functions in the experimental ischemia model. In another study, Brines et al showed that the infarct area was smaller in the rat brain with EPO treatment and it had a cell-protecting effect [9]. It was also shown that when EPO is applied in the central nervous system after a stroke, it decreased apoptosis and brain edema [12].…”

“…The peripheral nervous system is more successful in axonal regeneration as inhibitor myelin proteins are less dominant and Schwann cells are more active in distal. Therefore, agents considered to increase nerve regeneration are frequently used in experimental studies where peripheral nerve damage is formed [9,10]. Although medications, such as methylprednisolone and gabapentin, are proven to be effective on post-traumatic nerve injuries (spinal cord traumas and peripheral nerve injuries, etc.)…”

“…and are considered to be the reference point in the studies made, they are drugs with a difficult clinical application due to their present side effects [8]. Erythropoietin (EPO) is defined as a hematopoietic growth factor with a molecular weight of 30.400 Da and is composed of 165 amino glycoproteins [9,10]. EPO is secreted in renal tubular cells in adults and through hepatic cells in the fetus [10].…”

“…It is a drug with low side effect profile and is used in anemia treatment [11]. In recent years, it has drawn attention in experimental studies on nerve damages with its proven anti-inflammatory, neuroprotective and neuroregenerative effects with minimum side effects [9].Our aim in this study was to show the effects of EPO which is known for its neuroprotective, neuroregenerative and anti-inflammatory characteristics in experimental crush type of sciatic nerve damage in rats and to compare it with gabapentin which is known for its effects on acute phase reactants.…”