The erythropoietin-derived peptide mimetic pHBSP affects cellular and cognitive consequences in a rat post-status epilepticus model

Abstract

SUMMARYPurpose: The selection of a minimal active sequence of erythropoietin allowed the design of peptide mimetics that exert beneficial effects in the central nervous system but lack an erythropoietic effect. Erythropoietin has been suggested as a promising therapeutic and prophylactic for epilepsies based on its neuroprotective, neuroregenerative, and antiinflammatory potency. Therefore, it is of particular interest to evaluate whether the nonerythropoietic erythropoietin-derived peptide pHBSP can affect epileptogenesis. Methods: In a post-status epilepticus model in rats, we determined the effects of pHBSP and of recombinant human erythropoietin with short-term administration following status epilepticus. Key Findings: Both pHBSP and erythropoietin further enhanced the status epilepticus-associated increase in hippocampal cell proliferation. Thereby, pHBSP seemed to promote neuronal differentiation and survival resulting in a significant increase in neurogenesis. Neither pHBSP nor erythropoietin affected the number of animals exhibiting spontaneous recurrent seizures as well as the seizure frequency in the chronic phase. In the Morris water maze, pHBSP attenuated cognitive deficits in epileptic animals. Significance: In conclusion, the helix B-derived erythropoietin peptide pHBSP can modulate the cellular and cognitive consequences of a status epilepticus. The impact of pHBSP on spatial learning might indicate that the peptide allows beneficial effects on epileptogenesis-associated cognitive deficits. However, it needs to be considered that learning deficits were not abolished by pHBSP and that the effects were not observed consistently until the end of the study. Therefore, adjustment of timing, duration, and dose of peptide administration might be necessary to further evaluate the efficacy of pHBSP.

Lacosamide treatment following status epilepticus attenuates neuronal cell loss and alterations in hippocampal neurogenesis in a rat electrical status epilepticus model

“…Of interest, we did not observe any SE‐associated neuronal loss in the hilus of the hippocampus. This finding is consistent with recent data from our group and other groups, indicating a surprising resistance of the hilus to seizure‐induced neuronal cell loss (Loscher & Brandt, ; Seeger et al., ). It has been hypothesized that the reduced sensitivity of hilar neurons observed in recent studies compared with earlier studies is related to a genetic drift in the rat strain used, also considering that animal facilities and breeding sites have been reorganized at Harlan Winkelmann (Loscher & Brandt, ).…”

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

“…The neuroprotective activity of the EPO derivative in the peripheral nervous system has also been examined in rat models of post-status epilepticus model and neuropathic pain. Specifically, pHBSP mediated effects on hippocampal cell proliferation and neurogenesis, with significant improvement in epileptogenesis-associated cognitive deficits (Seeger et al, 2011). In addition, administration of pHBSP was effective in providing long-term relief of nerve injury-induced mechanical allodynia in both the spared nerve injury model, based on sciatic nerve surgical transection, and the neuritis model, which lacks gross nerve pathology (Swartjes et al, 2011;Pulman et al, 2013).…”

Finding a better drug for epilepsy: Antiepileptogenesis targets

“…Considering the neuroprotective, neuroregenerative, and antiinflammatory potential of EPO, it is of extreme interest to determine whether EPO‐derived mimetic peptides can exert disease‐modifying or antiepileptogenic effects. In a post‐SE model, the nonerythropoietic EPO‐peptide pHBSP (pyroglutamate helix B surface peptides) promoted hippocampal cell proliferation, neuronal differentiation, and survival of newborn neurons (Seeger et al., 2011). Moreover, this peptide reduced the activation of microglial cells, the production of proinflammatory cytokines, the microglial phagocytotic activity, and the formation of reactive oxygen species (ROS).…”