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

PURPOSE: 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.

Targeting of microglial KCa3.1 channels by TRAM-34 exacerbates hippocampal neurodegeneration and does not affect ictogenesis and epileptogenesis in chronic temporal lobe epilepsy models.

Blockade of KCa3.1 channels has been suggested as a novel strategy to reduce microglia activation. The concept has been confirmed by neuroprotective effects in a rat brain ischemia-reperfusion model and reduced microglia activation surrounding glioblastomas. Cumulating evidence exists that microglia activation significantly contributes to epileptogenesis as well as intrinsic severity in the chronic epileptic brain. Taken together these data raised the question whether the KCa3.1 channel blocker triarylmethane-34 (TRAM-34) might also exert beneficial effects in chronic epilepsy models. In a rat post-status epilepticus model TRAM-34 treatment following the insult did not result in neuroprotective effects. Whereas status epilepticus-associated neurodegeneration remained unaffected in the piriform cortex, loss of pyramidal cells in the hippocampal CA1 and CA3a region and of neuropeptide Y-positive interneurons in the hilus proved to be exacerbated by pharmacological KCa3.1 blockade. The development of spontaneous seizures and of behavioral and cognitive alterations was comparable in animals receiving TRAM-34 treatment or the respective vehicle. The kindling model of temporal lobe epilepsy with a massive stimulation paradigm with frequent seizure elicitation in fully kindled rats was used to assess a putative disease-modifying effect. However, sub-chronic TRAM-34 treatment failed to exert relevant effects on seizure generation and thresholds. In conclusion, the data obtained in two different chronic epilepsy models argue against using KCa3.1 blockers as disease-modifying or antiepileptogenic agents. Exacerbation of neuronal cell loss in TRAM-34 pre-treated epileptic animals rather indicates that translational development of the compound needs to carefully consider the pathophysiological mechanisms associated with different brain insults.

Impact of the erythropoietin-derived peptide mimetic Epotris on the histopathological consequences of status epilepticus.

The design of peptide mimetics offers interesting opportunities to selectively include beneficial and exclude undesirable effects of a parent molecule. Epotris represents a novel erythropoietin mimetic, which lacks an erythropoietic activity. The present study evaluates the potential of this peptide to interfere with the histopathological consequences of electrical-induced status epilepticus in rats. The peptide attenuated status epilepticus-associated expansion of the neuronal progenitor cell population in a significant manner. Moreover, Epotris affected the number of persistent basal dendrites exhibited by neuronal progenitor cells. In contrast, hippocampal cell loss remained unaffected by administration of this peptide mimetic. Status epilepticus resulted in obvious microglial activation in different brain regions involved in seizure generation and spread. Epotris diminished the microglial response caused by prolonged seizure activity in the thalamus but not in other brain regions. The study renders support that the Epotris' sequences from binding site 2 in helix C of Epo play a role in receptor interaction and cytokine function. In addition, the data demonstrate that Epotris can exert limited in vivo effects on the cellular consequences of prolonged seizure activity. When considering further testing it should be taken in mind that Epotris administration only attenuated selected cellular consequences of status epilepticus and did not completely prevent cellular alterations.

Targeting the prostaglandin E2 EP1 receptor and cyclooxygenase-2 in the amygdala kindling model in mice.

The prostaglandin E2 EP1 receptor as well as the inflammatory enzyme cyclooxygenase-2 have been suggested as targets for disease modulation, improvement of therapeutic response, and restoration of pharmacosensitivity in epilepsies. Translational development of respective add-on approaches requires careful analysis of putative effects on ictogenesis. Therefore we evaluated the impact of the EP1 receptor antagonist SC-51089, the EP1 receptor agonist misoprostol and the COX-2 inhibitors celecoxib and NS-398 in the mouse amygdala kindling model of temporal lobe epilepsy. Neither celecoxib nor NS-398 affected the generation, spread and termination of seizure activity. Whereas SC-51089 did not affect the seizure threshold, the highest dose (30mg/kg) significantly decreased the seizure severity when administered 60min before stimulation. Moreover, SC-51089 significantly prolonged seizure duration at the highest dose. The EP1 receptor agonist misoprostol exerted contrasting effects on seizure duration with a significant decrease in the duration of motor seizure activity. The data suggest that doses of COX-2 inhibitors and EP1 receptor antagonists which exert disease modulating or antiepileptic drug potentiating effects do not negatively affect seizure control in temporal lobe epilepsy. The contrasting impact of the EP1 receptor antagonist and agonist suggests that EP1 receptors can influence endogenous mechanisms involved in termination of seizure activity.