title: The PI3K/Akt and ERK1/2 signaling pathways mediate the erythropoietin-modulated calcium influx in kainic acid-induced epilepsy.
abstract: Erythropoietin (EPO) suppresses epileptogenesis and limits the neuronal damage associated with recurrent seizures, but the neurocellular mechanism is unclear. Dysregulation of intracellular calcium homeostasis is a key pathogenic event leading to the progression of epileptic activity, suggesting that EPO may suppress seizures by stabilizing intracellular calcium. In this study, we examined the effects of EPO on voltage-gated Ca(2+) influx in cultured rat hippocampal neurons and population spike (PS) amplitude in kainic acid (KA)-induced rats and the mechanisms responsible. KA injection markedly increased EPO and EPO receptor expression and the amplitude of PS in the hippocampal CA3 region, evoked by perforant pathway stimulation. Intracerebroventricular injection of exogenous rat recombinant EPO reversed KA-induced PS amplitude in the hippocampal CA3 region. Similarly, rat recombinant EPO pretreatment attenuates the increased voltage-gated calcium current's (I(Ca)) amplitude and density induced by KA in cultured hippocampal neurons. In contrast, transient transfection of rat EPO small interfering RNS (siRNA) further enhanced I(Ca) amplitude and density in the presence of KA, whereas a scrambled control siRNA had no effect. Further, EPO activates the PI3K and ERK1/2 pathways in cultured hippocampal neurons, and the PI3K/Akt inhibitor LY294002 and ERK1/2 inhibitor U0126 both blocked, at least in part, the suppressive effect of exogenous EPO on KA-induced calcium currents. This study indicates that both endogenous and exogenous EPO decrease KA-sensitive calcium influx and concomitant hyperexcitability in hippocampal neurons. The results also demonstrate that the PI3K/Akt and ERK1/2 signaling pathways mediate the EPO-modulated calcium influx in KA-induced epilepsy.
authors.affiliation: Department of Basic Medicine, Medical College, Affiliated Zhongshan Hospital, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: Honghua
authors.initials: H
authors.lastname: Zheng
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Wang
authors.forename: Zhengang
authors.initials: Z
authors.lastname: Tang
authors.forename: Weihong
authors.initials: W
authors.lastname: Zheng
authors.forename: Zhengli
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D015153:Blotting, Western; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D055724:Electrophysiological Phenomena / Q000187:drug effects; D004827:Epilepsy / Q000139:chemically induced* / Q000503:physiopathology*; D004921:Erythropoietin / Q000494:pharmacology* / Q000502:physiology*; D005071:Evoked Potentials / Q000502:physiology; D018690:Excitatory Amino Acid Agonists; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007608:Kainic Acid; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000502:physiology*; D018408:Patch-Clamp Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection
chemical_list: D018690:Excitatory Amino Acid Agonists; D011994:Recombinant Proteins; D004921:Erythropoietin; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D007608:Kainic Acid; D002118:Calcium