The combined therapy of intrahippocampal transplantation of adult neural stem cells and intraventricular erythropoietin-infusion ameliorates spontaneous recurrent seizures by suppression of abnormal mossy fiber sprouting

Adult neural stem cells (NSCs) possess the potentials to self-renew and exert neuroprotection. In this study, we examined whether adult NSCs had anti-epileptic effects in rats with status epilepticus (SE) induced by kainic acid (KA) and whether co-administration of erythropoietin (EPO) enhanced anti-epileptic effects or cell survival. Adult NSCs were transplanted into KA-lesioned hippocampus with or without intracerebroventricular EPO infusion. Electronic encephalography (EEG) was recorded for 3 weeks after transplantation. The frequency of abnormal spikes in rats with NSC transplantation decreased significantly compared to those of rats without NSC transplantation. Most of the transplanted NSCs differentiated into GFAP-positive astrocytes. EPO infusion significantly enhanced the survival of NSCs, but not neuronal differentiation or migration. NSC transplantation increased the number of neuropeptide Y (NPY) and glutamic acid decarboxylase 67 (GAD67)-positive interneurons. NSC transplantation also suppressed mossy fiber sprouting into the inner molecular layer with subsequent reduction of hippocampal excitability, which finally prevented the development of spontaneous recurrent seizures in adult rats after KA-induced SE. This study might shed light on the cytoarchitectural mechanisms of temporal lobe epilepsy as well as clarify the effect of adult NSC transplantation with intracerebroventricular EPO infusion for temporal lobe epilepsy.