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.
Jing
Meng
M
Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 2-5-1, Shikata-cho, Okayama 700-8558, Japan.
Shingo
Tetsuro
T
Yasuhara
Takao
T
Kondo
Akihiko
A
Morimoto
Takamasa
T
Wang
Feifei
F
Baba
Tanefumi
T
Yuan
Wen Ji
WJ
Tajiri
Naoki
N
Uozumi
Takashi
T
Murakami
Mayu
M
Tanabe
Mariko
M
Miyoshi
Yasuyuki
Y
Zhao
Shiguang
S
Date
Isao
I
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D053687:Adult Stem Cells / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation; D002465:Cell Movement; D002470:Cell Survival; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D004569:Electroencephalography; D004921:Erythropoietin / Q000627:therapeutic use*; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D015918:Infusion Pumps, Implantable; D007395:Interneurons / Q000187:drug effects; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology / Q000628:therapy*; D012815:Signal Processing, Computer-Assisted; D013226:Status Epilepticus / Q000139:chemically induced / Q000503:physiopathology / Q000628:therapy*; D033581:Stem Cell Transplantation
D004921:Erythropoietin; D007608:Kainic Acid