Abstracts

Rationale: Status epilepticus (SE) manifested as extended seizures and the maximal expression of epilepsy with a high morbidity and mortality and may also eventually cause deterioration of cognitive function with the mechanisms underlying neuronal cell death and aberrant mossy fiber sprouting (MFS) in the hippocampus. Intravenous infusion of mesenchymal stem cells (MSCs) is safe and provides functional improvements via multiple therapeutic mechanisms including neuroprotection. The present study aimed to test the hypothesis that systemically delivered MSCs provide neuroprotection to reduce epileptogenesis in an experimental SE model with lithium-pilocarpine injection in the rat. Methods: SE was induced using the lithium-pilocarpine injection model. The seizure frequency was scored using a video-monitoring system and the Morris water maze test was carried out to evaluate cognitive function. Comparisons were made between MSCs- and vehicle-infused rats. Immunohistochemical staining was performed to detect Green fluorescent protein (GFP)+ MSCs and to quantify the number of GAD67+ and NeuN+ neurons in the hippocampus. Manganese-enhanced magnetic resonance imaging (MEMRI) and Timm staining were also performed to assess the MFS. Results: MSC infusion inhibited epileptogenesis and preserved cognitive function after SE. The infused GFP+ MSCs were accumulated in the hippocampus and were associated with the preservation of GAD67+ and NeuN+ hippocampal neurons. Furthermore, the MSC infusion suppressed the aberrant MFS in the hippocampus as evidenced by MEMRI and Timm staining. Conclusions: This study demonstrated that the intravenous infusion of MSCs mitigated epileptogenesis, thus advancing MSCs as an effective approach for epilepsy in clinical practice. Funding: This work was supported by JSPS KAKENHI [grant number 16K09993]; Grants-in-Aid for Regional R&D Proposal-Based Program [grant number H26 T-1-37, H29 SL-2] from the Northern Advancement Center for Science & Technology of Hokkaido, Japan; Akiyama Life Science Foundation; Morinaga Houshikai; RR&D and BLRD Services of the U.S. Department of Veterans Affairs (B7335R, B9260L); National Multiple Sclerosis Society [grant number RG2135]; and Connecticut Stem Cell Research Program [grant number 12-SCB-Yale-05]. The sponsors had no role in the design or conduct of this study.