Zonisamide facilitates survival of human iPS cell-derived dopaminergic neurons in the rat striatum

It is reported that the transplantation of dopaminergic (DA) progenitors derived from pluripotent stem cells improves the behavior of Parkinson's disease (PD) model animals. However, the number of survived DA neurons was reported to be about 10% of the transplanted cells. This low survivability limits the clinical application of this stem cell-based therapy for PD. Recently, it was reported that zonisamide (ZNS) increased the number of survived DA neurons upon the transplantation of mouse induced pluripotent stem (iPS) cell-derived DA progenitors in the mouse striatum. It is not known, however, whether ZNS exerts the same effect on human DA neurons. We induced DA progenitors from human iPS cells and transplanted them into the rat striatum with daily administration of ZNS. The number of survived DA neurons was evaluated one and four months after transplantation by immunohistochemistry. To assess the mechanism of action of ZNS, we performed a microarray analysis to compare the gene expression profile in striatum treated with or without ZNS. The immunofluorescense study at one and four months revealed that the number of survived DA neurons was significantly increased with the administration of ZNS. The microarray analysis revealed that the expression of Slitrk6 was up-regulated in rat striatum treated with ZNS. SLIT and NTRK like protein 6 (SLITRK6) was expressed by cholinergic neurons in the striatum. In addition, survival and neurite extension were enhanced when human iPS cell-derived DA progenitors were cultured on SLITRK6-expressing HEK293T cells. ZNS promotes the survival of DA neurons after the transplantation of human iPS cell-derived DA progenitors in the rat striatum. SLITRK6 is suggested to be involved in this supportive effect of ZNS by modulating the environment of the host brain. In order to assess the indirect effect of ZNS, we performed a microarray analysis of the rat striatum with or without administration of ZNS for seven successive days.