Exogenous GDNF increase the migration of the neural stem cells with no protection against kainic acid-induced excitotoxic cell death in rats

Abstract

Glia cell line-derived neurotrophic factor (GDNF) is a potent survival factor for several neuron types. In this study, we have evaluated the utility of adenovirus-based vectors (Ad) and hippocampal neural stem cells (NSCs) as genetic tools for the delivery of a therapeutic protein, GDNF, in hippocampus tissues damaged by kainic acid (KA)-induced excitotoxicity. The experimental animals were treated with KA 3 days prior to exposure to Ad-GDNF, NSCs, and NSCs infected with Ad-GDNF (Ad-GDNF-NSCs). Seven days after the treatments with Ad-GDNF, NSCs and Ad-GDNF-NSCs, the effects of the treatments were evaluated. GAD-67 labeled cells originating from the transplanted NSCs were observed at increased levels in the Ad-GDNF-NSCs-treated rats as compared to the NSCs-only rats. In situ apoptosis assays showed that the levels of TUNEL-positive cells were slightly, but not significantly, reduced in the Ad-GDNF and Ad-GDNF-NSCs groups, as compared to the saline and NSCs only groups. GDNF expression by NSCs and Ad-GDNF was upregulated as the consequence of adenoviral gene delivery in the NSCs and Ad-GDNF-treated rats, and the transplanted NSCs were shown to have migrated to the hippocampal regions in Ad-GDNF-NSCs rats to a greater degree than in the NSCs-only rats. Furthermore, in the region in which the NSCs were detected, GDNF and GAD-67 expression were increased. These results indicate that the migration and differentiation of NSCs may be associated with the expression of GDNF. However, cell death consequent to KA administration was not prevented by upregulated GDNF and NSCs transplantation. Collectively, our results indicate that GDNF may exert effects on the migration and differentiation of NSCs, but there are no protective properties with regard to excitotoxically damaged hippocampal tissue. (C) 2012 Elsevier B.V. All rights reserved.