To investigate the protective and therapeutic effects of Neurturin (NTN)-expressing c17.2 neural stem cells (NSCs) on rat models of Parkinson's disease (PD).
Background: Genetically engineered NSCs are promising vectors for the treatment of neurodegenerative diseases, especially PD. NTN, a member of the glial cell line-derived neurotrophic factor (GDNF) family, has been demonstrated to act specifically on mesencephalic dopaminergic neurons, suggesting its protective and therapeutic potentials for PD.
Methods: A NTN-secreting c17.2 NSC line was generated. NTN-c17.2, Mock-c17.2 and PBS were injected into the striatum of rats in NTN, Mock and PBS groups, respectively, before and after injection of 6-OHDA into the same striatum of rats. The rotational behavior, dopamine and its metabolites, tyrosine hydroxylase (TH)-positive neurons and neurotrophic factors expression were detected by Northern blotting, apomorphine/amphetamine, HPLC, immunohistochemical staining, in suit hybridization and RT-PCR, respectively.
Results: NTN-releasing NSCs engrafted and integrated in the host striatum with good success, gave rise to neurons, astrocytes and oligodendrocytes, and maintained stable, high-level NTN expression. Inverse transfer of NTN protein into the substantia nigra was able to protect dopaminergic neurons from 6-OHDA toxicity. The behavioral asymmetry in the NTN-c17.2 group was more improved compared with the PBS and Mock-17.2 groups in protective and therapeutic studies. HPLC analysis indicated that the contents of dopamine and its metabolites in the corpus striatum of the NTN-c17.2 group and the Mock-c17.2 group were significantly higher than in the PBS group. RT-PCR assays showed that GDNF, NGF and BDNF mRNAs were expressed in the Mock-c17.2 cells.
Conclusion: The transplantation of NTN-secreting NSCs exerted protective and therapeutic effects on PD rat model, with the protective effect being more significant than the therapeutic effect. The therapeutic effect of Mock-c17.2 cell grafts may be associated with neurotrophic factors produced by NSCs. NTN-c17.2 cell grafts may reinforece the therapeutic effect by high expression of NTN.