Gene Therapy with Adenoviral GDNF Vector in the Animal Model of Parkinson's Disease

Sung, Ki Han; Yoon, In Gyu; Jung, Hyun Sil; Kim, Eul Seon; Kim, Hyun Joo; Kim, Yang Ho; Bong, Sik Yoon; Kim, Seon; Kim, Jae Bong; Baek, Sun Yong

Abstract

A recombinant adenoviral vector encoding human GDNF gene (Ad -GDNF) was developed to investigate the effect of GDNF gene in 6 -OHDA -induced Parkinson's disease rat. The changes of rotatory behavior and density of TH -immunoreactive axon terminals and number of cell bodies were observed by the GDNF expression. Adult male Sprague -Dawley rats were used. Parkinson's disease (PD) rat models were prepared by the injection of 6 -OHDA into the striatum. After 1 week, the animals showing apomorphine -induced rotatory behavior above 7 turns/ min were defined as PD rat model. Ad -GDNF was injected into the striatum of animal model and tested the apomorphine -induced rotatory behavior at 1 week after injection. These animals were perfused with Zamboni fixative to investigate the morphological changes after rotatory behavior test. Instead of Ad -GDNF, Ad -LacZ injected PD rats were used as a control. The following results are obtained: 1. The apomorphine -induced rotational behavior was significantly reduced by the treatment of PD rat by the injection of Ad -GDNF. The Ad -LacZ injected PD rat showed no change in rotatory behavior. 2. The density of TH -ir axon terminals in the striatum was significantly increased by the Ad -GDNF injection (75% of normal side), but there was no change in the density by the Ad -LacZ injection (37% of normal side) compared to 6 - OHDA lesioned striatum. This means the Ad -GDNF injection prevented the degenerative change of TH -ir axon terminals in the stritum of the PD rat. 3. The number of TH -ir cell body was significantly recovered by the Ad -GDNF (82% of normal side), but there was not recovered by the Ad -LacZ injection (60% of normal side) compared to 6 -OHDA lesion. This means the retrogradely transported Ad -GDNF induced the TH expression in the dopaminergic neurons of the substantia nigra. Gene therapy with Ad -GDNF prevented the degeneration of dopaminergic neurons and axon terminals in the 6 - OHDA -induced PD rat.