Delayed infusion of GDNF promotes recovery of motor function in the partial lesion model of Parkinson's disease

Here we studied the effects of glial cell line-derived neurotrophic factor (GDNF) in a rat model that represents the symptomatic stages of Parkinson's disease. GDNF was infused starting 2 weeks after an intrastriatal 6-hydrox ydopamine (6-OHDA) lesion in order to halt the ongoing degeneration of the nigrostriatal dopaminergic neurons. GDNF or vehicle was infused in the stri atum or the lateral ventricle via an osmotic minipump over a total 4-week p eriod (2-6 weeks postlesion). Motor function was evaluated by the stepping, paw reaching and drug-induced motor asymmetry tests before the pump infusi on was initiated, and was repeated once during (5 weeks postlesion) and twi ce after the withdrawal of the minipumps (7 and 11 weeks postlesion). We fo und that within two weeks following the lesion approximate to 40% of the ni gral TH-positive neurons were lost. In the vehicle infusion groups there wa s an additional 20% cell loss between 2 and 12 weeks after the lesion. This latter cell loss occurred mainly in the caudal part of the SN whereas the cell loss in the rostral SN was almost complete within the first two weeks. Ventricular GDNF infusion completely blocked the late degenerating neurons in the caudal SN and had long lasting behavioural effects on the stepping test and amphetamine rotation, extending to 6 weeks after withdrawal of the factor. Striatal infusion affected the motor behaviour transiently during the infusion period but the motor performance of these animals returned to baseline upon cessation of the GDNF delivery, and the delayed nigral cell l oss was marginally affected. We conclude that intraventricular GDNF can suc cessfully block the already initiated degenerative process in the substanti a nigra, and that the effects achieved via the striatal route, when GDNF is given acutely after the lesion, diminish as the fibre terminal degeneratio n proceeds.