INTRACEREBROVENTRICULAR GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR IMPROVES MOTOR FUNCTION AND SUPPORTS NIGROSTRIATAL DOPAMINE NEURONS IN BILATERALLY 6-HYDROXYDOPAMINE LESIONED RATS

In order to evaluate the efficacy of glial cell line-derived neurotrop hic factor (GDNF) in a model of advanced Parkinson's disease, we studi ed rats with extensive bilateral lesions of the nigrostriatal pathway. Adult male F344 rats were injected bilaterally into the medial forebr ain bundle with the neurotoxin 6-hydroxydopamine. Locomotor ability as measured by total distance traveled in an open field over 20 min, as well as von Frey hair testing of sensorimotor neglect, was monitored w eekly. Bats demonstrating severe motor impairment and sensorimotor neg lect were used for this study and were sorted to achieve similar avera ge behavioral scores between the two treatment groups, After 2 weeks o f pretesting, the rats received 250 mu g GDNF or vehicle injected into the right lateral cerebral ventricle. Three weeks later, an additiona l 500 mu g GDNF or vehicle was injected into the contralateral ventric le, The rats were monitored for another 2 weeks prior to sacrifice. Be havioral results indicated that von Frey hair scores were inconsistent between tests for each rat and were unchanged following GDNF treatmen t. However, GDNF recipients demonstrated significant improvement in lo comotor ability compared to vehicle recipients. High-pressure liquid c hromatography-electrochemical detection analysis of neurotransmitter l evels revealed a significant increase in dopamine content within the s ubstantia nigra and ventral tegmenta, but not the striata, of GDNF-tre ated rats. Further, immunohistochemical staining of tissues from match ed pairs of rats revealed increased numbers of tyrosine hydroxylase-po sitive ventral mesencephalic neurons in one of the two pairs of rats e xamined. These results suggest that intracerebroventricular GDNF admin istration improves motor ability and supports nigrostriatal dopaminerg ic neurons in a model of severe Parkinson's disease. (C) 1997 Academic Press.