Intraputamenal infusion of GDNF in aged rhesus monkeys: distribution and dopaminergic effects

Abstract

Site-specific delivery of trophic factors in the brain may be important for achieving therapeutic efficacy without unwanted side effects. This study evaluated the site-specific infusion of glial cell line-derived neurotrophic factor (GDNF) into the right putamen of aged rhesus monkeys. After 4 weeks of continuous infusion at a rate of 22.5 microg/day, GDNF had diffused up to 11 mm from the catheter openings in the putamen into the rostral putamen, internal capsule, external capsule, caudate nucleus, and globus pallidus. Anisotropic flow along the external capsule tracts carried GDNF into the anterior amygdaloid area. Backflow of GDNF along the catheter track from the frontal cortex infiltrated juxtaposed corpus callosal and cortical tissue. GDNF was carried by retrograde transport to dopamine neurons in the ipsilateral substantia nigra, stimulating an 18% increase in the number of tyrosine hydroxylase (TH)-positive dopamine neurons and a 28% increase in dopamine neuron perikaryal size. Also, TH-positive fiber density was increased in the ipsilateral globus pallidus, caudate nucleus, and putamen. Anatomic effects from GDNF stimulation of the dopaminergic system were restricted to the ipsilateral hemisphere. Retrograde GDNF labeling was also present in a few TH-positive neurons in the locus coeruleus and a large cluster of TH-negative neurons in the ventral anterior thalamus. Anterograde transport of GDNF was evident in axons in the pyramidal tract from the cerebral peduncle to the caudal spinal cord. Tissue injury from the intraparenchymal catheter and continuous infusion was confined primarily to a narrow zone surrounding the track and was mild to moderate in severity.