Reversal of experimental parkinsonism by using selective chemical ablation of the medial globus pallidus (original) (raw)

ARKINSON'S disease is produced by deregulated, dysfunctional neural activity in the medial globus pallidus (GPm). 8,13,14,38 Clinical studies have empirically identified the GPm as an effective target for ablation to relieve the syndrome. 6,20,26 Despite advances in surgical technique and the use of electrophysiological monitoring to identify pallidal neurons, 19,25,35 techniques now in use for ablation using radiofrequency or radiation 12,17,33 are inherently not selective and jeopardize the internal capsule and the optic tract, which lie adjacent to the GPm. 18,20 Therefore, the extent and location of pallidal lesions that can be made safely with those techniques are limited. Selectively active neurotoxins such as excitotoxins 1 provide a chemical means of destroying pallidal neurons while preserving adjacent glial cells and axonal fibers of passage that may be damaged when using nonselective techniques. 9,15 However, these agents cannot be administered by traditional techniques for regional drug delivery in the human central nervous system, because those delivery techniques rely on diffusion of molecules from the point of administration. In contrast, it has recently been shown that high-flow microinfusion can be used to produce interstitial convection of fluid in the brain at relatively homogeneous concentrations 11,24,29 and to deliver drugs efficiently to large nuclei 24 or other brain regions. 23 Initially, to test the feasibility of using high-flow micro-infusion of an excitotoxin to lesion a large nucleus in the primate brain, we perfused the GPm in two naive rhesus macaques with either kainic acid or ibotenic acid. Subsequently, to test the therapeutic potential of this paradigm in six monkeys that previously had been rendered unilaterally parkinsonian by intracarotid infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 2 we compared the behavior and brain tissue characteristics in three animals infused with kainic acid with those in another three animals that received control infusions. Materials and Methods The housing, care, handling, procedures, and anesthesia used for the rhesus macaques in this study were in accordance with the Guidelines on the Use of Animals in Experimental Research from the National Institutes of Health and were approved by the National Institute of Neurologic Disorders and Stroke Animal Care and Use Committee. Direct Interstitial Infusion of the GPm Operative procedures were identical for the determination of feasibility and for examining the therapeutic potential of neurotoxin infusion. After anesthesia had been induced by intramuscular administration of ketamine (10 mg/kg) and xylazine (3 mg/kg) and intravenous administration of thiopental-sodium (2-6 mg/kg), each macaque underwent placement of a No. 4 French endotracheal tube.