Convection-enhanced selective excitotoxic ablation of the neurons of the globus pallidus internus for treatment of parkinsonism in nonhuman primates.
OBJECTIVE
Selective treatment of central nervous system (CNS) structures holds therapeutic promise for many neurological disorders, including Parkinson's disease (PD). The ability to inhibit or augment specific neuronal populations within the CNS reliably by using present therapeutic techniques is limited. To overcome this problem, the authors modeled and developed a method in which convection was used to deliver compounds to deep brain nuclei in a reproducible, homogeneous, and targeted manner. To determine the feasibility and clinical efficacy of convective drug delivery for treatment of a neurological disorder, the investigators selectively ablated globus pallidus internus (GPi) neurons with quinolinic acid (QA), an excitotoxin, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced model of primate parkinsonism.


METHODS
After the parameters of convective distribution to the GPi were confirmed by infusion of biotinylated albumin into the GPi of a primate (Macaca mulatta), seven adult monkeys of this species were rendered either fully parkinsonian by intravenous injections of MPTP (five animals) or hemiparkinsonian by a right-sided intracarotid injection of this agent (two monkeys). Using convection-enhanced delivery to the GPi, animals were infused with either QA (three fully parkinsonian, two hemiparkinsonian) or saline (two fully parkinsonian). The three fully parkinsonian animals that underwent GPi lesioning with QA had substantial improvement of PD symptoms, manifested by a marked increase in activity (34 +/- 2.5%; mean +/- standard deviation) and dramatic improvement of parkinsonian clinical scores. In contrast, the control animals did not improve (activity monitor change = -1.5 +/- 0.5%). The two hemiparkinsonian animals that underwent QA lesioning of the GPi had dramatic recovery of extremity use. Histological examination revealed selective neural ablation of GPi neurons (mean loss 87%) with sparing of surrounding gray and white matter structures. No animal developed worsening signs of PD or neurological deficits after infusion.


CONCLUSIONS
Convection-enhanced delivery of QA permits selective, region-specific (GPi), and safe lesioning of neuronal subpopulations, resulting in dramatic improvement in parkinsonian symptomatology. The properties of convection-enhanced delivery indicate that this method could be used for chemical neurosurgery for medically refractory PD and that it may be ideal for cell-specific therapeutic ablation or trophic treatment of other targeted structures associated with CNS disorders.
Lonser
R R
RR
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, and Bioengineering and Physical Science Program, National Institutes of Health, Bethesda, Maryland 20892-1414, USA.
Corthésy
M E
ME
Morrison
P F
PF
Gogate
N
N
Oldfield
E H
EH
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000418:Albumins / Q000493:pharmacokinetics; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D015259:Dopamine Agents; D016503:Drug Delivery Systems; D005110:Extracellular Space / Q000378:metabolism; D005240:Feasibility Studies; D005917:Globus Pallidus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008253:Macaca mulatta; D008956:Models, Chemical; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D017378:Quinolinic Acid / Q000008:administration & dosage*; D015203:Reproducibility of Results
D000418:Albumins; D000978:Antiparkinson Agents; D015259:Dopamine Agents; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D017378:Quinolinic Acid