Intermittent convection-enhanced delivery of GDNF into rhesus monkey putamen: absence of local or cerebellar toxicity

Autor: Krystof S. Bankiewicz, Erich Mohr, Matthias Luz, H. Christian Fibiger, John Bringas, Diane E. Stockinger, Kristen J. Nikula, Chris Boiko, Philip C. Allen, Owen T. Lewis, Max Woolley
Rok vydání: 2018
Předmět:
0301 basic medicine
Male
Cerebellum
Parkinson's disease
Health
Toxicology and Mutagenesis
animal diseases
Drug Evaluation
Preclinical
Neurodegenerative
Pharmacology
Toxicology
0302 clinical medicine
Drug Delivery Systems
Neurotrophic factors
Glial cell line-derived neurotrophic factor
Chronic
Toxicity Tests
Chronic
Infusion Pumps
biology
Putamen
Pharmacology and Pharmaceutical Sciences
General Medicine
Infusion Pumps
Implantable
GDNF
Preclinical
medicine.anatomical_structure
Neuroprotective Agents
Purkinje cells
Neurological
Toxicity
Stem Cell Research - Nonembryonic - Non-Human
Implantable
Cerebellar Purkinje cell
Convection
Neuroprotection
Drug Administration Schedule
Organ Toxicity and Mechanisms
03 medical and health sciences
Toxicity Tests
medicine
Animals
Glial Cell Line-Derived Neurotrophic Factor
No-Observed-Adverse-Effect Level
Convection-enhanced delivery
business.industry
urogenital system
Neurosciences
Stem Cell Research
Spinal cord
Macaca mulatta
Brain Disorders
030104 developmental biology
nervous system
biology.protein
Parkinson’s disease
Rhesus monkey
Drug Evaluation
business
030217 neurology & neurosurgery
Zdroj: Archives of Toxicology
Archives of toxicology, vol 92, iss 7
ISSN: 1432-0738
Popis: Glial cell line-derived neurotrophic factor (GDNF) has demonstrated neurorestorative and neuroprotective effects in rodent and nonhuman primate models of Parkinson’s disease. However, continuous intraputamenal infusion of GDNF (100 µg/day) resulted in multifocal cerebellar Purkinje cell loss in a 6-month toxicity study in rhesus monkeys. It was hypothesized that continuous leakage of GDNF into the cerebrospinal fluid compartment during the infusions led to down-regulation of GDNF receptors on Purkinje cells, and that subsequent acute withdrawal of GDNF then mediated the observed cerebellar lesions. Here we present the results of a 9-month toxicity study in which rhesus monkeys received intermittent intraputamenal infusions via convection-enhanced delivery. Animals were treated with GDNF (87.1 µg; N = 14) or vehicle (N = 6) once every 4 weeks for a total of 40 weeks (11 treatments). Four of the GDNF-treated animals were utilized in a satellite study assessing the impact of concomitant catheter repositioning prior to treatment. In the main study, eight animals (5 GDNF, 3 control) were euthanized at the end of the treatment period, along with the four satellite study animals, while the remaining eight animals (5 GDNF, 3 control) were euthanized at the end of a 12-week recovery period. There were no GDNF-related adverse effects and in particular, no GDNF-related microscopic findings in the brain, spinal cord, dorsal root ganglia, or trigeminal ganglia. Therefore, 87.1 µg/4 weeks is considered the no observed adverse effect level for GDNF in rhesus monkeys receiving intermittent, convection-enhanced delivery of GDNF for 9 months. Electronic supplementary material The online version of this article (10.1007/s00204-018-2222-z) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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