title: Continuous intranigral infusion is not associated with observable behavioral deficits or marked pathology: a preclinical safety study.
abstract: OBJECTIVE A better understanding of the effects of chronically delivering compounds to the substantia nigra and nearby areas is important for the development of new therapeutic approaches to treat alpha-synucleinopathies, like Parkinson's disease. Whether chronic intranigral delivery of an infusate could be achieved without causing motor dysfunction or marked pathology remains unclear. The authors evaluated the tolerability of continuously delivering an infusate directly into the rhesus monkey substantia nigra via a programmable pump coupled to a novel intraparenchymal needle-tip catheter surgically implanted using MRI-guided techniques. METHODS The MRI contrast agent gadopentetate dimeglumine (Magnevist, 5 mM) was used to noninvasively evaluate catheter patency and infusion volume associated with 2 flow rates sequentially tested in each of 3 animals: 0.1 µl/min for 14 days into the right substantia nigra and 0.1 µl/min for 7 days plus 0.2 µl/min for an additional 7 days into the left substantia nigra. Flow rate tolerability was assessed via clinical observations and a microscopic examination of the striatum and midbrain regions. RESULTS Evaluation of postsurgical MRI indicated that all 6 catheters remained patent throughout the study and that the volume of distribution achieved in the left midbrain region at a rate of up to 0.2 µl/min (2052 ± 168 mm3) was greater than that achieved in the right midbrain region at a constant rate of 0.1 µl/min (1225 ± 273 mm3) by nearly 2-fold. Both flow rates provided sufficient infusate coverage of the rhesus (and possibly the human) midbrain region. There were no indications of observable deficits in behavior. Histopathological evaluations confirmed that all catheter tips were placed in or near the pars compacta region of the substantia nigra in all animals. There was no evidence of infection at any of the 6 catheter sites. Mild to moderate microglial reactions were observed at most catheter track sites and were comparable between the 2 infusion rates. Finally, there was neither observable decrease of tyrosine hydroxylase staining in the striatum nor detectable necrosis of neurons in the pars compacta region of the substantia nigra in any of the animals. CONCLUSIONS The data from this study support the feasibility of using a pump-and-catheter system for chronic intranigral infusion and lay the foundation for using this approach to treat Parkinson's disease or other related degenerative diseases that would benefit from targeted drug delivery to the substantia nigra or to other brainstem regions.
authors.affiliation: Departments of 1 Anatomy and Neurobiology and.
authors.forename: Richard
authors.initials: R
authors.lastname: Grondin
authors.affiliation: Departments of 1 Anatomy and Neurobiology and.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ai
authors.affiliation: Radiology, University of Kentucky Medical Center, Lexington, Kentucky.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Hardy
authors.affiliation: Tox Path Specialists LLC, Frederick, Maryland.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Butt
authors.affiliation: Medtronic Inc., Minneapolis, Minnesota; and.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Nelson
authors.affiliation: Medtronic Inc., Minneapolis, Minnesota; and.
authors.forename: Jack D
authors.initials: JD
authors.lastname: Lemmon
authors.affiliation: Alnylam Pharmaceuticals Inc., Cambridge, Massachusetts.
authors.forename: David
authors.initials: D
authors.lastname: Bumcrot
authors.affiliation: Departments of 1 Anatomy and Neurobiology and.
authors.forename: Don M
authors.initials: DM
authors.lastname: Gash
authors.affiliation: Departments of 1 Anatomy and Neurobiology and.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Gerhardt
authors.affiliation: Departments of 1 Anatomy and Neurobiology and.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002408:Catheters, Indwelling; D003287:Contrast Media; D005240:Feasibility Studies; D005260:Female; D019786:Gadolinium DTPA; D007260:Infusion Pumps; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D023421:Models, Animal; D061214:Patient Safety; D013378:Substantia Nigra / Q000000981:diagnostic imaging / Q000473:pathology
chemical_list: D003287:Contrast Media; D019786:Gadolinium DTPA
keywords: GDNF = glial cell–line derived neurotrophic factor; HLA = human leukocyte antigen; IM = intramuscularly; MRI; Magnevist; PB = phosphate buffer; PD = Parkinson's disease; Parkinson's disease; TH = tyrosine hydroxylase; gadopentetate dimeglumine; rhesus; segmentation; siRNA = small interfering RNA; substantia nigra