Chronic Intracerebral Delivery of Trophic Factors via a Programmable Pump as a Treatment for Parkinsonism

Grondin, Richard; Zhang, Zhiming; Elsberry, Dennis D.; Gerhardt, Greg A.; Gash, Don M.

doi:10.1385/1-59259-142-6:257

Cited by 10 publications

(13 citation statements)

References 30 publications

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“…Similar results were also seen in our previous studies of GDNF. 1,11,12 The histological findings indicated that the NHP brain can tolerate multiple surgical implants of the catheter as well as handle the flow rate and volume of the infusion through the putamenal catheter without observed behavioral change. Those results suggest that the flow rate could be used to achieve maximal distribution with minimal damage to the brain tissue.…”

Section: Discussionmentioning

confidence: 99%

“…During the first of the 4 surgeries, the pump was subcutaneously implanted in the lateral abdominal region as previously described. 11,12 The pump was connected to the cranial anchor via the proximal catheter, which was primed with the Gd-DTPA solution prior to attachment to the pump. Once the pump and proximal catheter were implanted (for Sites 2-4, the pump was already implanted), the primed anchor was connected to the distal catheter and a single bolus of between 50-100 μl was delivered at 10 μl/minute.…”

Section: Surgical Proceduresmentioning

confidence: 99%

“…12 The entire striatum was cut into 40-μm-thick sections, and every 12th section was stained with hematoxylin and eosin and cresyl violet (Nissl) for gross and microscopic assessment of the tissue damage from the surgical procedures and drug infusion.…”

Section: Histologymentioning

confidence: 99%

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Continuous intraputamenal convection-enhanced delivery in adult rhesus macaques

Fan

Nelson

Ai³

et al. 2015

JNS

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OBJECT Assessing the safety and feasibility of chronic delivery of compounds to the brain using convection-enhanced delivery (CED) is important for the further development of this important therapeutic technology. The objective of this study was to follow and model the distribution of a compound delivered by CED into the putamen of rhesus monkeys. METHODS The authors sequentially implanted catheters into 4 sites spanning the left and right putamen in each of 6 rhesus monkeys. The catheters were connected to implanted pumps, which were programmed to deliver a 5-mM solution of the MRI contrast agent Gd-DTPA at 0.1 μl/minute for 7 days and 0.3 μl/minute for an additional 7 days. The animals were followed for 28 days per implant cycle during which they were periodically examined with MRI. RESULTS All animals survived the 4 surgeries with no deficits in behavior. Compared with acute infusion, the volume of distribution (Vd) increased 2-fold with 7 days of chronic infusion. Increasing the flow rate 3-fold over the next week increased the Vd an additional 3-fold. Following withdrawal of the compound, the half-life of Gd-DTPA in the brain was estimated as 3.1 days based on first-order pharmacokinetics. Histological assessment of the brain showed minimal tissue damage limited to the insertion site. CONCLUSIONS These results demonstrate several important features in the development of a chronically implanted pump and catheter system: 1) the ability to place catheters accurately in a predetermined target; 2) the ability to deliver compounds in a chronic fashion to the putamen; and 3) the use of MRI and MR visible tracers to follow the evolution of the infusion volume over time.

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Section: Discussionmentioning

confidence: 99%

Section: Surgical Proceduresmentioning

confidence: 99%

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Continuous intraputamenal convection-enhanced delivery in adult rhesus macaques

Fan

Nelson

Ai³

et al. 2015

JNS

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“…The implantable pump is connected to a catheter, which is usually made of polyurethane. The catheters are stereotactically implanted into the brain as per previously described procedures [98]. Prior studies have used different types of catheters (1 mm O.D.)…”

Section: B Effects Of Gdnf In Non-human Primates: Proof Of Conceptmentioning

confidence: 99%

“…The catheter is then seated in the groove of an L-shaped nylon device anchored against the skull using two nylon screws, and connecting tubing is tunneled to the pump that is subcutaneously implanted in the lateral abdominal region of the nonhuman primate [98].…”

Section: B Effects Of Gdnf In Non-human Primates: Proof Of Conceptmentioning

confidence: 99%

The Impact of Neurotechnology on Rehabilitation

Berger

Gerhardt

Liker

et al. 2008

IEEE Rev. Biomed. Eng.

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This paper present results of a multi-disciplinary project that is developing a microchip-based neural prosthesis for the hippocampus, a region of the brain responsible for the formation of long-term memories. Damage to the hippocampus is frequently associated with epilepsy, stroke, and dementia (Alzheimer's disease) and is considered to underlie the memory deficits related to these neurological conditions. The essential goals of the multi-laboratory effort include: (1) experimental study of neuron and neural network function--how does the hippocampus encode information? (2) formulation of biologically realistic models of neural system dynamics--can that encoding process be described mathematically to realize a predictive model of how the hippocampus responds to any event? (3) microchip implementation of neural system models--can the mathematical model be realized as a set of electronic circuits to achieve parallel processing, rapid computational speed, and miniaturization? and (4) creation of hybrid neuron-silicon interfaces-can structural and functional connections between electronic devices and neural tissue be achieved for long-term, bi-directional communication with the brain? By integrating solutions to these component problems, we are realizing a microchip-based model of hippocampal nonlinear dynamics that can perform the same function as part of the hippocampus. Through bi-directional communication with other neural tissue that normally provides the inputs and outputs to/from a damaged hippocampal area, the biomimetic model could serve as a neural prosthesis. A proof-of-concept will be presented in which the CA3 region of the hippocampal slice is surgically removed and is replaced by a microchip model of CA3 nonlinear dynamics--the "hybrid" hippocampal circuit displays normal physiological properties. How the work in brain slices is being extended to behaving animals also will be described.

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Trophic factor distribution predicts functional recovery in parkinsonian monkeys

Gash

Zhang

et al. 2005

Annals of Neurology

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Glial cell line-derived neurotrophic factor (GDNF) promotes the survival, growth, and regeneration of dopamine neurons in the midbrain that degenerate in Parkinson's disease. However, translating successful animal studies into effective clinical therapy for Parkinson's disease has proved difficult. In this article, using pulsed infusion for convection-enhanced delivery of GDNF, we have analyzed two variables hypothesized to be important for achieving efficacy: dose and GDNF distribution in the target tissue. Motor functions were significantly improved in rhesus monkeys with unilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism that received midbrain infusion of GDNF for 10 weeks. The volume of distribution of GDNF in the five trophic factor recipients varied more than fivefold, from 59 to 325 mm3, and significantly correlated with motor function improvements. Significant increases were evident in the number of midbrain dopamine neurons immunopositive for tyrosine hydroxylase in both the substantia nigra and ventral tegmental area. Based on neurochemical and quantitative morphological measures, GDNF administration promoted recovery of both the nigrostriatal and ventral tegmental area-nucleus accumbens dopaminergic pathways without producing evident side effects. Increasing the dose threefold did not increase efficacy, suggesting that after achieving a critical threshold, GDNF tissue distribution is more important than dose for trophic stimulation of dopamine neurons.

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Chronic Intracerebral Delivery of Trophic Factors via a Programmable Pump as a Treatment for Parkinsonism

Cited by 10 publications

References 30 publications

Continuous intraputamenal convection-enhanced delivery in adult rhesus macaques

Continuous intraputamenal convection-enhanced delivery in adult rhesus macaques

The Impact of Neurotechnology on Rehabilitation

Trophic factor distribution predicts functional recovery in parkinsonian monkeys

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