Dataset Information

Glial Cell Line-Derived Neurotrophic Factor and Chondroitinase Promote Axonal Regeneration in a Chronic Denervation Animal Model.

ABSTRACT: Functional recovery following nerve injury declines when target re-innervation is delayed. Currently, no intervention exists to improve outcomes after prolonged denervation. We explored the neuroregenerative effects of glial cell line-derived neurotrophic factor (GDNF) and chondroitinase (CDN) in a chronic denervation animal model. A fibrin-based sustained delivery method for growth factors was optimized in vitro and in vivo, and then tested in our animal model. GDNF, CDN, and GDNF+CDN were injected into the denervated stump at the time of nerve repair. Histomorphometry and retrograde labeling were used to assess axonal regeneration. The mechanisms promoting such regeneration were explored with immunofluorescence. Five weeks after repair, the GDNF+CDN group had the highest number and maturity of axons. GDNF was noted to preferentially promote axonal maturity, whereas CDN predominantly increased the number of axons. GDNF favored motor neuron regeneration, and upregulated Ki67 in Schwann cells. CDN did not favor motor versus sensory regeneration and was noted to cleave inhibitory endoneurial proteoglycans. Early measures of nerve regeneration after delayed repair are improved by activating Schwann cells and breaking down the inhibitory proteoglycans in the distal nerve segment, suggesting a role for GDNF+CDN to be translated for human nerve repairs.

SUBMITTER: Sarhane KA

PROVIDER: S-EPMC6985423 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Glial Cell Line-Derived Neurotrophic Factor and Chondroitinase Promote Axonal Regeneration in a Chronic Denervation Animal Model.

Sarhane Karim A KA Tuffaha Sami H SH Ibrahim Zuhaib Z Cashman Christopher R CR Krick Kellin K Martin Russell R Broyles Justin M JM Cooney Damon S DS Lee W P Andrew WPA Mi Ruifa R Mao Hai-Quan HQ Höke Ahmet A Brandacher Gerald G

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20191001 4

Functional recovery following nerve injury declines when target re-innervation is delayed. Currently, no intervention exists to improve outcomes after prolonged denervation. We explored the neuroregenerative effects of glial cell line-derived neurotrophic factor (GDNF) and chondroitinase (CDN) in a chronic denervation animal model. A fibrin-based sustained delivery method for growth factors was optimized in vitro and in vivo, and then tested in our animal model. GDNF, CDN, and GDNF+CDN were inje ...[more]

PMID: 31148054

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Project description:We investigated the effects of glial cell line-derived neurotrophic factor (GDNF) in Parkinson's disease, using intermittent intraputamenal convection-enhanced delivery via a skull-mounted transcutaneous port as a novel administration paradigm to potentially afford putamen-wide therapeutic delivery. This was a single-centre, randomized, double-blind, placebo-controlled trial. Patients were 35-75 years old, had motor symptoms for 5 or more years, and presented with moderate disease severity in the OFF state [Hoehn and Yahr stage 2-3 and Unified Parkinson's Disease Rating Scale motor score (part III) (UPDRS-III) between 25 and 45] and motor fluctuations. Drug delivery devices were implanted and putamenal volume coverage was required to exceed a predefined threshold at a test infusion prior to randomization. Six pilot stage patients (randomization 2:1) and 35 primary stage patients (randomization 1:1) received bilateral intraputamenal infusions of GDNF (120 µg per putamen) or placebo every 4 weeks for 40 weeks. Efficacy analyses were based on the intention-to-treat principle and included all patients randomized. The primary outcome was the percentage change from baseline to Week 40 in the OFF state (UPDRS-III). The primary analysis was limited to primary stage patients, while further analyses included all patients from both study stages. The mean OFF state UPDRS motor score decreased by 17.3 ± 17.6% in the active group and 11.8 ± 15.8% in the placebo group (least squares mean difference: -4.9%, 95% CI: -16.9, 7.1, P = 0.41). Secondary endpoints did not show significant differences between the groups either. A post hoc analysis found nine (43%) patients in the active group but no placebo patients with a large clinically important motor improvement (?10 points) in the OFF state (P = 0.0008). 18F-DOPA PET imaging demonstrated a significantly increased uptake throughout the putamen only in the active group, ranging from 25% (left anterior putamen; P = 0.0009) to 100% (both posterior putamina; P < 0.0001). GDNF appeared to be well tolerated and safe, and no drug-related serious adverse events were reported. The study did not meet its primary endpoint. 18F-DOPA imaging, however, suggested that intermittent convection-enhanced delivery of GDNF produced a putamen-wide tissue engagement effect, overcoming prior delivery limitations. Potential reasons for not proving clinical benefit at 40 weeks are discussed.

Dataset Information

Glial Cell Line-Derived Neurotrophic Factor and Chondroitinase Promote Axonal Regeneration in a Chronic Denervation Animal Model.

Publications

Glial Cell Line-Derived Neurotrophic Factor and Chondroitinase Promote Axonal Regeneration in a Chronic Denervation Animal Model.

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