GDNF-induced cerebellar toxicity: A brief review.
Identifieur interne : 001D63 ( Ncbi/Merge ); précédent : 001D62; suivant : 001D64GDNF-induced cerebellar toxicity: A brief review.
Auteurs : Matthias Luz [Canada] ; Erich Mohr [Canada] ; H Christian Fibiger [Canada]Source :
- Neurotoxicology [ 1872-9711 ] ; 2016.
English descriptors
- KwdEn :
- Animals, Cerebellum (drug effects), Cerebellum (pathology), Cerebellum (physiopathology), Dose-Response Relationship, Drug, Glial Cell Line-Derived Neurotrophic Factor (administration & dosage), Glial Cell Line-Derived Neurotrophic Factor (adverse effects), Humans, Infusions, Intraventricular, Microinjections, Neuroprotective Agents (administration & dosage), Neuroprotective Agents (adverse effects), Putamen (drug effects).
- MESH :
- chemical , administration & dosage : Glial Cell Line-Derived Neurotrophic Factor, Neuroprotective Agents.
- chemical , adverse effects : Glial Cell Line-Derived Neurotrophic Factor, Neuroprotective Agents.
- drug effects : Cerebellum, Putamen.
- pathology : Cerebellum.
- physiopathology : Cerebellum.
- Animals, Dose-Response Relationship, Drug, Humans, Infusions, Intraventricular, Microinjections.
Abstract
Recombinant-methionyl human glial cell line-derived neurotrophic factor (GDNF) is known for its neurorestorative and neuroprotective effects in rodent and primate models of Parkinson's disease (PD). When administered locally into the putamen of Parkinsonian subjects, early clinical studies showed its potential promise as a disease-modifying agent. However, the development of GDNF for the treatment of PD has been significantly clouded by findings of cerebellar toxicity after continuous intraputamenal high-dose administration in a 6-month treatment/3-month recovery toxicology study in rhesus monkeys. Specifically, multifocal cerebellar Purkinje cell loss affecting 1-21% of the cerebellar cortex was observed in 4 of 15 (26.7%; 95% confidence interval [CI]: 10.5-52.4%) animals treated at the highest dose level tested (3000μg/month). No cerebellar toxicity was observed at lower doses (450 and 900μg/month) in the same study, or at similar or higher doses (up to 10,000μg/month) in subchronic or chronic toxicology studies testing intermittent intracerebroventricular administration. While seemingly associated with the use of GDNF, the pathogenesis of the cerebellar lesions has not been fully understood to date. This review integrates available information to evaluate potential pathogenic mechanisms and provide a consolidated assessment of the findings. While other explanations are considered, the existing evidence is most consistent with the hypothesis that leakage of GDNF into cerebrospinal fluid during chronic infusions into the putamen down-regulates GDNF receptors on Purkinje cells, and that subsequent acute withdrawal of GDNF generates the observed lesions. The implications of these findings for clinical studies with GDNF are discussed.
DOI: 10.1016/j.neuro.2015.10.011
PubMed: 26535469
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When administered locally into the putamen of Parkinsonian subjects, early clinical studies showed its potential promise as a disease-modifying agent. However, the development of GDNF for the treatment of PD has been significantly clouded by findings of cerebellar toxicity after continuous intraputamenal high-dose administration in a 6-month treatment/3-month recovery toxicology study in rhesus monkeys. Specifically, multifocal cerebellar Purkinje cell loss affecting 1-21% of the cerebellar cortex was observed in 4 of 15 (26.7%; 95% confidence interval [CI]: 10.5-52.4%) animals treated at the highest dose level tested (3000μg/month). No cerebellar toxicity was observed at lower doses (450 and 900μg/month) in the same study, or at similar or higher doses (up to 10,000μg/month) in subchronic or chronic toxicology studies testing intermittent intracerebroventricular administration. While seemingly associated with the use of GDNF, the pathogenesis of the cerebellar lesions has not been fully understood to date. This review integrates available information to evaluate potential pathogenic mechanisms and provide a consolidated assessment of the findings. While other explanations are considered, the existing evidence is most consistent with the hypothesis that leakage of GDNF into cerebrospinal fluid during chronic infusions into the putamen down-regulates GDNF receptors on Purkinje cells, and that subsequent acute withdrawal of GDNF generates the observed lesions. The implications of these findings for clinical studies with GDNF are discussed.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26535469</PMID><DateCreated><Year>2016</Year><Month>02</Month><Day>14</Day></DateCreated><DateCompleted><Year>2016</Year><Month>12</Month><Day>13</Day></DateCompleted><DateRevised><Year>2016</Year><Month>12</Month><Day>30</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1872-9711</ISSN><JournalIssue CitedMedium="Internet"><Volume>52</Volume><PubDate><Year>2016</Year><Month>Jan</Month></PubDate></JournalIssue><Title>Neurotoxicology</Title><ISOAbbreviation>Neurotoxicology</ISOAbbreviation></Journal><ArticleTitle>GDNF-induced cerebellar toxicity: A brief review.</ArticleTitle><Pagination><MedlinePgn>46-56</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.neuro.2015.10.011</ELocationID><ELocationID EIdType="pii" ValidYN="Y">S0161-813X(15)30011-5</ELocationID><Abstract><AbstractText>Recombinant-methionyl human glial cell line-derived neurotrophic factor (GDNF) is known for its neurorestorative and neuroprotective effects in rodent and primate models of Parkinson's disease (PD). When administered locally into the putamen of Parkinsonian subjects, early clinical studies showed its potential promise as a disease-modifying agent. However, the development of GDNF for the treatment of PD has been significantly clouded by findings of cerebellar toxicity after continuous intraputamenal high-dose administration in a 6-month treatment/3-month recovery toxicology study in rhesus monkeys. Specifically, multifocal cerebellar Purkinje cell loss affecting 1-21% of the cerebellar cortex was observed in 4 of 15 (26.7%; 95% confidence interval [CI]: 10.5-52.4%) animals treated at the highest dose level tested (3000μg/month). No cerebellar toxicity was observed at lower doses (450 and 900μg/month) in the same study, or at similar or higher doses (up to 10,000μg/month) in subchronic or chronic toxicology studies testing intermittent intracerebroventricular administration. While seemingly associated with the use of GDNF, the pathogenesis of the cerebellar lesions has not been fully understood to date. This review integrates available information to evaluate potential pathogenic mechanisms and provide a consolidated assessment of the findings. While other explanations are considered, the existing evidence is most consistent with the hypothesis that leakage of GDNF into cerebrospinal fluid during chronic infusions into the putamen down-regulates GDNF receptors on Purkinje cells, and that subsequent acute withdrawal of GDNF generates the observed lesions. The implications of these findings for clinical studies with GDNF are discussed.</AbstractText><CopyrightInformation>Copyright © 2015 The Authors. Published by Elsevier B.V. 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uniqKey="Luz M" first="Matthias" last="Luz">Matthias Luz</name></noRegion><name sortKey="Fibiger, H Christian" sort="Fibiger, H Christian" uniqKey="Fibiger H" first="H Christian" last="Fibiger">H Christian Fibiger</name><name sortKey="Mohr, Erich" sort="Mohr, Erich" uniqKey="Mohr E" first="Erich" last="Mohr">Erich Mohr</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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