GDNF-induced cerebellar toxicity: A brief review.
Identifieur interne : 000346 ( Main/Exploration ); précédent : 000345; suivant : 000347GDNF-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
Affiliations:
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: 000341
- to stream PubMed, to step Curation: 000341
- to stream PubMed, to step Checkpoint: 000341
- to stream Ncbi, to step Merge: 001D63
- to stream Ncbi, to step Curation: 001D63
- to stream Ncbi, to step Checkpoint: 001D63
- to stream Main, to step Merge: 000347
- to stream Main, to step Curation: 000346
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">GDNF-induced cerebellar toxicity: A brief review.</title>
<author><name sortKey="Luz, Matthias" sort="Luz, Matthias" uniqKey="Luz M" first="Matthias" last="Luz">Matthias Luz</name>
<affiliation wicri:level="1"><nlm:affiliation>MedGenesis Therapeutix Inc., Canada. Electronic address: matthiasluz@medgenesis.com.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>MedGenesis Therapeutix Inc.</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mohr, Erich" sort="Mohr, Erich" uniqKey="Mohr E" first="Erich" last="Mohr">Erich Mohr</name>
<affiliation wicri:level="1"><nlm:affiliation>MedGenesis Therapeutix Inc., Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>MedGenesis Therapeutix Inc.</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Fibiger, H Christian" sort="Fibiger, H Christian" uniqKey="Fibiger H" first="H Christian" last="Fibiger">H Christian Fibiger</name>
<affiliation wicri:level="1"><nlm:affiliation>MedGenesis Therapeutix Inc., Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>MedGenesis Therapeutix Inc.</wicri:regionArea>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PubMed</idno>
<date when="2016">2016</date>
<idno type="RBID">pubmed:26535469</idno>
<idno type="pmid">26535469</idno>
<idno type="doi">10.1016/j.neuro.2015.10.011</idno>
<idno type="wicri:Area/PubMed/Corpus">000341</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000341</idno>
<idno type="wicri:Area/PubMed/Curation">000341</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000341</idno>
<idno type="wicri:Area/PubMed/Checkpoint">000341</idno>
<idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000341</idno>
<idno type="wicri:Area/Ncbi/Merge">001D63</idno>
<idno type="wicri:Area/Ncbi/Curation">001D63</idno>
<idno type="wicri:Area/Ncbi/Checkpoint">001D63</idno>
<idno type="wicri:Area/Main/Merge">000347</idno>
<idno type="wicri:Area/Main/Curation">000346</idno>
<idno type="wicri:Area/Main/Exploration">000346</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en">GDNF-induced cerebellar toxicity: A brief review.</title>
<author><name sortKey="Luz, Matthias" sort="Luz, Matthias" uniqKey="Luz M" first="Matthias" last="Luz">Matthias Luz</name>
<affiliation wicri:level="1"><nlm:affiliation>MedGenesis Therapeutix Inc., Canada. Electronic address: matthiasluz@medgenesis.com.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>MedGenesis Therapeutix Inc.</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mohr, Erich" sort="Mohr, Erich" uniqKey="Mohr E" first="Erich" last="Mohr">Erich Mohr</name>
<affiliation wicri:level="1"><nlm:affiliation>MedGenesis Therapeutix Inc., Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>MedGenesis Therapeutix Inc.</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Fibiger, H Christian" sort="Fibiger, H Christian" uniqKey="Fibiger H" first="H Christian" last="Fibiger">H Christian Fibiger</name>
<affiliation wicri:level="1"><nlm:affiliation>MedGenesis Therapeutix Inc., Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>MedGenesis Therapeutix Inc.</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">Neurotoxicology</title>
<idno type="eISSN">1872-9711</idno>
<imprint><date when="2016" type="published">2016</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Cerebellum (drug effects)</term>
<term>Cerebellum (pathology)</term>
<term>Cerebellum (physiopathology)</term>
<term>Dose-Response Relationship, Drug</term>
<term>Glial Cell Line-Derived Neurotrophic Factor (administration & dosage)</term>
<term>Glial Cell Line-Derived Neurotrophic Factor (adverse effects)</term>
<term>Humans</term>
<term>Infusions, Intraventricular</term>
<term>Microinjections</term>
<term>Neuroprotective Agents (administration & dosage)</term>
<term>Neuroprotective Agents (adverse effects)</term>
<term>Putamen (drug effects)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>Glial Cell Line-Derived Neurotrophic Factor</term>
<term>Neuroprotective Agents</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="adverse effects" xml:lang="en"><term>Glial Cell Line-Derived Neurotrophic Factor</term>
<term>Neuroprotective Agents</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cerebellum</term>
<term>Putamen</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Cerebellum</term>
</keywords>
<keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Cerebellum</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Dose-Response Relationship, Drug</term>
<term>Humans</term>
<term>Infusions, Intraventricular</term>
<term>Microinjections</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">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.</div>
</front>
</TEI>
<affiliations><list><country><li>Canada</li>
</country>
</list>
<tree><country name="Canada"><noRegion><name sortKey="Luz, Matthias" sort="Luz, Matthias" 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)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Canada/explor/ParkinsonCanadaV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000346 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 000346 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Wicri/Canada |area= ParkinsonCanadaV1 |flux= Main |étape= Exploration |type= RBID |clé= pubmed:26535469 |texte= GDNF-induced cerebellar toxicity: A brief review. }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:26535469" \ | HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \ | NlmPubMed2Wicri -a ParkinsonCanadaV1
This area was generated with Dilib version V0.6.29. |