Lentivector-mediated delivery of GDNF protects complex motor functions relevant to human Parkinsonism in a rat lesion model.
Although viral vector-mediated delivery of glial cell-line derived neurotrophic factor (GDNF) to the brain has considerable potential as a neuroprotective strategy in Parkinson's disease (PD), its ability to protect complex motor functions relevant to the human condition has yet to be established. In this study, we used an operant task that assesses the selection, initiation and execution of lateralized nose-pokes in Lister Hooded rats to assess the efficacy with which complex behaviours are protected against neurotoxic lesions by prior injection of a lentiviral vector expressing GDNF. Unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB) caused rats to attempt fewer trials and to make more procedural errors. Lesioned rats also developed a pronounced ipsilateral bias, with a corresponding drop in contralateral accuracy. They were also slower to react to contralateral stimuli and to execute movements bilaterally. Rats that were pre-treated 4 weeks prior to lesion surgery with an equine infectious anaemia virus (EIAV) vector carrying GDNF [EIAV-GDNF, injected into the striatum and above the substantia nigra (SN)] performed significantly better on all of these parameters than control rats. In addition to the operant task, EIAV-GDNF successfully rescued contralateral impairments in the corridor, staircase, stepping and cylinder tasks, and prevented drug-induced rotational asymmetry. This study confirms that GDNF can protect against 6-OHDA-induced impairments in complex as well as simple behaviours, and reinforces the use of EIAV-based vectors for the treatment of PD.
Dowd
Eilís
E
Brain Repair Group, School of Biosciences, Cardiff University, Wales, UK. DowdE@cf.ac.uk
Monville
Christelle
C
Torres
Eduardo M
EM
Wong
Liang-Fong
LF
Azzouz
Mimoun
M
Mazarakis
Nicholas D
ND
Dunnett
Stephen B
SB
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003216:Conditioning, Operant / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology; D005260:Female; D007839:Functional Laterality / Q000502:physiology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics*; D009068:Movement / Q000502:physiology; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy*; D051381:Rats; D011930:Reaction Time / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; D051100:Glial Cell Line-Derived Neurotrophic Factor; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D001616:beta-Galactosidase; D001058:Apomorphine