Elevated GDNF levels following viral vector-mediated gene transfer can increase neuronal death after stroke in rats.
Previous studies have indicated that administration of glial cell line-derived neurotrophic factor (GDNF) counteracts neuronal death after stroke. However, in these studies damage was evaluated at most a few days after the insult. Here, we have explored the long-term consequences of two routes of GDNF delivery to the rat striatum prior to stroke induced by 30 min of middle cerebral artery occlusion (MCAO): striatal transduction with a recombinant lentiviral vector or transduction of the substantia nigra with a recombinant adeno-associated viral vector and subsequent anterograde transport of GDNF to striatum. Despite high GDNF levels, stereological quantification of striatal neuron numbers revealed no protection at 5 or 8 weeks after MCAO. In fact, anterograde GDNF delivery exacerbated neuronal loss. Moreover, supply of GDNF did not alleviate the striatum-related behavioral deficits. Thus, we demonstrate that the actions of GDNF after stroke are more complex than previously believed and that high levels of this factor, which are neuroprotective in models of Parkinson's disease, can increase ischemic damage. Our findings also underscore the need for quantitative assessment of long-term neuronal survival and behavioral changes to evaluate the therapeutic potential of factors such as GDNF.
Arvidsson
Andreas
A
Section of Restorative Neurology, Wallenberg Neuroscience Center, BMC A11 SE-221 84, Lund, Sweden. andreas.arvidsson@neurol.lu.se
Kirik
Deniz
D
Lundberg
Cecilia
C
Mandel
Ronald J
RJ
Andsberg
Gunnar
G
Kokaia
Zaal
Z
Lindvall
Olle
O
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D016923:Cell Death / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D003342:Corpus Striatum / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques / Q000009:adverse effects*; D005822:Genetic Vectors / Q000009:adverse effects* / Q000235:genetics / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D016086:Lentivirus / Q000235:genetics; D008297:Male; D009069:Movement Disorders / Q000235:genetics / Q000503:physiopathology / Q000821:virology; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009414:Nerve Growth Factors / Q000009:adverse effects* / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D014161:Transduction, Genetic / Q000379:methods; D017211:Treatment Failure; D015854:Up-Regulation / Q000235:genetics
C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D001058:Apomorphine