Neuroprotection from NMDA excitotoxic lesion by Cu/Zn superoxide dismutase gene delivery to the postnatal rat brain by a modular protein vector.
BACKGROUND
Superoxide mediated oxidative stress is a key neuropathologic mechanism in acute central nervous system injuries. We have analyzed the neuroprotective efficacy of the transient overexpression of antioxidant enzyme Cu/Zn Superoxide dismutase (SOD) after excitotoxic injury to the immature rat brain by using a recently constructed modular protein vector for non-viral gene delivery termed NLSCt. For this purpose, animals were injected with the NLSCt vector carrying the Cu/Zn SOD or the control GFP transgenes 2 hours after intracortical N-methyl-D-aspartate (NMDA) administration, and daily functional evaluation was performed. Moreover, 3 days after, lesion volume, neuronal degeneration and nitrotyrosine immunoreactivity were evaluated.


RESULTS
Overexpression of Cu/Zn SOD transgene after NMDA administration showed improved functional outcome and a reduced lesion volume at 3 days post lesion. In secondary degenerative areas, increased neuronal survival as well as decreased numbers of degenerating neurons and nitrotyrosine immunoreactivity was seen. Interestingly, injection of the NLSCt vector carrying the control GFP transgene also displayed a significant neuroprotective effect but less pronounced.


CONCLUSIONS
When the appropriate levels of Cu/Zn SOD are expressed transiently after injury using the non-viral modular protein vector NLSCt a neuroprotective effect is seen. Thus recombinant modular protein vectors may be suitable for in vivo gene therapy, and Cu/Zn SOD should be considered as an interesting therapeutic transgene.
Peluffo
Hugo
H
Departament de Biologia Cellular, Fisiologia i Immunologia, Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193, Spain. hugo.peluffo@uab.es
Acarin
Laia
L
Arís
Anna
A
González
Pau
P
Villaverde
Antoni
A
Castellano
Bernardo
B
González
Berta
B
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism; D001927:Brain Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D016923:Cell Death / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D008297:Male; D016202:N-Methylaspartate; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000378:metabolism; D009498:Neurotoxins; D051381:Rats; D020318:Rats, Long-Evans; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis
D018696:Neuroprotective Agents; D009498:Neurotoxins; C002744:3-nitrotyrosine; D014443:Tyrosine; D016202:N-Methylaspartate; D013482:Superoxide Dismutase