Direct intracerebral administration of glial cell line-derived neurotrophic factor (GDNF) is neuroprotective against ischemia-induced cerebral injury. Utilizing viral vectors to deliver and express therapeutic genes presents an opportunity to produce GDNF within localized regions of an evolving infarct. We investigated whether a Herpes simplex virus (HSV) amplicon-based vector encoding GDNF (HSVgdnf) would protect neurons against ischemic injury. In primary neuronal cultures HSVgdnf reduced oxidant?induced injury compared to the control vector HSVlac. To test protective effects in vivo, HSVgdnf or HSVlac was injected into the cerebral cortex prior to or subsequent to a 60 minute unilateral occlusion of the middle cerebral artery (MCA). Control stroke animals developed bradykinesia and motor asymmetry; pretreatment with HSVgdnf significantly reduced such motor deficits. Animals receiving HSVlac or HSVgdnf after the ischemic insult did not exhibit any behavioral improvement. Histological analyses performed one month after stroke revealed a reduction in ischemic tissue loss in rats pretreated with HSVgdnf. Similarly, these animals exhibited less immunostaining for glial fibrillary acidic protein (GFAP) and caspase-3. Taken together, our data indicate that HSVgdnf pretreatment provides protection against cerebral ischemia and supports the utilization of the HSV amplicon for therapeutic delivery of trophic factors to the CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Intramural Research (Z01)
Project #
1Z01DA000443-01
Application #
6535689
Study Section
(CNL)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2001
Total Cost
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Li, Yazhou; Perry, TracyAnn; Kindy, Mark S et al. (2009) GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc Natl Acad Sci U S A 106:1285-90
Chen, Yuan-Hao; Harvey, Brandon K; Hoffman, Alexander F et al. (2008) MPTP-induced deficits in striatal synaptic plasticity are prevented by glial cell line-derived neurotrophic factor expressed via an adeno-associated viral vector. FASEB J 22:261-75
Chen, Guann-Juh; Harvey, Brandon K; Shen, Hui et al. (2006) Activation of adenosine A3 receptors reduces ischemic brain injury in rodents. J Neurosci Res 84:1848-55
Woods, Amina S; Kaminski, Rafal; Oz, Murat et al. (2006) Decoy peptides that bind dynorphin noncovalently prevent NMDA receptor-mediated neurotoxicity. J Proteome Res 5:1017-23
Israelsson, Charlotte; Lewen, Anders; Kylberg, Annika et al. (2006) Genetically modified bone morphogenetic protein signalling alters traumatic brain injury-induced gene expression responses in the adult mouse. J Neurosci Res 84:47-57
Wang, Yun; Chang, Chen-Fu; Chou, Jenny et al. (2005) Dietary supplementation with blueberries, spinach, or spirulina reduces ischemic brain damage. Exp Neurol 193:75-84
Harvey, Brandon K; Hoffer, Barry J; Wang, Yun (2005) Stroke and TGF-beta proteins: glial cell line-derived neurotrophic factor and bone morphogenetic protein. Pharmacol Ther 105:113-25
Shen, Hui; Chen, Guann-Juh; Harvey, Brandon K et al. (2005) Inosine reduces ischemic brain injury in rats. Stroke 36:654-9
Harvey, B K; Chang, C F; Chiang, Y H et al. (2003) HSV amplicon delivery of glial cell line-derived neurotrophic factor is neuroprotective against ischemic injury. Exp Neurol 183:47-55
Chang, Chen-Fu; Lin, Shinn-Zong; Chiang, Yung-Hsiao et al. (2003) Intravenous administration of bone morphogenetic protein-7 after ischemia improves motor function in stroke rats. Stroke 34:558-64

Showing the most recent 10 out of 11 publications