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Brain Advance Access published online on February 24, 2009
Brain, doi:10.1093/brain/awp014
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© The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Neuroprotective effect of herpes simplex virus-mediated gene transfer of erythropoietin in hyperglycemic dorsal root ganglion neurons

Munmun Chattopadhyay1,2, Claire Walter1,2, Marina Mata1,2 and David J. Fink1,2

1 Department of Neurology, University of Michigan, Ann Arbor, MI, USA 2 Ann Arbor VA Healthcare System, Ann Arbor, MI, USA

Correspondence to: Munmun Chattopadhyay, Department of Neurology, 5248 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA E-mail: munmunc{at}umich.edu

We examined the efficacy of herpes simplex virus vector-mediated gene transfer of erythropoietin in preventing neuropathy in mouse model of streptozotocin-diabetes. A replication-incompetent herpes simplex virus vector with erythropoietin under the control of the human cytomegalovirus promoter (vector DHEPO) was constructed. DHEPO expressed and released erythropoietin from primary dorsal root ganglion neurons in vitro, and following subcutaneous inoculation in the foot, expressed erythropoietin in dorsal root ganglion neurons in vivo. At 2 weeks after induction of diabetes, subcutaneous inoculation of erythropoietin prevented the reduction in sensory nerve amplitude characteristic of diabetic neuropathy measured 4 weeks later, preserved autonomic function measured by pilocarpine-induced sweating, and prevented the loss of nerve fibres in the skin and reduction of neuropeptide calcitonin gene-related peptide in the dorsal horn of spinal cord of the diabetic mice. We further investigated whether vector-mediated local expression of erythropoietin in dorsal root ganglion neurons can protect in vivo as well as in vitro hyperglycemia-induced axonal degeneration. Our findings show that the AKT/GSK-3β dependent pathway plays an important role in mediating the protection of erythropoietin against diabetic neuropathy. Herpes simplex virus-mediated transfer of erythropoietin to dorsal root ganglia may prove useful in treatment of diabetic neuropathy.

Key Words: diabetes; gene therapy; herpes simplex virus; erythropoietin

Abbreviations: CGRP, Calcitonin gene-related peptide; DRG, dorsal root ganglia; EPO, erythropoietin; GSK-3β, glycogen synthase kinase-3β; HSV, herpes simplex virus; PGP 9.5, protein gene product 9.5; PI3K, phosphoinositide 3-kinase; STZ, streptozotocin

Received October 2, 2008. Revised November 25, 2008. Accepted January 8, 2009.


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