Neuroprotective effect of herpes simplex virus-mediated gene transfer of erythropoietin in hyperglycemic dorsal root ganglion neurons.
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-3beta 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.
Chattopadhyay
Munmun
M
Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA. munmunc@umich.edu
Walter
Claire
C
Mata
Marina
M
Fink
David J
DJ
D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000517:prevention & control; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D003929:Diabetic Neuropathies / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004921:Erythropoietin / Q000096:biosynthesis* / Q000235:genetics; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006400:Hematocrit; D006358:Hot Temperature; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D051379:Mice; D017288:Pain Threshold; D010523:Peripheral Nervous System Diseases / Q000517:prevention & control; D011984:Sensory Receptor Cells / Q000502:physiology; D018139:Simplexvirus / Q000235:genetics*; D012867:Skin / Q000294:innervation
D004921:Erythropoietin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D015740:Calcitonin Gene-Related Peptide