SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy.
Hyperglycemia-induced oxidative stress is an inciting event in the development of diabetic complications including diabetic neuropathy. Our observations of significant oxidative stress and morphological abnormalities in mitochondria led us to examine manganese superoxide dismutase (SOD2), the enzyme responsible for mitochondrial detoxification of oxygen radicals. We demonstrate that overexpression of SOD2 decreases superoxide (O(2)(-)) in cultured primary dorsal root ganglion (DRG) neurons and subsequently blocks caspase-3 activation and cellular injury. Underexpression of SOD2 in dissociated DRG cultures from adult SOD2(+/-) mice results in increased levels of O2-, activation of caspase-3 cleavage and decreased neurite outgrowth under basal conditions that are exacerbated by hyperglycemia. These profound changes in sensory neurons led us to explore the effects of decreased SOD2 on the development of diabetic neuropathy (DN) in mice. DN was assessed in SOD2(+/-) C57BL/6J mice and their SOD2(+/+) littermates following streptozotocin (STZ) treatment. These animals, while hyperglycemic, do not display any signs of DN. DN was observed in the C57BL/6Jdb/db mouse, and decreased expression of SOD2 in these animals increased DN. Our data suggest that SOD2 activity is an important cellular modifier of neuronal oxidative defense against hyperglycemic injury.
Vincent
Andrea M
AM
Department of Neurology, University of Michigan, 5017 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-0588, USA.
Russell
James W
JW
Sullivan
Kelli A
KA
Backus
Carey
C
Hayes
John M
JM
McLean
Lisa L
LL
Feldman
Eva L
EL
D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000235:genetics; D003921:Diabetes Mellitus, Experimental; D003929:Diabetic Neuropathies / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology* / Q000517:prevention & control; D004789:Enzyme Activation; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051336:Mitochondrial Membranes; D009431:Neural Conduction; D009475:Neurons, Afferent / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000172:deficiency / Q000378:metabolism*; D014162:Transfection; D000099156:Superoxide Dismutase 2
D053148:Caspase 3; D018696:Neuroprotective Agents; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2