TY - JOUR
T1 - Neurons undergo apoptosis in animal and cell culture models of diabetes
AU - Russell, James W.
AU - Sullivan, Kelli A.
AU - Windebank, Anthony J.
AU - Herrmann, David N.
AU - Feldman, Eva L.
N1 - Funding Information:
The authors thank Ms. Judy Boldt for expert secretarial assistance; Mr. Jim Beals for photographic preparation; Dr. Anu Srinivasan, IDUN Pharmaceuticals, La Jolla, California, for supplying the CM-1 antibody; Mr. Chris Edwards and the Cell Biology Core, University of Michigan, for electron microscopy support; Linda Hudson, M.S., and the Morphometry Core, Michigan Diabetes and Research Training Center, University of Michigan, for morphometry support; and Drs. Douglas Greene and Phillip Low for insightful discussions. This work was supported by NIH NS01938 and a Veterans Administration Merit Review Award (J.W.R.), NIH NS14304 (A.J.W.), NIH NS07222 (D.N.H.), NIH NS32843 and NS38849 (E.L.F.), and grants from the Juvenile Diabetes Association (E.L.F.) and the American Diabetes Association (E.L.F.).
PY - 1999/10
Y1 - 1999/10
N2 - Recent clinical trials indicate that the severity of diabetic neuropathy is correlated with the level of patient glycemic control. In the current study, hyperglycemia induces apoptotic changes in dorsal root ganglion neurons and Schwann cells in vivo both in streptozotocin-treated diabetic rats and in rats made acutely hyperglycemic with infused glucose. Typical apoptotic nuclear and cytoplasmic changes are observed. In addition mitochondrial changes recently reported to occur as part of the apoptotic cascade, such as ballooning of mitochondria and disruption of the internal cristae, are seen in diabetic dorsal root ganglion neurons and Schwann cells. Similar changes have been reported in neurons in the presence of oxidative stress. In order to study the neurotoxic effects of high glucose we developed an in vitro model using rat dorsal root ganglion neurons. In dorsal root ganglion cultured in defined medium, addition of moderate glucose levels results in neurite degeneration and apoptosis. These changes are coupled with activation of caspase-3, dependent on the concentration of glucose. The apoptotic changes observed in vitro are similar to those observed in vivo. In contrast, addition of IGF-I, even at physiological concentrations, prevents activation of caspase-3 and neuronal apoptosis in vitro. We suggest that oxidative stress may promote the mitochondrial changes in diabetic animals and lead to activation of programmed cell death pathways. These results imply a new pathogenetic mechanism for diabetic sensory neuropathy.
AB - Recent clinical trials indicate that the severity of diabetic neuropathy is correlated with the level of patient glycemic control. In the current study, hyperglycemia induces apoptotic changes in dorsal root ganglion neurons and Schwann cells in vivo both in streptozotocin-treated diabetic rats and in rats made acutely hyperglycemic with infused glucose. Typical apoptotic nuclear and cytoplasmic changes are observed. In addition mitochondrial changes recently reported to occur as part of the apoptotic cascade, such as ballooning of mitochondria and disruption of the internal cristae, are seen in diabetic dorsal root ganglion neurons and Schwann cells. Similar changes have been reported in neurons in the presence of oxidative stress. In order to study the neurotoxic effects of high glucose we developed an in vitro model using rat dorsal root ganglion neurons. In dorsal root ganglion cultured in defined medium, addition of moderate glucose levels results in neurite degeneration and apoptosis. These changes are coupled with activation of caspase-3, dependent on the concentration of glucose. The apoptotic changes observed in vitro are similar to those observed in vivo. In contrast, addition of IGF-I, even at physiological concentrations, prevents activation of caspase-3 and neuronal apoptosis in vitro. We suggest that oxidative stress may promote the mitochondrial changes in diabetic animals and lead to activation of programmed cell death pathways. These results imply a new pathogenetic mechanism for diabetic sensory neuropathy.
UR - http://www.scopus.com/inward/record.url?scp=0032702965&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032702965&partnerID=8YFLogxK
U2 - 10.1006/nbdi.1999.0254
DO - 10.1006/nbdi.1999.0254
M3 - Article
C2 - 10527803
AN - SCOPUS:0032702965
SN - 0969-9961
VL - 6
SP - 347
EP - 363
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 5
ER -