Oxidative Injury and Apoptosis of Dorsal Root Ganglion Neurons
We evaluated the effects of chronic hyperglycemia on L5 dorsal root ganglion (DRG) neurons using immunohistochemical and electrophysiologic techniques for evidence of oxidative injury. Experimental diabetic neuropathy was induced by streptozotocin. To evaluate the pathogenesis of the neuropathy, we studied peripheral nerve after 1, 3, and 12 months of diabetes. Electrophysiologic abnormalities were present from the first month and persisted over 12 months. 8-Hydroxy-2'-deoxyguanosine labeling was significantly increased at all time points in DRG neurons, indicating oxidative injury. Caspase-3 labeling was significantly increased at all three time points, indicating commitment to the efferent limb of the apoptotic pathway. Apoptosis was confirmed by a significant increase in the percentage of neurons undergoing apoptosis at 1 month (8%), 3 months (7%), and 12 months (11%). These findings support the concept that oxidative stress leads to oxidative injury of DRG neurons, with mitochondrium as a specific target, leading to impaired mitochondrial function and apoptosis, manifested clinically as a predominantly sensory neuropathy.
The precise pathogenesis of diabetic neuropathy is unknown. However, a number of putative pathophysiologic mechanisms exist. Hyperglycemia is reported to result in oxidative stress, polyol pathway overactivity, increased advanced glycation end products, nerve hypoxia/ischemia, deficiency of
-linolenic acid , increase in protein kinase C, especially ß-isoform , and growth factor(s) deficiency . These pathways all converge in producing oxidative stress . Oxidative stress seems to be more severe at the dorsal root ganglion (DRG) than at the nerve , and recent findings that beyond 6 months of diabetes, diabetic rats develop florid radicular pathology and vacuolar degeneration of DRG neurons have led to the present hypothesis that a primary target of diabetic neural complications is the sensory neuron .
We wished to evaluate, in chronic experimental diabetic neuropathy (EDN), the role of oxidative injury as a function of duration of diabetes on DRG neurons. To achieve these goals, we undertook immunohistochemical studies of oxidative injury, mitochondrial function, caspase-3, and TdT-mediated dUTP-biotin nick end labeling (TUNEL) of DRG neurons.
We evaluated the effects of chronic hyperglycemia on L5 dorsal root ganglion (DRG) neurons using immunohistochemical and electrophysiologic techniques for evidence of oxidative injury. Experimental diabetic neuropathy was induced by streptozotocin. To evaluate the pathogenesis of the neuropathy, we studied peripheral nerve after 1, 3, and 12 months of diabetes. Electrophysiologic abnormalities were present from the first month and persisted over 12 months. 8-Hydroxy-2'-deoxyguanosine labeling was significantly increased at all time points in DRG neurons, indicating oxidative injury. Caspase-3 labeling was significantly increased at all three time points, indicating commitment to the efferent limb of the apoptotic pathway. Apoptosis was confirmed by a significant increase in the percentage of neurons undergoing apoptosis at 1 month (8%), 3 months (7%), and 12 months (11%). These findings support the concept that oxidative stress leads to oxidative injury of DRG neurons, with mitochondrium as a specific target, leading to impaired mitochondrial function and apoptosis, manifested clinically as a predominantly sensory neuropathy.
The precise pathogenesis of diabetic neuropathy is unknown. However, a number of putative pathophysiologic mechanisms exist. Hyperglycemia is reported to result in oxidative stress, polyol pathway overactivity, increased advanced glycation end products, nerve hypoxia/ischemia, deficiency of
-linolenic acid , increase in protein kinase C, especially ß-isoform , and growth factor(s) deficiency . These pathways all converge in producing oxidative stress . Oxidative stress seems to be more severe at the dorsal root ganglion (DRG) than at the nerve , and recent findings that beyond 6 months of diabetes, diabetic rats develop florid radicular pathology and vacuolar degeneration of DRG neurons have led to the present hypothesis that a primary target of diabetic neural complications is the sensory neuron .
We wished to evaluate, in chronic experimental diabetic neuropathy (EDN), the role of oxidative injury as a function of duration of diabetes on DRG neurons. To achieve these goals, we undertook immunohistochemical studies of oxidative injury, mitochondrial function, caspase-3, and TdT-mediated dUTP-biotin nick end labeling (TUNEL) of DRG neurons.