Oxidative Injury and Apoptosis of Dorsal Root Ganglion Neurons in Chronic Experimental Diabetic Neuropathy

Abstract

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. Diabetes 52: [165][166][167][168][169][170][171] 2003

Expression of antiapoptotic and proapoptotic molecules in diabetic retinas

“…Oxidative stress has been implicated in impaired mitochondrial function and activation of programmed cell death caspase pathway in diabetic neurons. [1][2][3] There is overwhelming evidence for an involvement of reactive oxygen species in triggering mitochondria to release several essential players of apoptosis, such as cytochrome c, and AIF, into cytosol. 28,49 Several studies demonstrated that oxidative stress is increased in the retina with diabetes and is believed to play a significant role in the development of diabetic retinopathy.…”

“…Several in vitro and in vivo studies demonstrated that oxidative stress induced by hyperglycaemia leads to oxidative injury of neurons, which in turn activates the death pathways implicated in neuronal apoptosis. [1][2][3] Retinas from diabetic rats showed increased oxidative stress, and administration of antioxidants inhibited the development of retinopathy. [4][5][6] Increased apoptosis of neural retinal cells in experimental diabetes in rats and diabetes mellitus in humans was recently documented.…”

Oxidative injury and neuropathy in diabetes and impaired glucose tolerance

“…This data supports the concept that increased oxidative stress occurs with IGT as well as frank diabetes and may contribute to the neuro-axonal dysfunction associated with neuropathy. Increased immunoreactivity was detected across all neuronal sizes in diabetic and IGT animals; however, levels of MDA were clearly increased in the largest DRG neurons, a population of cells reported to be lost in diabetic animals (Schmeichel et al, 2003). The role of oxidized lipids in inducing cellular damage is an ongoing area of investigation.…”

“…Evidence from multiple sources indicates that oxidative stress due to hyperglycemia-induced generation of reactive oxygen species (ROS) is an important mechanism leading to both the development and progression of DN (Cameron et al, 1993;Nagamatsu et al, 1995;Hohman et al, 1997;Tomlinson, 1998;Stevens et al, 2000;Obrosova, 2002;Russell et al, 2002;Schmeichel et al, 2003;Vincent and Feldman, 2004). There is evidence of increased systemic oxidative stress in the ZDF rat (Chinen et al, 2007;Oltman et al, 2005;Oltman et al, 2006;Serkova et al, 2006;Sonta et al, 2004); however, an association between oxidative stress and the development of neuropathy is not yet established in the ZDF rat with IGT.…”

Transforming growth factor-β induces cellular injury in experimental diabetic neuropathy

“…Despite the significant pathology associated with nerve degeneration, the etiology of neuropathy is still unclear. Several pathways have been suggested to be associated with glucose neurotoxicity (Tomlinson and Gardiner 2008) and diabetic neuropathy, for example oxidative stress (Cameron et al, 1993;Coppey et al, 2001;Obrosova et al, 2005;Pop-Busui et al, 2006;Russell et al, 2002), altered polyol metabolism (Cameron and Cotter 1997), mitochondrial dysfunction (Huang et al, 2003a;Montal, 1998;Russell et al, 2002), activation of certain cysteine proteases (caspases) (Russell et al, 1999;Srinivasan et al, 2000) (Cheng and Zochodne 2003;Schmeichel et al, 2003), and regulation of growth factors and their intermediate signaling pathways (Sayers et al, 2003;Tomlinson et al, 1996). However, the role of cytokines such as transforming growth factor β (TGF-β) in development of diabetic neuropathy is not clearly defined.…”