Oxidative stress and programmed cell death in diabetic neuropathy

Andrea M. Vincent, Michael Brownlee, James W. Russell

Research output: Contribution to journalArticlepeer-review

271 Scopus citations


Recent evidence in both animal models and human sural nerve biopsies indicates an association with oxidative stress, mitochondrial (Mt) membrane depolarization (MMD), and induction of programmed cell death (PCD). In streptozotocin (STZ)-treated diabetic rats, hyperglycemia induces typical apoptotic changes as well as swelling and disruption of the Mt cristae in diabetic dorsal root ganglion neurons (DRG) and Schwann cells (SC), but these changes are only rarely observed in control neurons. In human sural nerve biopsies, from patients with diabetic sensory neuropathy, there is transmission electromicrograph evidence of swelling and disruption of the Mt and cristae compared to patients without peripheral neuropathy. In human SH-SY5Y neurons, rat sensory neurons, and SC, in vivo, there is an increase in reactive oxygen species (RES) after exposure to 20 mM added glucose. In parallel, there is an initial Mt membrane hyperpolarization followed by depolarization (MMD). In turn, MMD is coupled with cleavage of caspases. Various strategies aimed at inhibiting the oxidative burst, or stabilizing the ΔΨM, block induction of PCD. First, growth factors such as NGF can block induction of Res and/or stabilize the ΔΨM. This, in turn, is associated with inhibition of PCD. Second, reduction of Res generation in neuronal Mt prevents neuronal PCD. Third, up-regulation of uncoupling proteins (UCPs), which stabilize the ΔΨM, blocks induction of caspase cleavage. Collectively, these findings indicate that hyperglycemic conditions observed in diabetes mellitus are associated with oxidative stress-induced neuronal and SC death, and targeted therapies aimed at regulating Res may prove effective in therapy of diabetic neuropathy.

Original languageEnglish (US)
Pages (from-to)368-383
Number of pages16
JournalAnnals of the New York Academy of Sciences
StatePublished - 2002


  • Apoptosis
  • Diabetes
  • Mitochondria
  • Neuropathy
  • Oxidative stress

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • History and Philosophy of Science


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