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Nitric oxide synthase activity and expression in experimental diabetic neuropathy
D W Zochodne1, V M Verge, C Cheng
1Neuroscience Research Group and the Department of Clinical Neurosciences, University of Calgary, Alberta, Canada.
Journal of Neuropathology and Experimental Neurology
|September 27, 2000
Summary
Diabetic neuropathy alters nitric oxide synthase (NOS) activity in dorsal root ganglia (DRG). Increased NOS activity in diabetic rats may compensate for complications, while declines in immunological NOS (iNOS) suggest impaired macrophage function.
Area of Science:
- Neuroscience
- Biochemistry
- Diabetology
Background:
- Diabetic neuropathy is a common complication of diabetes mellitus.
- The role of nitric oxide synthase (NOS) in experimental diabetic neuropathy remains unclear.
- Specific isoforms of NOS, including neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS), may be affected differently.
Purpose of the Study:
- To investigate changes in NOS activity and expression in the dorsal root ganglia (DRG) of rats with experimental diabetes.
- To correlate NOS activity with the expression of nNOS, eNOS, and iNOS.
- To understand the potential mechanisms underlying altered NOS activity in diabetic neuropathy.
Main Methods:
- Streptozotocin-induced diabetes model in rats with short-term (2 months) and long-term (12 months) duration.
- Measurement of NOS enzymatic activity in lumbar DRG.
- Immunohistochemistry and RT-PCR to assess the expression of nNOS, eNOS, and iNOS mRNA and proteins in DRG and sciatic nerves.
Main Results:
- NOS enzymatic activity in DRG significantly increased after 12 months of diabetes.
- This increase in NOS activity was not correlated with changes in nNOS expression.
- eNOS mRNA levels increased in 2-month diabetic DRG with novel eNOS localization in capsular and perineurial cells; however, no changes in eNOS expression were observed in 12-month diabetic sciatic nerves or DRG.
- iNOS mRNA levels decreased in peripheral nerves of diabetic rats at both time points but remained unchanged in DRG.
- The observed increase in DRG NOS activity was not explained by the synthesis of novel NOS isoforms.
Conclusions:
- Diabetic neuropathy leads to increased NOS activity in DRG, potentially as a compensatory mechanism against nitric oxide (NO) "quenching" by advanced glycosylation endproducts.
- Declines in iNOS expression in peripheral nerves may indicate impaired macrophage function in diabetic neuropathy.
- The differential regulation of NOS isoforms suggests complex roles in the pathogenesis of experimental diabetic neuropathy.