Two Phases of Nitrergic Neuropathy in Streptozotocin-Induced Diabetic Rats

• Published in: Diabetes (New York, N.Y.) Vol. 52; no. 9; pp. 2353 - 2362
• Main Authors: CELLEK, Selim, FOXWELL, Neale A, MONCADA, Salvador
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.09.2003
• Subjects: Animals; Apoptosis; Associated diseases and complications; Biological and medical sciences; Blood Glucose - drug effects; Cell death; Development and progression; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetes. Impaired glucose tolerance; Diabetic Neuropathies - drug therapy; Diabetic Neuropathies - metabolism; Diabetic Neuropathies - pathology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Ganglia, Autonomic - metabolism; Ganglia, Autonomic - pathology; Glucose; Hypoglycemic Agents - pharmacology; Insulin; Insulin - pharmacology; Male; Medical sciences; Metabolism; Nerve Fibers - enzymology; Nerve Fibers - pathology; Neurodegeneration; Neurons; Nitric oxide; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type I; Penis; Penis - innervation; Peptides; Physiological aspects; Pylorus - innervation; Rats; Rats, Wistar; Weight Loss - drug effects; United Kingdom > UK; Germany; Endocrinopathy; Nervous system diseases; Vertebrata; Mammalia; Rat; Animal; Diabetes mellitus; Rodentia; Neuropathy; Streptozotocin
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.52.9.2353

Two Phases of Nitrergic Neuropathy in Streptozotocin-Induced Diabetic Rats Selim Cellek , Neale A. Foxwell and Salvador Moncada From the Wolfson Institute for Biomedical Research, University College London, London, U.K Address correspondence and reprint requests to Dr. Selim Cellek, Wolfson Institute for Biomedical Research, University College London, Gower Street, Cruciform Building, London, WC1E 6BT, U.K. E-mail: s.cellek{at}ucl.ac.uk Abstract The distinction between metabolic and structural changes occurring in autonomic neurons during diabetes has not been fully clarified. Here we demonstrate that nitric oxide synthase-containing (nitrergic) neurons innervating the penis and gastric pylorus of streptozotocin-induced diabetic rats undergo a selective degenerative process in two phases. In the first phase, nitrergic nerve fibers lose some of their neuronal nitric oxide synthase content and function. In the second phase, nitrergic degeneration takes place in the cell bodies in the ganglia, leading to complete loss of nitrergic function. The changes in the first phase are reversible with insulin replacement; however, the neurodegeneration in the second phase is irreversible. Neurodegeneration is due to apoptotic cell death in the ganglia, which is selective for the nitrergic neurones. AGE, advanced glycation end product ChAT, choline acetyl transferase EFS, electrical field stimulation eNOS, endothelial nitric oxide synthase iNOS, inducible nitric oxide synthase l-NAME, NG-nitro-l-arginine methyl ester MPG, major pelvic ganglion NANC, nonadrenergic noncholinergic NOS, nitric oxide synthase nNOS, neuronal nitric oxide synthase ROS, reactive oxygen species sGC, soluble guanylyl cyclase SP, substance P STZ, streptozotocin TH, tyrosine hydroxylase TTX, tetrodotoxin TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling VAChT, vesicular acetylcholine transporter VIP, vasoactive intestinal peptide Footnotes Accepted May 29, 2003. Received March 3, 2003. DIABETES