Prosaposin Gene Expression and the Efficacy of a Prosaposin-derived Peptide in Preventing Structural and Functional Disorders of Peripheral Nerve in Diabetic Rats

• Published in: Journal of neuropathology and experimental neurology Vol. 58; no. 6; pp. 628 - 636
• Main Authors: Calcutt, Nigel A, Campana, W Marie, Eskeland, Nahida L, Mohiuddin, Liza, Dines, Kevin C, Mizisin, Andrew P, OʼBrien, John S
• Format: Journal Article
• Language: English
• Published: England American Association of Neuropathologists, Inc 01-06-1999; Oxford University Press
• Subjects: Animals; Blood Glucose - metabolism; Body Weight - physiology; Diabetic Neuropathies - metabolism; Diabetic Neuropathies - physiopathology; Dose-Response Relationship, Drug; Female; Gene Expression; Genes; Glycoproteins - genetics; Neural Conduction; Peptides; Protein Precursors - genetics; Rats; Rats, Sprague-Dawley; RNA; Saposins; Sciatic Nerve - physiopathology
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1097/00005072-199906000-00007

We have recently demonstrated that prosaposin is a neurotrophic and myelinotrophic factor with the active trophic sequence located at the N-terminal region of the saposin C domain. There are also reports that prosaposin mRNA is increased distal to a physical nerve injury and that exogenous prosaposin treatment induces subsequent neuronal sprouting, suggesting involvement in repair processes. In the present study, we show that prosaposin mRNA is significantly (p <0.0S) elevated in the peripheral nerve of streptozotocin-diabetic rats, a model of insulin-deficient diabetes in which nerve injury arises from the metabolic trauma of hyperglycemia and its consequences. A 14 amino acid peptide derived from the neurotrophic region of prosaposin prevented the development of deficits in both large and small fiber function caused by diabetes in rats. The dose-dependent prevention of nerve conduction slowing by TX14(A) was accompanied by preservation of axonal caliber and sodium-potassium ATPase activity, while prevention of thermal hypoalgesia was associated with attenuation of the decline in nerve substance P levels. It is concluded that nerve subject to the metabolic injury of uncontrolled diabetes responds by increasing prosaposin gene expression, and that prosaposin-derived neurotrophic peptides may provide a novel therapeutic approach to treatment of diabetic and other peripheral neuropathies.