Prosaposin gene expression and the efficacy of a prosaposin-derived peptide in preventing structural and functional disorders of peripheral nerve in diabetic rats.
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 < 0.05) 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 TX 14(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.
Calcutt
N A
NA
Department of Pathology, University of California San Diego, La Jolla 92093-0612, USA.
Campana
W M
WM
Eskeland
N L
NL
Mohiuddin
L
L
Dines
K C
KC
Mizisin
A P
AP
O'Brien
J S
JS
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D003929:Diabetic Neuropathies / Q000378:metabolism / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression; D006023:Glycoproteins / Q000235:genetics*; D009431:Neural Conduction; D011498:Protein Precursors / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D049231:Saposins; D012584:Sciatic Nerve / Q000503:physiopathology
D001786:Blood Glucose; D006023:Glycoproteins; D011498:Protein Precursors; C483347:Psap protein, rat; D049231:Saposins