Protective Effect of a Prosaposin-Derived, 18-Mer Peptide on Slowly Progressive Neuronal Degeneration after Brief Ischemia

Abstract

Summary:Slowly progressive degeneration of the hippocampal CA1 neurons was induced by 3-minute transient global ischemia in gerbils. Sustained degeneration of hippocampal CA1 neurons was evident 1 month after ischemia. To investigate the effects of an 18-mer peptide comprising the hydrophilic sequence of the rat saposin C domain (18MP) on this sustained neuronal degeneration, an intracerebroventricular 18MP infusion was initiated 3 days after ischemia. Histopathologic and behavior evaluations were conducted 1 week and 1 month after induction of ischemia. When compared with the vehicle infusion, 18MP treatment significantly increased the response latency time in a passive avoidance task. Increased neuronal density was also evident, as was the number of intact synapses in the hippocampal CA1 region at 1 week and 1 month after ischemia. 18MP treatment also significantly decreased the number of TUNEL-positive CA1 neurons 1 week after ischemia. Subsequent in vitro experiments using cultured neurons demonstrated that the 18MP at optimal extracellular concentrations of 1 to 100 fg/mL prevented nitric oxideinduced neuronal damage as expected and significantly upregulated the expressions of bcl-x L mRNA and its translated protein. These results suggest that the gerbil model of 3-minute ischemia is useful in studying the pathogenesis of slowly progressive neuronal degeneration after stroke and in evaluating effects of novel therapeutic agents. It is likely that the 18MP at low extracellular concentrations prevents neuronal apoptosis possibly through up-regulation of the mitochondrial antiapoptotic factor Bcl-x L .

The protective role of prosaposin and its receptors in the nervous system

“…For example, the infusion of prosaposin into the lateral ventricles of gerbils prior to the induction of ischemia was found to prevent learning disabilities resulting from ischemic damage (Sano et al, 1994). Similar results were found when an 18-amino-acid prosaptide was infused into the lateral ventricles of gerbils (Kotani et al, 1996b; Morita et al, 2001). These behavioral effects were found to be accompanied by cellular changes consistent with protection of cells from apoptotic death (Morita et al, 2001; Sano et al, 1994).…”

“…Similar results were found when an 18-amino-acid prosaptide was infused into the lateral ventricles of gerbils (Kotani et al, 1996b; Morita et al, 2001). These behavioral effects were found to be accompanied by cellular changes consistent with protection of cells from apoptotic death (Morita et al, 2001; Sano et al, 1994). The infusion of the 18-amino-acid prosaptide into the lateral ventricles or the injection of the retro-inverso prosaptide D5 were also able to prevent secondary degeneration in the thalamus following occlusion of the left middle cerebral artery (Igase et al, 1999; Lu et al, 2000).…”

Role of saposin C and D in auditory and vestibular function

“…However, it was unclear from these earlier studies whether these severe inner ear deficits were due to the actions of prosaposin itself, which is known to have intrinsic nerve growth factor–like qualities, or one of its cleaved end products, saposin A–D. In an attempt to answer this question, two transgenic mice, one carrying a null mutation of saposin C, and a second carrying a combined null mutation of saposin C and D, were studied .…”

The Exon 8-Containing Prosaposin Gene Splice Variant Is Dispensable for Mouse Development, Lysosomal Function, and Secretion

“…Several studies demonstrated that prosaposin prevents nerve degeneration and promotes nerve regeneration in animal models of nerve injuries, including a strong protective action against ischemic and wound stab damage of hippocampal neurons (24,30,43,54). The relative abundance of the exon 8-containing prosaposin isoform was recently shown to sharply decline following ischemia and stab wound in rat brain (19).…”