Prosaptide exacerbates ischemia-induced behavioral deficits in vivo; An effect that does not involve mitogen-activated protein kinase activation

Prosaposin is a 517 amino acid membrane component and secreted protein(5,7, 9) that is proteolytically cleaved to generate the four small glycoproteins ; saposins A, B, C and D.(9,13,19) Prosaposin's ability to promote neurite outgrowth(31) and to protect neurons from programmed cell death(28) in vitr o, as well as to rescue neurons from ischemia and other damage in vivo(11,1 2,15,25) implied that prosaposin was neurotrophic/neuroprotectant.(1,7,24,3 1) The neurotrophic sequence of prosaposin was isolated to smaller peptide fragments termed prosaptides(15,31) within the amino terminal portion of sa posin C.(1,6,8,10,17,20,21,28) The proposed use of synthetic prosaptides as peripherally administered neuroprotective and/or neurotrophic therapeutic agents has stemmed from their ability to cross the blood-brain barrier,(27) as well as their reported neurotrophic activity in vitro.(15,23,31) Few st udies, however, have attempted to characterize these peptides, presumably d ue to their reported instability following peripheral administration,(27) W ith the recent design of a stable Il-mer retroinverso prosaptide,(15,31) it has become feasible to investigate the pharmacological effects of a stable version of these peptides in the validated rabbit spinal cord ischemia mod el that has been used extensively in the development of therapeutics to tre at ischemic stroke.(4,14,16,18) Our results show not only that prosaptide w as not neurotrophic/neuroprotectant in vivo, but rather it worsened ischemi a-induced behavioral deficits. (C) 2000 IBRO, Published by Elsevier Science Ltd. All rights reserved.