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 vitro, as well as to rescue neurons from
ischemia and other damage in vivo(11,12,15,25) implied that prosaposin was neurotrophic/
neuroprotectant.(1,7,24,31) The neurotrophic sequence of prosaposin was isolated to smaller
peptide fragments termed prosaptides(15,31) within the amino terminal portion of
saposin 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 studies, however, have attempted to characterize these
peptides, presumably due to their reported instability following peripheral administration.(27) With the recent design of a stable 11-mer retro-inverso
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 model that has been used extensively in the development of
therapeutics to treat
ischemic stroke.(4,14,16,18) Our results show not only that
prosaptide was not neurotrophic/
neuroprotectant in vivo, but rather it worsened
ischemia-induced behavioral deficits.