Protective effect of a prosaposin-derived, 18-mer peptide on slowly progressive neuronal degeneration after brief ischemia.
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 oxide-induced neuronal damage as expected and significantly up-regulated 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).
Morita
F
F
Department of Anatomy, Ehime University School of Medicine, Shitsukawa, Shigenobu-cho, Onsen-gun, Ehime, Japan.
Wen
T C
TC
Tanaka
J
J
Hata
R
R
Desaki
J
J
Sato
K
K
Nakata
K
K
Ma
Y J
YJ
Sakanaka
M
M
D000595:Amino Acid Sequence; D000818:Animals; D002452:Cell Count; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D015870:Gene Expression / Q000187:drug effects; D005849:Gerbillinae; D006023:Glycoproteins / Q000494:pharmacology*; D006624:Hippocampus / Q000473:pathology; D020287:In Situ Nick-End Labeling; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D008297:Male; D008969:Molecular Sequence Data; D009410:Nerve Degeneration / Q000188:drug therapy*; D009474:Neurons / Q000166:cytology; D018696:Neuroprotective Agents / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D049231:Saposins; D013569:Synapses / Q000502:physiology; D051020:bcl-X Protein
D006023:Glycoproteins; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; C483347:Psap protein, rat; D012333:RNA, Messenger; D049231:Saposins; D051020:bcl-X Protein; D009599:Nitroprusside