Reduction of neurological damage by a peptide segment of the amyloid beta/A4 protein precursor in a rabbit spinal cord ischemia model.
Although found as a precursor of Alzheimer amyloid, substantial evidence suggests that beta/A4 protein precursor (APP) is involved in regulation of neuronal growth and survival. Recently, we have obtained evidence that the trophic properties of APP are fully preserved in a 17-amino acid sequence. If APP is neurotrophic, then it would be anticipated that administration of the growth-promoting segment of the APP 17-mer peptide might attenuate the neuronal dysfunction or loss or behavioral deficits associated with neuronal injury, such as that accompanying central nervous system ischemia. We evaluated this 17-mer peptide in a rabbit spinal cord ischemia model and found that this peptide alleviates paraplegia resulting from ischemia/reperfusion. Ischemia of the distal lumbar cord was produced by temporary occlusion of the abdominal aorta. Saline, 17-mer APP peptide, or a control peptide (200, 500, or 1000 nM) was administered intrathecally 20 min prior to ischemia and once daily for 3 days thereafter. The neurologic and morphologic outcomes were evaluated after 4 days. Durations of ischemia encompassing all grades of neurologic function were included. The 500 nM dose of 17-mer APP peptide significantly reduced neurologic damage. The average ischemia duration necessary to produce permanent neurologic damage increased from 27.9 +/- 1.9 min in saline-injected controls and 27.7 +/- 2.0 in scrambled sequence peptide-injected controls to 40.2 +/- 4.0 min in the 500 nM 17-mer APP-injected group. The 200 nM dose produced a nonsignificant trend toward reduced neurologic damage.(ABSTRACT TRUNCATED AT 250 WORDS)
Bowes
M P
MP
Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla 92093-0624.
Masliah
E
E
Otero
D A
DA
Zivin
J A
JA
Saitoh
T
T
D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000494:pharmacology*; D000818:Animals; D007150:Immunohistochemistry; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D011817:Rabbits; D012016:Reference Values; D013116:Spinal Cord / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D016708:Synaptophysin / Q000032:analysis / Q000096:biosynthesis; D013997:Time Factors
D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D010455:Peptides; D016708:Synaptophysin