Central penetration and stability of N-terminal tripeptide of insulin-like growth factor-I, glycine-proline-glutamate in adult rat.
Insulin-like growth factor-I is a neurotrophic factor and can prevent neurons from ischemic brain injury. However, the large molecular weight and metabolic effects can be problematic in its central delivery. Glycine-proline-glutamate (GPE) is the N-terminal tripeptide of insulin-like growth factor-I, which is naturally cleaved in the plasma and brain tissues. GPE reduces neuronal loss from hypoxic-ischemic brain injury following central administration. Central penetration and the stability of GPE in the plasma and central nervous system were examined in rats using radioimmunoassay and HPLC. GPE was rapidly metabolised in the plasma (8 min) after intraperitoneal administration. Despite having a short half-life in plasma, GPE was detected in the cerebrospinal fluid up to 40 min after intraperitoneal administration. With present of peptidase inhibitors, GPE existed in the brain tissue up to 3 h after intracerebroventricular administration, suggesting a role for peptolysis in its stability. The endopeptidase inhibitors 4- (2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) reduced GPE metabolism in the brain tissue while acid peptidase inhibitor pepstatin-A decreased GPE metabolism in the plasma. GPE reduced neuronal loss in the CA1-2 sub-region of the hippocampus given (intraperitoneally) after 30 min of hypoxic-ischemic injury in adult rats, further suggested the effectiveness of GPE central uptake. These results indicated that GPE crosses the blood-CSF and the functional CSF-brain barriers. The longer half-life of GPE in the CNS may be due to its unique enzymatic stability.
Baker
A M
AM
Liggins Institute, Faculty of Medical and Health Science, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
Batchelor
D C
DC
Thomas
G B
GB
Wen
J Y
JY
Rafiee
M
M
Lin
H
H
Guan
J
J
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002555:Cerebrospinal Fluid / Q000737:chemistry; D004355:Drug Stability; D006624:Hippocampus / Q000187:drug effects; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007700:Kinetics; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D010436:Pepstatins / Q000494:pharmacology; D010537:Peritoneum / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D009842:Oligopeptides; D010436:Pepstatins; D011480:Protease Inhibitors; D007334:Insulin-Like Growth Factor I; D007930:Leucine; C012211:ubenimex; C031375:pepstatin; C062053:glycyl-prolyl-glutamic acid