[Neuroprotective effects of novel derivatives of vasoactive intestinal peptide and pituitary adenylate cyclase-activating peptide in two brain ischemic models on mice].
BACKGROUND
Vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP), are members of a VIP/secretin/glucagon family. These peptides were demonstrated to possess the neuroprotective properties. However, these peptides are not suited to be developed as a medicine for brain ischemia because of their susceptibilities to endopeptidases.


METHODS
We examined the effects of IK 312548 (IK), VIP derivative, and Ac-PACAP, PACAP derivative, on the 10 min two-vessel occlusion (2 VO) model in C 57 BL/6 N mice lacking a part of the posterior communicating artery, and the 30 min middle cerebral artery occlusion (MCAO) model in ICR mice. A 10 ml x kg(-1) dose of each derivative (final concentration; 1 fmol x kg(-1) and 100 pmol x kg(-1)) was injected intraperitoneally (i.p.) to each animal just after the preparation of brain ischemia.


RESULTS
In 2 VO experiments, the number of neuronal cells in hippocampus was significantly reduced. However IK and Ac-PACAP treatments inhibited such reductions of neuronal cells in a dose-dependent manner. Particularly, between 1 pmol x kg(-1) and 100 pmol x kg(-) IK, and also between 10 fmol x kg(-1) and 1 pmol x kg(-1) Ac-PACAP significantly protected neuronal cell loss. In MCAO experiments, more than 60% of hemisphere was damaged. By treatment of IK (1-100 pmol x kg(-1)) and Ac-PACAP (1 fmol-1 pmol x kg(-1)), the range of brain damage decreased in a dose-dependent manner.


CONCLUSIONS
Ac-PACAP and IK after the brain ischemia could pass the blood-brain barrier and protect brain cell damage.
Takeda
Naoko
N
Department of Anesthesiology, Tokyo Medical University.
Murozono
Michihiro
M
Watanabe
Seigo
S
Isshiki
Atsushi
A
Watanabe
Yasuo
Y
D000818:Animals; D002545:Brain Ischemia / Q000473:pathology* / Q000503:physiopathology; D002560:Cerebrovascular Circulation; D006624:Hippocampus / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009479:Neuropeptides / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*
C495402:Adcyap1 protein, mouse; D009414:Nerve Growth Factors; D009479:Neuropeptides; D018696:Neuroprotective Agents; D018377:Neurotransmitter Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D014660:Vasoactive Intestinal Peptide