Prevention of ischemia-induced death of hippocampal neurons by pituitary adenylate cyclase activating polypeptide.
Because neurons in the CA1 region of the hippocampus are vulnerable to forebrain ischemia, this model has been used for evaluating neuroprotective agents. We evaluated the 38-amino-acid variant of pituitary adenylate cyclase activating polypeptide (PACAP38), which had been previously shown to be neuroprotective in vitro against gp120-induced hippocampal neuronal death at concentrations as low as 0.1 pM. Ischemic death of rat CA1 neurons was prevented by infusing PACAP38 either intracerebroventricularly (1 pmol/h) or intravenously (16-160 pmol/h). Intravenous PACAP38 was effective even if the infusion was begun 24 h after ischemia. The results suggest that a concentration of PACAP38 in the brain which prevents the ischemic death of CA1 neurons can be reached by the systemic administration of a low dose of the peptide. The results are compatible with the previous reports that PACAP38 is transported from the circulation to the brain. Although the exact mechanisms remain to be determined, astrocytes in the CA1 subfield activated by ischemia appear to mediate the neuroprotection with PACAP38. These results are in contrast to those with other neuroprotective compounds and should be clinically important.
Uchida
D
D
US-Japan Biomedical Research Laboratories, Tulane University, Hebert Center, Belle Chasse, LA 70037, USA.
Arimura
A
A
Somogyvári-Vigh
A
A
Shioda
S
S
Banks
W A
WA
D000818:Animals; D001921:Brain / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D007262:Infusions, Intravenous; D007263:Infusions, Parenteral; D002546:Ischemic Attack, Transient / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D009479:Neuropeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D016548:Prosencephalon; D051381:Rats; D014018:Tissue Distribution
C495403:Adcyap1 protein, rat; D009479:Neuropeptides; D018696:Neuroprotective Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide