Neuropeptide PACAP inhibits hypoxic activation of brain microglia: a protective mechanism against microglial neurotoxicity in ischemia.
Hypoxia is one of the important physiological stimuli that are often associated with a variety of pathological states such as ischemia, respiratory diseases, and tumorigenesis. In the central nervous system, hypoxia that is accompanied by cerebral ischemia not only causes neuronal cell injury, but may also induce pathological microglial activation. We have previously shown that hypoxia induces inflammatory activation of cultured microglia and their inducible nitric oxide synthase induction via p38 mitogen-activated protein kinase (MAPK) pathway, and a neuropeptide PACAP selectively inhibits microglial signal transduction. Based on these findings, we hypothesized that the neuropeptide may inhibit the hypoxic activation of microglia, and this may provide a neuroprotection against inflammation-induced neuronal injury. When this possibility was tested using cultured microglia and PC12 cells, we found that PACAP attenuates inflammatory activation of microglia under hypoxic condition, and protects cocultured PC12 cells from microglial neurotoxicity. In addition, the neuropeptide reduced the hypoxia-induced activation of p38 MAPK, indicating that the p38 MAPK is a molecular target of the PACAP action in microglia. The neuroprotective effects of PACAP in animal models of cerebral hypoxia/ischemia may be partly due to its direct actions on brain microglia and neurotoxic inflammation.
Suk
Kyoungho
K
Department of Pharmacology, School of Medicine, Kyungpook National University, 101 Dong-In, Joong-gu, Daegu, 700-422 South Korea. ksuk@knu.ac.kr
Park
Jae-Hoon
JH
Lee
Won-Ha
WH
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D002545:Brain Ischemia / Q000517:prevention & control*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods; D000860:Hypoxia / Q000188:drug therapy; D017628:Microglia / Q000187:drug effects*; D009414:Nerve Growth Factors / Q000494:pharmacology / Q000627:therapeutic use*; D009479:Neuropeptides / Q000494:pharmacology / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018377:Neurotransmitter Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D016716:PC12 Cells; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D016548:Prosencephalon / Q000166:cytology; D051381:Rats; D013778:Tetrazolium Salts; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C495403:Adcyap1 protein, rat; D009414:Nerve Growth Factors; D009479:Neuropeptides; D018696:Neuroprotective Agents; D018377:Neurotransmitter Agents; D009573:Nitrites; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D013778:Tetrazolium Salts; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D048051:p38 Mitogen-Activated Protein Kinases; C022616:thiazolyl blue