Neuroprotective effects of prostaglandin E2 or cAMP against microglial and neuronal free radical mediated toxicity associated with inflammation.
Prostaglandin E(2) (PGE(2)), a product of the cyclooxygenation of arachidonic acid released from membrane phospholipids, plays a critical role in inflammatory neurodegenerative conditions. Despite its classic role as a proinflammatory molecule, exogenous PGE(2) was suggested to have protective roles against neuronal death, although the exact protective mechanisms of PGE(2) are not yet defined. Thus, the aim of this study was to examine the effect of exogenous PGE(2) on inflammatory neurotoxicity. Lipopolysaccharide (LPS) induced neuronal toxicity, which was associated with terminal transferase dUTP nick end labeling (TUNEL)-positive neuronal death with increased caspase-3 activity. In neuron-glial coculture, LPS markedly induced inducible nitric oxide synthase/nitric oxide (iNOS/NO) release from microglial cells, but not from neurons; however, LPS-induced oxidative stress such as reactive oxygen species (ROS), measured with 2,7-dichlorofluorescein diacetate oxidation, was increased in neurons, but not in microglial cells. Exogenous PGE(2) (1 microg/ml) rescued the neurons, reducing iNOS/NO release from microglial cells and ROS formation from neurons. PGE(2) has been known to increase intracelluar cyclic adenosine monophosphate (cAMP) levels. In this study, we found that intracellular cAMP elevating agents, forskolin, and cAMP analogue, dbcAMP and 8-Br-cAMP, also prevented LPS-induced neuronal death. Thus, these results indicate that exogenous PGE(2) protects against LPS-induced neuronal apoptotic cell death through the intracellular cAMP system, and is associated with the modulation of NO from microglial cells and ROS production from neurons.
Kim
Eun Joo
EJ
Department of Physiology, Ajou University, Suwon, Korea.
Kwon
Kyoung Ja
KJ
Park
Jee-Young
JY
Lee
Soo Hwan
SH
Moon
Chang-Hyun
CH
Baik
Eun Joo
EJ
D000199:Actins; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D005576:Colforsin; D000242:Cyclic AMP / Q000494:pharmacology*; D015232:Dinoprostone / Q000494:pharmacology*; D004347:Drug Interactions / Q000502:physiology; D005333:Fetus; D005452:Fluoresceins / Q000737:chemistry; D005609:Free Radicals / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008813:Mice, Inbred ICR; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D012333:RNA, Messenger; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000199:Actins; D005452:Fluoresceins; D005609:Free Radicals; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D009573:Nitrites; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D005576:Colforsin; C029569:diacetyldichlorofluorescein; D009569:Nitric Oxide; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D015232:Dinoprostone