Stimulation of 5-HT1A receptor with 8-OH-DPAT inhibits hydrogen peroxide-induced neurotoxicity in cultured rat cortical cells.
We investigated the effect of 8-hydroxy-2-(N,N-dipropylamino)tetralin (8-OH-DPAT), a specific 5-HT(1A) receptor agonist, on H(2)O(2)-induced neuronal cell death in cultured rat cortical cells. H(2)O(2) produced a concentration-dependent reduction of cell viability, which was significantly reduced by (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (MK-801), an N-methyl-d-aspartate (NMDA) receptor antagonist. Pretreatment of 8-OH-DPAT over the concentration range of 1-100 microM significantly inhibited the H(2)O(2) (100 microM)-induced neuronal cell death as assessed by a MTT assay and the number of apoptotic nuclei, evidenced by Hoechst 33342 staining. The protective effect of 8-OH-DPAT (100 microM) was completely blocked by the simultaneous treatment of 1-(2-methoxyphenyl)-4-[4-(2-phthalimideo)butyl]piperazine (NAN-190, 10muM), a selective 5-HT(1A) receptor antagonist, but not in the presence of the dopamine receptor blocker spiperone (10 microM), indicating that the protective effect of 8-OH-DPAT was mediated via 5-HT(1A) receptors. In addition, 8-OH-DPAT inhibited the H(2)O(2)-induced elevation of glutamate release into the medium and cytosolic Ca(2+) concentration ([Ca(2+)](c)), generation of reactive oxygen species (ROS), and caspase-3 activity. These results suggest that the activation of 5-HT(1A) receptor with 8-OH-DPAT may ameliorate an oxydative stress-induced apoptosis of neuronal cell by interfering with the increase of [Ca(2+)](c), and then by inhibiting glutamate release, generation of ROS and caspase activity.
Lee
Hyun Joo
HJ
College of Veterinary Medicine and Research, Institute of Veterinary Medicine, Chungbuk National University, San 48, Gaesin-dong, Heungduk-Gu, Cheongju, Chungbuk 361-763, Republic of Korea.
Ban
Ju Yeon
JY
Cho
Soon Ock
SO
Seong
Yeon Hee
YH
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism* / Q000502:physiology; D058825:Serotonin 5-HT1 Receptor Agonists
D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D006861:Hydrogen Peroxide