The 5-HT1A receptor agonist Bay x 3702 inhibits apoptosis induced by serum deprivation in cultured neurons.
We examined whether the highly selective 5-HT1A receptor agonist (-)-(R)-2-[4-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-amino]butyl]-11 ,2-benz-isothiazol-3(2H)-one 1,1-dioxide monohydrochloride (Bay x 3702) could inhibit neuronal apoptosis induced by serum deprivation. In primary cultures of chick embryonic neurons and in mixed neuronal/glial cultures from neonatal rat hippocampus, Bay x 3702 (1 microM) rescued serum-deprived neurons from apoptosis. The antiapoptotic effect of Bay x 3702 (1 microM) was blocked in chick neurons by the selective 5-HT1A receptor antagonists 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazin]ethyl]-N-2-pyridinyl-be nzamide hydrochloride (p-MPPI, 10 microM) and 4-[3-benzotriazol-1-propyl]-1-(2-methoxyphenyl)-piperazine (BPMP, 10 microM) as well as by anti-nerve growth factor (anti-NGF) antibodies and in rat neurons by N-[2-4-(2-methoxy)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexane-carbo xamide trihydrochloride (WAY 100635, 10 microM). We found only under control conditions (medium with serum), but not in serum-deprived cultures, that NGF secretion was 6-fold increased by Bay x 3702 (1 microM) compared to untreated cultures. Additionally, Bay x 3702 (4 microg/kg i.v.), infused within a period of 4 h, significantly increased the NGF content of the rat hippocampus, but not of the striatum. In summary, our data suggest that Bay x 3702 inhibited growth factor withdrawal-induced apoptosis by the stimulation of 5-HT1A receptors and that the NGF signalling pathway is involved in the mechanism of action.
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001578:Benzopyrans / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D002746:Chlorpromazine / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects; D007124:Immunoenzyme Techniques; D008297:Male; D009414:Nerve Growth Factors / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D020318:Rats, Long-Evans; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*